Pulmonary fibrosis-related genes

Compiled below is a list of genes that have been shown to affect pulmonary fibrosis when they are manipulated.
As there are few in vivo experimental models of pulmonary fibrosis, the majority of the data is, as of yet, comprised of genes discovered in the bleomycin mouse model.

Abbreviations:
BLM - Bleomycin model
KO - Knockout
OE - Overexpression

Targeted gene/protein ENSEMBL ID Mouse strain
(Genetic background)		 Genetic / non-genetic manipulation Gender Age Dose/Route of administration Regimen Main effects (KO/OE/treated vs WT/control mice) Direction of experimental manipulation on the gene's activity Effect on fibrosis, observed in the experiment Gene effect on fibrosis inferred from the experiment Other effects Comments/Relevance to IPF References PMID
Ackr2 ENSMUSG00000044534 C57BL/6J KO Ackr2-/- or Ackr2+/- male 8-10 wk Bleomycin sulfate 3.75 mg/kg, intranasally single dose, follow-up 0-21 days Reduced lung inflammation, fibrosis and lethality down_manip anti_fib pro_fib In WT mice, Ackr2 was upregulated in response to BLM and normalized over time Russo et al 2018 29469612
Aebp1 (Aclp) ENSMUSG00000020473 C57BL/6J × 129Sv KO Aebp1-/- male and female 10-12 wk Bleomycin sulfate 0.0011 U/g, intratracheally single dose, follow-up 0-28 days Reduced lung fibrosis (fewer myofibroblasts and less collagen in the lung), despite equivalent levels of BLM-induced inflammation down_manip anti_fib pro_fib Highly expressed in IPF lungs.
The cultured on collagen Aclp-deficient lung fibroblasts exhibited changes in cell spreading, proliferation, and contraction of the collagen matrix.
The addition of recombinant discoidin-like domain of Aclp to cultured Aclp-deficient lung fibroblasts restored cell spreading and increased the contraction of collagen gels		 Schissel et al 2009 19179605
Akt1 ENSMUSG00000001729 C57BL/6 Overexpression of Akt1 female 8-10 wk BLM 0.25 - 1.50 U/kg, intratracheally;
Thoracic irradiation 10 and 20 GY 		BLM single dose, follow-up 0-14 days
Thoracic irradiation single dose, follow-up 6 wk		 Reduced lung fibrosis up_manip anti_fib anti_fib [See KO Gadd45α; the same paper]
The lung collagen levels were significantly decreased in KO Gadd45α mice overexpressing Akt at
3 wk post BLM 		Mathew et al 2015 26498248
Akt1 ENSMUSG00000001729 C57BL/6 KO Akt1+/- or Akt1-/- NA NA BLM 1.75-2 U/kg, intratracheally single dose, follow-up 0-21 days Reduced lung fibrosis down_manip anti_fib pro_fib Increased macrophage apoptosis [See other KO Akt1/2]
Highly expressed in IPF alveolar macrophages		 Larson-Casey et al 2016 26921108
Akt2 ENSMUSG00000004056 C57BL/6 KO Akt2+/-
Inhibition of Akt protein		 male 6-8 wk BLM 5 mg/kg in 50 μl, intratracheally;
LY294002 (Akt inhibitor) 50 mg/kg, intraperitoneally (to WT only)		 BLM single dose;
LY294002 once a day, 0-14 days (to WT only); Follow-up 0-14 days		 Reduced lung fibrosis (both KO and Akt inhibitor) down_manip anti_fib pro_fib LY294002 (Akt inhibitor) attenuated the p21WAF1 senescence marker in BLM-treated WT mouse lungs → reduced lung fibrosis (as assessed by lower collagen1α) [See other KO Akt1/2]
The protein kinase B (PKB)/Akt [PKB is also known as Akt] signaling pathway is negatively regulated by Pten and plays a critical role in the regulation of cell growth and cell survival.
In vitro: AEC senescence was accelerated by Pten knockdown and attenuated by Pten overexpression.		 Qiu et al 2019 31527305
Akt2 ENSMUSG00000004056 C57BL/6 KO Akt2-/- male 6 wk BLM 1.4-1.5 U/kg, intratracheally single dose, follow-up 0-21 days Reduced lung inflammation and fibrosis down_manip anti_fib pro_fib [See other KO Akt1/2]
Akt2-mediated signaling enhanced IPF by modulating macrophage activation.
They suggest that inhibition of Akt2 may be a potential strategy for treating IPF		 Nie et al 2017 28455433
Alox5 ENSMUSG00000025701 129/Sv KO Alox5 NA 2-7 mo BLM 0.025 or 0.05 U, intratracheally single dose, follow-up 0-21 days Reduced lung inflammation and fibrosis down_manip anti_fib pro_fib The levels of prostaglandin E2, an antiinflammatory and antifibrotic molecule, was significantly greater in the BLM-treated KO vs WT mice [NB! Three main pathways of arachidonic acid (AA) cascade -- redistribution of AA towards prostaglandins; Kozak & Fraifeld 2004; see also Higuchi et al 2016 on Ptger4 KO and overexpression] [See also Ltc4s overexpression; Hirata et al 2013]
Alox5 gene encodes 5-lipoxygenase, an enzyme of arachidonic acid cascade, which produce leukotriens.		 Peters-Golden et al 2002 11790660
Angptl2 ENSMUSG00000004105 C57BL/6N KO Angptl2 male 9 wk Bleomycin hydrochloride 1 U/kg, intratracheally single dose, follow-up 0-14 days Promoted lung fibrosis down_manip pro_fib anti_fib In KO mice, collagen type I (COL1A1 and COL1A2) and hydroxyproline contents were increased. Induction of inflammatory cytokines (TNF-α and IL-6) and of the macrophage marker CD68 mRNA was comparable in lung of WT and Angptl2 KO mice Motokawa et al 2016 27542805
Anxa2 ENSMUSG00000032231 C57BL/6J KO Anxa2-/- female 6-8 wk BLM 2.5 U/kg in 50 μl saline, intratracheally single dose, follow-up 0-21 days Reduced lung injury and fibrosis down_manip anti_fib pro_fib [See KO Anxa2; Schuliga et al 2017]
Anxa2 is identified as a direct binding target of BLM.
A CRISPR-Cas9-engineered ANXA2E139A mutation in lung epithelial cells ablates BLM binding and activates TFEB (transcription factor EB), a master regulator of macroautophagy/autophagy, resulting in substantial acceleration of autophagic flux		 Wang et al 2018 29172997
Anxa2 ENSMUSG00000032231 C57Bl/6 KO Anxa2-/- female 10-16 wk BLM 4 U/kg, intranasally single dose, follow-up 0-21 days Reduced lung injury, inflammation and fibrosis down_manip anti_fib pro_fib [See KO Anxa2; Wang et al 2018]
Increased levels of annexin A2 in renal and liver fibrosis suggest a role in fibrotic disease.
ANXA2 protein levels were lower in IPF lungs. [Possible explanaition of the discrepancy between clinical and experimental data] However, when defining the role of annexin A2 in IPF, other measures of annexin A2 activity, such as cellular distribution, need to be assessed. They found the presence of detectable annexin A2 in SMA-immunoreactive fibroblasts [myofibroblasts] in IPF lungs.
Anxa2 (Annexin A2) contributes to lung injury and fibrosis by augmenting factor Xa fibrogenic activity 		Schuliga et al 2017 28283478
Apcs ENSMUSG00000026542 C57BL/6 KO Apcs-/- male 4-6 wk BLM 3 U/kg, oropharyngeally;
SAP (serum amyloid P component) 50 μg in PBS, intraperitoneally		 BLM single dose;
SAP one dose daily, 24 h after BLM up to Day 21;
Follow-up 0-21 days		 Promoted lung inflammation and fibrosis down_manip pro_fib anti_fib Exogenous SAP reduced BLM-induced lung inflammation and fibrosis in both KO and WT mice Apcs-/- (Amyloid P component, serum) = ‘‘SAP knockout mice’’.
SAP (pentaxin-2) is a member of the pentraxin family of proteins that includes C-reactive protein. SAP acts as an acute phase resonse protein 		Pilling et al 2014 24695531
Arel1 ENSMUSG00000042350 C57BL/6J Overexpression of Arel1 male NA BLM 0.02 - 0.05 U, intratracheally single dose,follow-up 0-21 days Promoted lung inflammation and fibrosis up_manip pro_fib pro_fib [See KO Arel1; the same paper]
AREL1 is overexpressed in IPF 		Lear et al 2016 27162139
Arel1 ENSMUSG00000042350 C57BL/6J KO Arel1+/- male NA BLM 0.02–0.05 U, intratracheally single dose, follow-up 0-21 days Reduced lung inflammation and fibrosis down_manip anti_fib pro_fib [See Arel1 overexpression; the same paper]
AREL1 is overexpressed in IPF 		Lear et al 2016 27162139
Atp2a2 (SERCA2a) ENSMUSG00000029467 NA Overexpression of Atp2a2 NA NA BLM 4 U/kg, intratreachlly single dose, follow-up 0-14 days Reduced lung inflammation and fibrosis up_manip anti_fib anti_fib Decreased expression of SERCA2a at mRNA and protein levels in IPF lungs.
In vitro: in human IPF lung fibroblasts, SERCA2a overexpression inhibits cell proliferation, migration, and fibroblast-to-myofibroblast transition induced by TGF-β1		 Bisserier et al 2019 31879190
Brp39 (Chi3l1) ENSMUSG00000064246 C57BL/6 KO Brp39-/- male 8 wk BLM 1.25 U/kg, intratracheally single dose, follow-up 0-21 days Reduced lung inflammation and fibrosis down_manip anti_fib pro_fib Enhanced expression in IPF lungs Zhou et al 2014 24920662
Capn1
Calpain (protein)		 ENSMUSG00000024942 C57BL/6 Inhibition of Calpain
protein by Calpeptin 		male 8-10 wk BLM 5 mg/ml, intraperitoneally;
Calpeptin 0.2 mg/ml, intraperitoneally 		BLM once daily on Day 1, 5, 8, 11, and 15;
Calpeptin three doses weekly during the 1st wk;
Follow-up 0-28 days
Reduced BLM-induced lung fibrosiss via calpain inhibition down_manip anti_fib pro_fib The protective effect of Calpeptin -- through the suppression of EMT and
TGFβ1-Smad2/3 signaling pathway		 Dec1 (deleted in esophageal cancer 1) is upregulated in BLM-induced lung fibrosis.
Dec1 might be a key transcription factor in calpeptin-mediated inhibition of lung fibrosis		 Liu et al 2018 29666896
Cav1 ENSMUSG00000007655 C57BL/6 Overexpression of Cav1 male 9-11 wk BLM 2 U/kg, aspiration single dose, follow-up 0-21 days Reduced lung inflammation and fibrosis up_manip anti_fib anti_fib [See Cav1 KO and overexpression]
Decreased expression of Calveolin-1 in IPF lungs		 Lin et al 2019 31873099
Cav1 ENSMUSG00000007655 C57BL/6J × 129S6/SvEv KO Cav1-/- NA NA BLM 1.3 U/kg, intratracheally single dose, follow-up 0-21 days Reduced lung fibrosis down_manip anti_fib pro_fib [See Cav1 KO and overexpression]
Contrary to expectations, BLM induced much less lung fibrosis in Cav1 KO mice, as assessed by lung collagen content, histopathology, and αSMA-2 expression in the lungs.
Reduced matrix metalloproteinase (MMP)-2 and MMP-9 expressions indicated a low profile of SASP in the BLM-injured KO mice.
Decreased expression of Calveolin-1 in IPF lungs		 Shivshankar et al 2012 22362388
Cav1 ENSMUSG00000007655 C57BL/6 KO Cav1 male 6-8 wk BLM 8 U/kg, intranasally single dose, follow-up 0-21 days Promoted lung fibrosis down_manip pro_fib anti_fib [See Cav1 KO and overexpression]
Decreased expression of Calveolin-1 in IPF lungs		 Nagaraja et al 2018 30253845
Cav1 ENSMUSG00000007655 C57BL/6J KO Cav1-/- male 12 wk BLM 1 U/kg, intratracheally single dose, follow-up 0-14 days Severe lung dysfunction and fibrosis down_manip pro_fib anti_fib [See Cav1 KO and overexpression]
Decreased expression of Calveolin-1 in IPF lungs		 de Almeida et al 2013 24067367
Cav2 ENSMUSG00000000058 C57BL/6J KO Cav2-/- male 12 wk BLM 1 U/kg, intratracheally single dose, follow-up 0-14 days Severe lung dysfunction and fibrosis down_manip pro_fib anti_fib In WT mice, BLM reduced the expression of Cav-2 and its phosphorylation at tyrosine 19 de Almeida et al 2013 24067367
Ccl2 (Mcp1) ENSMUSG00000035385 C57BL/6 Overexpression of the mutant Ccl2 (act as a dominant negative inhibitor) male 6-8 wk BLM 1.5 U/kg, intratracheally single dose, follow-up 0-14 days Reduced lung fibrosis down_manip anti_fib pro_fib Overexpression of mutant Ccl2 reduced DNA damage and apoptosis MCP-1 -- Monocyte Chemoattractant Protein-1.
Increased expression of MCP1 at mRNA and protein levels in IPF lungs [Antoniades et al 1992; PMID 1608944]
The NH2-terminal deletion mutant of MCP-1/CCL2 (deletion of amino acids 2–8), so-called 7ND, specifically forms heterodimers with wild-type MCP-1/CCL2 and has a greatly reduced capacity to attract monocytes compared with WT MCP-1/CCL2, and, as such, it acts as a specific and dominant negative inhibitor of WT MCP-1/CCL2		 Inoshima et al 2004 15064241
Ccl2 (Mcp1) ENSMUSG00000035385 C57Bl/6 Overexpression of Ccl2 male 8-10 wk BLM 5 U/kg, intratracheally single dose, follow-up 0-21 days Reduced lung injury, inflammation and mortality, but NO impact on lung fibrosis up_manip anti_fib anti_fib Increased expression of MCP1 at mRNA and protein levels in IPF lungs [Antoniadis et al 1992; PMID 1608944]
They were surprised to find that Ccl2 overexpression did not impact the lung fibrosis after BLM. Yet, it seems that the protean functions of Ccl2 have competing effects on the mechanisms of fibrosis		 Liang et al 2012 22287613
Ccn1 ENSMUSG00000028195 C57BL/6 Overexpression of Ccn1 male 8 wk BLM 1.2 U/kg, intratracheally single dose, follow-up 0-10 days Promoted lung injury up_manip other invalid Ccn1 is upregulated in human acute lung injury Grazioli et al 2015 25713320
Ccn5 ENSMUSG00000027656 C57BL/6 Overexpression of Ccn5 male 8 wk BLM sulfate 2 mg/kg, intratracheally single dose, follow-up 0-14 days Reduced lung fibrosis up_manip anti_fib anti_fib In vitro: CCN5 overexpression in IPF lung fibroblasts suppressed the CCN2-promoted expression of α-SMA and collagen. Furthermore, CCN5 overexpression in lung fibroblasts decreased the expression of CCN2 Zhang et al 2014 24276150
Ccr2 ENSMUSG00000049103 C57BL/6J KO Ccr2-/- male 7-9 wk Bleomycin sulfate 1.25 mg/kg in 50 μl saline, oropharyngeally;
Crystalline silica 400 mg/kg in 50 μl saline, oropharyngeally		 single dose (either BLM, or Cryst silica);
Follow-up 0-28 days		 Reduced lung inflammation and fibrosis down_manip anti_fib pro_fib CCR2 is the major MCP-1 receptor, and MCP-1 binds to CCR2 with high affinity.
Increased expression of MCP1 at mRNA and protein levels in IPF lungs [Antoniadis et al 1992; PMID 1608944] [See also Ccl2 (Mcp1); Inoshima et al 2004]		 Shichino et al 2015 26456580
Ccr2 ENSMUSG00000049103 C57 BL/6 KO Ccr2-/- female 8-10 wk BLM 1 U/kg, intratracheally single dose, follow-up 0-21 days Reduced lung fibrosis down_manip anti_fib pro_fib In lungs of KO mice: the reduced expression of type I collagen, hydroxyproline, TNF-alpha,
TGF-beta 1, and a-SMA 		Gharaee-Kermani et al 2003 14609568
Ccr2 ENSMUSG00000049103 B6129F2/J KO Ccr2-/- NA NA BLM 0.025 U per mouse, intratracheally;
FITS stock -- 21 mg dissolved in 10 ml PBS → 50 μl per mouse, intratracheally 		BLM single dose;
FITS single dose;
Follow-up 0-21 days		 Reduced lung inflammation and fibrosis in both the FITC and BLM models down_manip anti_fib pro_fib FITS -- Fluorescein-5-isothiocyanate: FITS is used for induction of lung fibrosis.
The protection is specific for the Ccr2 deficiency , as Ccr5-/- mice are not protected.
CCR2 is the major MCP-1 receptor, and MCP-1 binds to CCR2 with high affinity.
Increased expression of MCP1 at mRNA and protein levels in IPF lungs [Antoniadis et al 1992; PMID 1608944] [See also Ccl2 (Mcp1); Inoshima et al 2004]		 Moore et al 2001 11591761
Cd19 ENSMUSG00000030724 C57BL/6 Overexpression of Cd19 NA 12-16 wk Bleomycin sulfate 8 mg/kg in 250 μl PBS, intratracheally single dose, follow-up 0-16 days Promoted lung inflammation and fibrosis and decreased survival up_manip pro_fib pro_fib [See CD19 KO; the same paper] Komura et al 2008 18975313
Cd19 ENSMUSG00000030724 C57BL/6 KO Cd19-/- NA 12-16 wk Bleomycin sulfate 8 mg/kg in 250 μl PBS, intratracheally single dose, follow-up 0-16 days Reduced lung inflammation and fibrosis and increased survival down_manip anti_fib pro_fib [See CD19 overexpression; the same paper] Komura et al 2008 18975313
Cd151 ENSMUSG00000025510 C57BL/6 KO Cd151 NA 8-10 wk BLM 1.2 U/kg, intratracheally single dose, follow-up 0-21 days Promoted lung fibrosis and mortality down_manip pro_fib anti_fib They suggest that the underlying mechanism could involve loss of epithelial integrity: deletion of CD151 in alveolar epithelial cells attenuates the strength of adhesion to the basement membrane, resulting in mesenchymal-like changes and increased p-Smad2 (phosphorylated Smad-2) signaling.
Decreased expression of CD151 in IPF lungs 		Tsujino et al 2012 22592804
Cdkn2b ENSMUSG00000073802 C57Bl/6 KO Cdkn2b-/- or Cdkn2b+/- NA 6-10 wk BLM 0.9 U/kg, intratracheally single dose, follow-up 0-21 days Promoted lung inflammation and fibrosis down_manip pro_fib anti_fib Levels of the cytokine CXCL1 were higher in BLM-treated mice vs saline-treated mice, but lower in Cdkn2b-/- and Cdkn2b+/- mice compared with WT.
Decreased expression of CDKN2B was associated with more severe fibrosis in IPF 		Scruggs et al 2018 29420051
Cflar (C-Flip) ENSMUSG00000026031 C57BL/6 Overexpression of Cflar* NA 11-12 wk BLM 0.08 mg, intratracheally single dose, follow-up 0-14 days Promoted lung fibrosis up_manip pro_fib pro_fib FLICE-likeinhibitory-protein (FLIP) allows escaping from immune surveillance and unremitted accumulation of myofibroblasts, thus promoting fibrosis [Bulvik et al 2020].
C-FLIP is overexpressed in lung myofibroblasts from humans with IPF and in lung myofibroblasts from BLM-treated WT mice [from the same paper].
[See Mir34a KO; Cui et al 2017a,b; and Bulvik et al 2020]
Myofibroblasts from fibrotic BLM-treated mouse lungs switch Fas-induced apoptosis toward proliferation and activate TNF receptor-associated factor and the NF-kB Ssignaling pathway		 Golan-Gerstl et al 2012 22582174
Chrna7 ENSMUSG00000030525 C57BL/6J KO Chrna7-/- male 8-10 wk BLM 0.5 - 1.5 - 3 mg/kg, intratracheally Three administrations: 3 mg/kg at Day 0;
1.5 mg/kg at Day 7; 0.5 mg/kg at Day 21;
Follow-up 0-21 days		 Reduced lung inflammation and fibrosis down_manip anti_fib pro_fib Sun et al 2017 28283678
Cryɑb ENSMUSG00000032060 SV129 KO Cryɑb NA NA BLM 0.07 U, intratracheally single dose, follow-up 0-21 days Reduced lung fibrosis down_manip anti_fib pro_fib The increase in HSP47 (chaperone of collagen, which is highly expressed during BLM-induced lung fibrotic response) was much lower in KO than in WT mice.
BLM-induced TGF-β1 activation was significantly reduced in KO mice 		CRYAB strongly expressed in IPF lungs.
The absence of αB-crystallin had no impact on the early inflammatory effect of BLM.		 Bellaye et al 2014 24307592
Cthrc1 MGP_129S1SvImJ_G0021812 129S6/SvEv KO Cthrc1-/- male 12 wk BLM 2.5 U/kg, intratracheally single dose, follow-up 0-14 days Promoted lung inflammation and fibrosis down_manip pro_fib anti_fib BLM exacerbated collagen deposition in Cthrc1 KO mice and produced an IPF-like phenotype
with reduced lung compliance and a consequent shift to a rapid, shallow breathing pattern, consistent with IPF		 Binks et al 2017 28292882
Ctsa ENSMUSG00000017760 C57BL/6 Overexpression of Ctsa NA 13 wk and 42 wk BLM 1.5 U/kg, intratracheally single dose, follow-up 0-14 days Reduced lung injury and fibrosis up_manip anti_fib anti_fib [See KO Map1lc3b-/-; the same paper]
[NB! Age-related differences in response to BLM]
They identified cathepsin A as a novel Map1lc3b binding partner and Ctsa overexpression in vitro drives MLE12 cells to apoptosis. Additionally, cathepsin A is increased in the AECII of aged LC3B-/- mice and in the lungs of patients with IPF. Their study reveals that Map1lc3b-mediated autophagy plays essential roles in AECII by modulating the functions of proteins like cathepsin A and protects alveolar epithelial cells from apoptosis and subsequent lung injury and fibrosis		 Kesireddy et al 2019 31431059
Ctsk ENSMUSG00000028111 FVB/N Overexpression of Ctsk NA 8-12 wk BLM 5 U/kg, intratracheally single dose, follow-up 0-14 days Reduced lung fibrosis (no difference in inflammation between TG and WT) up_manip anti_fib anti_fib Srivastava et al 2008 18638383
Cx3cr1 ENSMUSG00000052336 C57BL/6 KO Cx3cr1-/- male 8 wk BLM 0.075 U in 50 μl saline, intratracheally single dose, follow-up 0-21 days Reduced lung inflammation and fibrosis down_manip anti_fib pro_fib KO Cx3xr1 impaired wound healing in the skin with reduced macrophage
recruitment and fibroblast accumulation		 KO Cx3xr1 inhibited inflammatory markers M1 and M2 (macrophages 1 and 2) Ishida et al 2017 29203799
Cxcl10 ENSMUSG00000034855 FVB Overexpression of Cxcl10 NA NA BLM 0.075 U in 100 μl saline, intratracheally single dose, follow-up 0-14 days Reduced lung fibrosis and mortality up_manip anti_fib anti_fib [See Cxcl10 KO; the same paper]
NB! TG mice were of the FVB genetic background, which has substantially greater mortality after BLM than mice of either C57Bl/6 or C57Bl/6-129Sv/J 		Tager et al 2004 15205180
Cxcl10 ENSMUSG00000034855 C57BL/6 × 129Sv/J
(F1 hybrids)		 KO Cxcl10 NA NA BLM 0.020 U in 100 μl saline, intratracheally single dose, follow-up 0-14 days Promoted lung fibrosis down_manip pro_fib anti_fib [See Cxcl10 overexpression; the same paper] Tager et al 2004 15205180
Cxcl10 ENSMUSG00000034855 C57BL/6 KO Cxcl10-/-
Overexpression of Cxcl10-/- in Tcrb-/- mice		 male 6-8 wk BLM 2 U/kg in 100 μl PBS, oropharyngeally single dose, follow-up 0-45 days NO effect down_manip other invalid Overexpression of Cxcl10 resulted in a significantly attenuated fibrosis in Tcrb-/- mice [See Tcrb KO; the same paper]
NB! Overexpression of Cxcl10 resulted in a significantly attenuated fibrosis in BLM-treated
Tcrb-/- mice		 Pociask et al 2011 21356368
Cxcr3 ENSMUSG00000050232 C57BL/6J KO Cxcr3 NA NA BLM, intratracheally (dose NA);
IFN-γ protein 40,000 U/mouse in 30 μl PBS, intramuscularly 		BLM single dose;
IFN-γ protein in three doses: 20 h before and 24 h and
48 h after BLM instillation;
Follow-up 0-21 days		 Promoted lung inflammation, fibrosis and mortality
down_manip pro_fib anti_fib The fibrotic phenotype was reversed following the administration of exogenous IFN-γ Fibrosis pattern in the Cxcr3-deficient mice was more severe and extensive than in WT mice, and
suggestive of the cystic honeycomb pattern observed in patients with IPF		 Jiang et al 2004 15254596
Cxcr4 ENSMUSG00000045382 C57BL/6 KO Cxcr4+ /- male 6 wk BLM 2 U/kg, intratracheally single dose, follow-up 0-14 days Reduced lung fibrosis but enhanced inflammatory response down_manip anti_fib pro_fib Yang IV et al 2007 16998095
Cxxc5 ENSMUSG00000046668 C57BL/6 Overexpression of Cxxc5 male 8 wk BLM 2 mg/kg, intratreachlly single dose, follow-up 0-28 days Reduced lung fibrosis up_manip anti_fib anti_fib Cxxc5 overexpression inhibited TGF-β1-induced activation of the CD40/CD40L signaling pathway Cheng et al 2020 32337277
Cyp27b1 ENSMUSG00000006724 C57BL/6J KO Cyp27b1-/- male 4 wk BLM 1.5 mg/kg, intratracheally single dose, follow-up 0-14 days Promoted lung inflammation and interstitial fibrosis down_manip pro_fib anti_fib The enzyme Cyp27b1 carries out the second of two reactions to convert vitamin D to
its active form 1,25-dihydroxyvitamin D3 (calcitriol). Vitamin D deficiency exacerbates BLM-induced lung fibrosis, partially through aggravating TGF-β/Smad2/3-mediated EMT in the lungs.
Vitamin D deficiency was positively associated with mortality of patients with IPF [Tzilas et al 2019; PMID 30659895]		 Li et al 2019 31775746
Ddit3 ENSMUSG00000025408 C57BL/6 KO Ddit3-/- NA NA BLM 0.04 or 0.06 U/mouse, intratracheally single dose, follow-up 0-21 days Promoted lung inflammation, fibrosis and mortality down_manip pro_fib anti_fib [See KO Ddit3-/- -- discrepancy with Yao et al 2016; Tanaka et al 2015]
[See also KO Hspa5+/- -- the same paper]
Exacerbated fibrotic phenotype was associated with the accumulation of non-apoptotic
macrophages		 Ayaub et al 2016 27135434
Ddit3 ENSMUSG00000025408 C57BL/6 KO Ddit3-/- male 8-10 wk BLM 2 U/kg in 30 μl saline, intratracheally single dose, follow-up 0-21 days Reduced lung fibrosis down_manip anti_fib pro_fib [See KO Ddit3-/- -- discrepancy with Ayaub et al 2016]
Protected KO mice by attenuating M2 macrophage production 		Yao et al 2016 26883801
Ddit3 (Chop) ENSMUSG00000025408 C57BL/6J KO Ddit3 (Chop) NA NA BLM 3 mg/kg, intratracheally;
TUDCA (ERS inhibitor) 0.1 - 1 - 5 mg/kg, intratracheally (to WT)		 BLM single dose, follow-up 0-14 days;
TUDCA once a day, Day 0-14;
Follow-up 0-14 days 		Reduced lung fibrosis and inflammation in both BLM-treated KO mice and in BLM+TUDCA WT group down_manip anti_fib pro_fib In WT mice, TUDCA inhibit Ddit3 expression in a dose-dependent manner [SeeKO Ddit3-/- -- discrepancy with Ayaub et al 2016]
DDIT3 overexpressed in IPF lungs.
The mRNA expression of interleukin-1b and caspase 11, and the apoptotic cell death were suppressed in Chop KO mice vs WT mice.
TUDCA ‒ Tauroursodeoxycholic acid; a classic inhibitor of Endoplasmic Reticulum Stress
Inhibitited HSV1 infection‐induced acute lung injury in a mouse model of pulmonary fibrosis		 Tanaka et al 2015 26005208
Dio2 ENSMUSG00000007682 C57Bl/6 KO Dio2 female 9-12 wk BLM 1.5 U/kg, intratracheally;
TGF-β1 40 μg/kg, intratracheally 		single dose, BLM or TGF-β1 -- separately;
Follow-up 0-21 days		 Promoted lung fibrosis (both BLM and TGF-β1) down_manip pro_fib anti_fib Aerosolized delivery of tyroid hormones (T3 and T4) blunted lung fibrosis in
both BLM and TGF-β1 models		 DIO2 is overexpressed in IPF lungs Yu et al 2018 29200204
Dpp4 ENSMUSG00000035000 NA Overexpression of Dpp4
Inhibition of Dpp-4 protein		 NA NA BLM, intratracheally
Sitagliptin (a competitive inhibitor of Dpp-4 protein) 10 mg/kg, subcutaneously (to WT only [and KO])		 BLM single dose;
Sitagliptin once daily, 1-28 days;
Follow-up 0-28 days		 Promoted lung fibrosis down_manip pro_fib anti_fib Sitagliptin inhibitor reduced lung inflammation and fibrosis in WT mice [See KO Dpp4; the same paper + Suzuki et al 2017]
Sitagliptin is an antidiabetic drug. Often used in combination with metformin to treat type 2 diabetes.		 Soare et al 2020 31350829
Dpp4 ENSMUSG00000035000 NA KO Dpp4 NA NA BLM, intratreachlly
Sitagliptin (a competitive inhibitor of DPP-4 protei) 10 mg/kg, subcutaneously (to both WT and KO mice)		 BLM single dose;
Sitagliptin once daily, 1-28 days;
Follow-up 0-28 days		 Reduced lung fibrosis down_manip anti_fib pro_fib Sitagliptin inhibitor did not alter the effects of BLM in KO mice but reduced lung inflammation and fibrosis n WT mice [See Dpp4 overexpression; the same paper + Suzuki et al 2017]
Sitagliptin is an antidiabetic drug. Often used in combination with metformin to treat type 2 diabetes.		 Soare et al 2020 31350829
Dpp-4 (protein) ENSMUSG00000035000 C57BL/6 Inhibiting Dpp-4 protein
by Vildagliptin		 male 8 wk LPS 5 mg/kg, intraperitoneally;
Vildagliptin 10 mg/kg, intraperitoneally		 LPS for five consecutive days;
Vildagliptin once daily for 14 consecutive days, started a day before LPS;
Follow-up 0-28 days		 Reduced lung fibrosis in systemic LPS-induced lung injury down_manip anti_fib pro_fib Downregulating EndMT (endothelial-mesenchymal transition) [See Dpp4 overexpression and KO; Soare et al 2020] Suzuki et al 2017 29037205
Dusp1 ENSMUSG00000024190 CD57Bl/6 Overexpression of Dusp1 NA NA Bleomycin sulfate 1.0 U/kg, intratracheally once per week for 4 weeks; follow-up 0-28 days Reduced lung inflammation and fibrosis up_manip anti_fib anti_fib Overexpression of Dusp1 was sufficient to prevent the increase of Tnf, Il6 and Il1b mRNAs and to decrease phospho-p38 MAPK protein in FOXM1-deficient macrophages [See KO Foxm1; the same paper]
Loss of FOXM1 in lung macrophages promotes pulmonary fibrosis by activating p38 MAPK signaling pathway 		Goda et al 2020 32271749
Dusp10 ENSMUSG00000039384 C57BL/6 KO Dusp10-/- female 9-12 wk BLM 1.5 U/kg, intratracheally single dose, follow-up 0-14 days Reduced lung inflammation and fibrosis down_manip anti_fib pro_fib Enhance expression of DUSP10 in IPF pulmonary fibroblasts at mRNA and protein levels Xylourgidis et al 2019 31483681
Edn1 (Veet) ENSMUSG00000021367 NA KO Edn1 NA 8-10 wk BLM 10 µg/g body weight (50-60 μl saline), intratracheally single dose, follow-up 0-28 days Reduced lung fibrosis down_manip anti_fib pro_fib BLM-treated Veet KO mice had less muscularized arterioles, lower muscularization
index and attenuated adventitial collagen, and lower accumulation of fibroblasts and macrophages 		In WT mice, BLM induced pulmonary vascular remodeling promoted by endothelial-derived endothelin-1 and pulmonary hypertension secondary to BLM-induced pulmonary fibrosis Hartopo et al 2018 29947539
Elk1 ENSMUSG00000009406 C57BL/6 KO Elk1 male 5-7 wk Bleomycin sulfate 60 IU in 50 μl saline, oropharyngeally single dose, follow-up 0-28 days Promoted lung fibrosis down_manip pro_fib anti_fib Loss of Elk1 causes enhanced Itgb6 (subunit of the integrin αvβ6), whereas the GR agonist dexamethasone inhibits Itgb6 expression [See also KO Postn-/-]
Decreased expression of ELK1 in IPF lungs; its dysregulation is present in epithelium from IPF patients 		Tatler et al 2016 26861876
Epha2 ENSMUSG00000006445 NA KO Epha2 NA NA BLM 4 U/kg, intratracheally single dose, follow-up 0-4 days Reduced lung injury down_manip other invalid In KO mice: less oedema and less accumulation of leukocytes and chemokines (CXCL1 and CCL2) in the lungs Carpenter et al 2012 21799118
Fbln1 ENSMUSG00000006369 C57BL/6J KO Fbln1-/- female 6-8 wk Bleomycin sulfate 0.05 U/mouse, intratracheally single dose, follow-up 0-28 days Reduced lung fibrosis and improved lung function down_manip anti_fib pro_fib In WT mice, Fbln1 protein binds TGF-β1 binding protein to activate TGF-β1 with subsequent promotion of BLM-induced lung fibrosis.
Increased expression of human FBLN1C in IPF lungs		 Liu et al 2019 31343988
Fgf2 ENSMUSG00000037225 C57BL/6J × 129X1 Overexpression of Fgf2 NA 8-10 wk BLM 1 unit/kg, intratracheally single dose, follow-up 0-21 days Reduced lung fibrosis and mortality up_manip anti_fib anti_fib [See KO Fgf2; the same paper]
FGF2 is increased in bronchoalveolar lavage (BAL) fluid from patients with IPF [Inoue et al 1996, PMID: 8952537]
Mast cells are abundant in fibrotic tissue and may produce basic fibroblast growth factor (bFGF)]. The bFGF+ cells are abundant in IPF lungs. NB! Only one bFGF isoform (17.8 kd) was found in IPF [Inoue et al 1996, PMID: 8952537] → [Not clear if it is FGF2]
In vitro: Overexpression of Fgf2 reversed TGF-β1-induced collagen and αSMA expression and the formation of stress fibers in lung fibroblasts, without affecting either inflammation or epithelial gene expression 		Koo et al 2018 29873400
Fgf2 ENSMUSG00000037225 C57BL/6J × 129X1 KO Fgf2-/- NA 8-10 wk BLM 1 unit/kg, intratracheally single dose, follow-up 0-21 days Promoted lung fibrosis and mortality down_manip pro_fib anti_fib [See Fgf2 overexpression; the same paper]
FGF2 is increased in bronchoalveolar lavage (BAL) fluid from patients with IPF [Inoue et al 1996, PMID: 8952537]
Mast cells are abundant in fibrotic tissue and may produce basic fibroblast growth factor (bFGF)]. The bFGF+ cells are abundant in IPF lungs. NB! Only one bFGF isoform (17.8 kd) was found in IPF [Inoue et al 1996, PMID: 8952537] → [Not clear if it is FGF2]
In vitro: Overexpression of Fgf2 reversed TGF-β1-induced collagen and αSMA expression and the formation of stress fibers in lung fibroblasts, without affecting either inflammation or epithelial gene expression 		Koo et al 2018 29873400
Fgf10 ENSMUSG00000021732 C57BL/6 Overexpression of Fgf10 female 8 wk Bleomycin sulfate 0.1 mg/g mouse, subcutaneously via osmotic pump single dose, follow-up 0-28 days Reduced lung inflammation and fibrosis up_manip anti_fib anti_fib Fgf10 -- Fibroblast growth factor 10 Gupte et al 2009 19498056
Fhl2 ENSMUSG00000008136 C57Bl/6 KO Fhl2 male 2-4 mo BLM 2 U/kg, intratracheally single dose, follow-up 0-14 days Promoted lung inflammation and fibrosis down_manip pro_fib anti_fib Upregulation of Tenascin C, an ECM protein, and impaired activation of
inflammation-resolving macrophages in KO mice		 Alnajar et al 2013 24260575
Flt1 ENSMUSG00000029648 C57Bl/6 KO Flt1 male 6 wk BLM 0.1 μg in 50 μl saline, intratrachealy single dose, follow-up 0-21 days Reduced lung inflammation and fibrosis down_manip anti_fib pro_fib Activation of the SDF-1/CXCR4 axis in infiltrating VEGFR1+ cells in KO mice Amano et al 2019 31176171
Fosl2 ENSMUSG00000020009 C57BL/6 KO Fosl2-/- male 8-12 wk BLM 1.5 U/kg, intratracheally single dose, follow-up 0-21 days Reduced lung fibrosis down_manip anti_fib pro_fib Fosl2 coexpressed with COLVI (Collagen VI) in IPF lungs Ucero et al 2019 31135379
Foxm1 ENSMUSG00000001517 CD57Bl/6 KO Foxm1fl/fl NA NA Bleomycin sulfate 1.0 U/kg, intratracheally once per week for 4 weeks, follow-up 0-28 days Promoted lung inflammation and fibrosis down_manip pro_fib anti_fib [See Dusp1 overexpression; the same paper]
NB! KO Foxm1 in lung macrophages [in contrast to Penke et al 2018 -- in lung fibroblsts].
In IPF was obsereved an elevetad expression of FOXM1 in lungs.		 Goda et al 2020 32271749
Foxm1
(gene & protein)		 ENSMUSG00000001517 C57BL/6 KO Foxm1fl/fl
Inhibition of Foxm1 protein		 female 8-10 wk BLM 1.5 U/kg, oropharyngeally;
Sio A (inhibitor of Foxm1) 25 mg/kg, intraperitoneally 		BLM single dose;
Sio A inhibitor twice on Day 9 and Day 12;
Follow-up 0-28 days 		Reduced lung inflammation and fibrosis in both KO and WT mice
treated with Foxm1 inhibitor		 down_manip anti_fib pro_fib [See KO Foxm1; Goda et al 2020]
Sio A significantly attenuated basal FOXM1 expression in fibroblasts as well as the FGF2-induced upregulation of FOXM1 and of FOXM1 target genes.
NB! KO Foxm1 in lung fibroblsts [in contrast to Goda et al 2020 -- in lung macrophages].
In IPF was observed an elevetad expression of FOXM1 in lungs.		 Penke et al 2018 29733296
Fstl1 ENSMUSG00000022816 C57BL/6 KO Fstl1+/- male 6–8 wk BLM 2 U/kg in 20-25 μl (PBS), intratracheally single dose, follow-up 0-14 days Reduced lung inflammation and fibrosis down_manip anti_fib pro_fib Attenuated the TGF‑β1‑induced phosphorylation of the MAPK signaling components MAPK signaling is activated in the lungs of BLM‑treated mice.
FSTL1 is a novel regulator of fibroblasts (partly through MAPK and SMAD signaling), which plays
an important role in pathogenesis of IPF		 Jin YK et al 2018 30082522
Gab1 ENSMUSG00000031714 C57BL/6 KO Gab1 NA 4 wk BLM 2.5 U/kg, intratracheally;
LPS 3 ng/g, intratracheally		 single dose of BLM or LPS (separately), follow-up 0-28 days Promoted lung inflammation and fibrosis in both BLM and LPS (inflammation only) models down_manip pro_fib anti_fib In vivo, Gab1 deficiency leads to a decrease in SP (the surfactant proteins) synthesis and the appearance of disorganized lamellar bodies Wang et al 2016 27793798
Gadd45a ENSMUSG00000036390 C57BL/6 (WT)
129/Ola (KO)		 KO Gadd45a-/- or Gadd45a+/- female 8-10 wk BLM 0.25–1.50 U/kg, intratracheally;
Thoracic irradiation 10 and 20 GY 		BLM single dose, follow-up 0-14 days;
Thoracic irradiation single dose, follow-up 6 wk
Promoted lung fibrosis but did not alter the inflammatory response (no difference between KO and WT mice) down_manip pro_fib anti_fib Gadd45α KO also promoted radiation-induced lung injury [See Akt1 overexpression; the same paper] Mathew et al 2015 26498248
Gata3 ENSMUSG00000015619 C57BL/6 Overexpression of Gata3 NA 6-8 wk BLM 5 mg/kg, intratracheally;
IFN-γ (stock 1.7 x 108 U/ml) 0.25 μl/h via pump, subcutaneously		 BLM single dose, follow-up 0-28 days;
IFN-γ daily, one day before BLM and 13 days after BLM
(14 days in total) 		Promoted lung fibrosis and decreased survival;
No difference in inflammation between TG and WT mice		 up_manip pro_fib pro_fib The levels of TGF‑β1 was higher in the lungs of TG mice than in WT mice after BLM Exogenous administration of IFN-γ to Gata3-TG mice reduced BLM-induced lung fibrosis and thus increased survival. These results indicate that overexpression of Gata3 promoted lung fibrosis, possibly by reducing IFN-γ levels in the lung Kimura et al 2006 16816364
Glrx ENSMUSG00000021591 C57BL/6NJ Overexpression of Glrx male and female 3 mo, 18 mo and 24 mo BLM 5 U/kg, oropharyngeally single dose, follow-up 0-14 days Reduced lung fibrosis in young mice (3 mo) but not in aged mice
(18 and 24 mo) 		up_manip anti_fib anti_fib [NB! Age-related changes -- young, late middle-age, aged mice]
In WT mice, Glrx activated collagenase in lungs of BLM-treated aged mice.
Glrx-/- did not affect hydroxyproline content in fibrotic lungs of BLM-treated aged mice, thus demonstrating that the catalytic activity of Glrx is required for its ability to attenuate lung fibrosis.
GLRX mRNA and protein were slightly but significantly lower in IPF lungs 		Anathy et al 2018 29988126
Ggps1 ENSMUSG00000021302 C57BL/6 KO Ggps1-/- male 8-10 wk BLM 2.5 U/kg, intratracheally single dose, follow-up 0-21 days Promoted inflammatory response and lung fibrosis down_manip pro_fib anti_fib Modulated TGF‑β1/bone morphogenetic protein 4 (BMP 4) signaling in KO mice:
Enhanced TGF‑β1 but decrease BMP 4 levels		 Chen M et al 2019 31120854
GPR17 (protein) ENSMUSG00000052229 C57BL/6J Inhibition of GPR17 protein
by Cangrelor		 male 6-8 wk BLM 3 mg/kg, intratracheally;
Cangrelor 2.5 - 5 - 10 mg/kg, subcutaneously		 BLM single dose;
Cangrelor once daily, started 2 days before BLM and lasted totally 16 days;
Follow-up 0-14 days 		Reduced inflammatory response and lung fibrosis down_manip anti_fib pro_fib Zhan et al 2018 30036769
Has2 ENSMUSG00000022367 C57BL/6J Overexpression of Has2 NA NA BLM 2.5 U/kg, intratracheally;
MMI-0100 (MK2 inhibitor) 37.5 μg/kg, intraperitoneally -- WT only		 BLM single dose;
MMI-0100 once a day 3-21 days after BLM -- to WT only;
Follow-up 0-21 days 		Promote lung fibrosis up_manip pro_fib pro_fib MK2 inhibition attenuated hyaluronan accumulation and reduced collagen content in
BLM-injured WT mouse lungs, and eventually reduced lung fibrosis in WT mice		 [See KO Mapkapk2; the same paper and Li et al 2011]
Western blot: the increased levels of MK2 in mouse lung fibroblasts was associated with Has2 overexpression.
Fibroblasts isolated from IPF lungs expressed higher levels of HAS2		 Liang et al 2019 30130411
Has2 ENSMUSG00000022367 C57BL/6J Overexpression of Has2 NA NA BLM 1.75 U/kg or 2.5 U/kg, intratracheally single dose, follow-up 0-28 days Promoted lung inflammation, fibrosis and mortality up_manip pro_fib pro_fib [See Has2 KO; the same paper and Liang et al 2019]
In IPF, reduced expression of HAS2 in senescent lung fibroblasts (Li et al 2016,PMID 26987798 )		 Li et al 2011 21708929
Has2 ENSMUSG00000022367 C57BL/6J KO Has2 NA NA BLM 1.75 U/kg or 2.5 U/kg, intratracheally single dose, follow-up 0-28 days Reduced lung inflammation and fibrosis down_manip anti_fib pro_fib [See Has2 overexpression; the same paper and Liang et al 2019]
In IPF, reduced expression of HAS2 in senescent lung fibroblasts (Li et al 2016,PMID 26987798 )		 Li et al 2011 21708929
Havcr2 (Tim3) ENSMUSG00000020399 C57BL/6J Overexpression of Havcr2 male 6-8 wk BLM 2 U/kg in 30 μl saline, intratracheally single dose, follow-up 0-21 days Promoted lung fibrosis up_manip pro_fib pro_fib Tim3 is expressed on certain innate immune cells; acts as a phagocytic receptor for apoptotic cells.
Tim3 expression was increased in IPF patients		 Wang et al 2019 31162951
Hdac6 ENSMUSG00000031161 C57/BL6 KO Hdac6
Inhibition of Hdac6		 male 6-10 wk BLM 2 U/kg dissolved in 50 μl PBS, oropharyngeally;
Tubastatin (inhibitor of deacetylase activity) 80 mg/kg, intraperitoneally 		BLM single dose;
Tubastatin daily, from Day 1 to Day 21;
Follow-up 0-21 days		 Similar fibrotic response in lungs of BLM-treated KO and WT
mice (but not in BLM+Tubastatin-treated mice)		 down_manip other invalid Tubastatin-treated WT mice were protected against BLM-induced lung fibrosis, but KO mice were not. Expression of HDAC6 in humans with IPF was mildly increased.
Similar levels of collagen type 1 in WT and KO mice.
Different response of BLM-treated WT and KO mice to Tubastatin suggests that Tubastatin ameliorates lung fibrosis by targeting the TGFβ-PI3K-Akt pathway, likely via an HDAC6-independent mechanism. That is, Tubastatin may have off-target effects aside from HDAC6. This may be the most likely scenario, given that even high-dose Tubacin (which caused robust hyperacetylation of α-tubulin) failed to repress TGF-β1-induced type-1 collagen expression. 		Saito S et al 2017 29045477
Hif1a ENSMUSG00000021109 FVB KO Hif1afl/fl
Pharmacological inhibition of HIF-1a/PDK1 axis		 male 6-8 wk Bleomycin sulfate 0.05 U, intratracheally;
DCA (dichloroacetate) 1.5 g/L, orally in drinking water		 Bleomycin sulfate single dose;
DCA single dose on Day 0;
Follow-up 0-21 days 		Reduced lung inflammation and fibrosis down_manip anti_fib pro_fib DCA attenuated BLM-induced fibrosis in both WT and KO mice (reduced accumulation of αSMA1 myofibroblasts and collagen deposition by inhibition of HIF-1α/PDK1) NB! Genetic or pharmacological inhibition of the HIF-1a/PDK1 axis attenuated BLM-induced pulmonary fibrotic progression Goodwin et al 2018 28915065
Hmmr ENSMUSG00000020330 C57BL/6 Overexpression of Hmmr male NA Bleomycin sulfate 0.5 U/kg or 1 U/kg, intratracheally;
LPS 250 μl, intratracheally		 BLM or LPS separately, single dose;
Follow-up 0-28 days		 Promoted lung inflammation and fibrosis up_manip pro_fib pro_fib [See KO Hmmr; the same paper] Cui et al 2019 30098420
Hmmr ENSMUSG00000020330 C57BL/6 KO Hmmr male NA Bleomycin sulfate 1 U/kg, intratracheally single dose, follow-up 0-28 days Reduced lung inflammation and fibrosis down_manip anti_fib pro_fib [See Hmmr overexpression; the same paper] Cui et al 2019 30098420
Hpgds ENSMUSG00000029919 C57BL/6J KO Hpgds-/- NA NA BLM 1mg/kg in 50 μl saline, intratracheally single dose, follow-up 0-14 days Promoted lung inflammation and fibrosis down_manip pro_fib anti_fib Kida et al 2016 27992456
Hspa1a ENSMUSG00000091971 B6129SvF1 KO Hspa1a male 8-10 and 22-24 wk BLM 2 mg/kg, intratracheally single dose, follow-up 0-14 days Promoted lung fibrosis in young (8-10-wk-old) mice, but not
in older 22-24-we-old mice 		down_manip pro_fib anti_fib [Age-related changes in response to BLM could be attributed to a relatively short follow-up (up to 14 days); commonly, lung fibrosis manifested later]
In vitro: HSP70 (ortholog of mouse Hspa1a) mRNA and protein were decreased in IPF lung fibroblasts		 Sellares et al 2019 30543447
Hspa1b ENSMUSG00000067284 C57/BL6 Overexpression of Hspa1b male 6-8 wk BLM 5mg/kg, intratracheally single dose, follow-up 0-14 days Reduced lung inflammation and fibrosis up_manip anti_fib anti_fib The production of TGF-β1 and expression of pro-inflammatory cytokines was lower in the lung epithelial cells from the TG than WT mice after BLM In vitro: The reduced expression of Hspa1b stimulated TGF-β1-induced EMT-like phenotypes of mouse epithelial cells but did not affect the TGF-β1-dependent activation of lung fibroblasts Tanaka et al 2010 20513440
Hspa5 ENSMUSG00000026864 C57BL/6 KO Hspa5+/- NA NA BLM 0.04 or 0.06 U/mouse, intratracheally single dose, follow-up 0-21days Reduced lung inflammation and fibrosis down_manip anti_fib pro_fib Enhanced the BLM-induced UPR response (unfolded protein response,
a cellular stress response related to ER stress)		 [See KO Ddit3; the same paper] Ayaub et al 2016 27135434
Id1 ENSMUSG00000042745 C57BL/6 KO Id1-/- NA NA BLM 0.06 U per mouse, intratracheally single dose, follow-up 0-14 days Promoted lung fibrosis down_manip pro_fib anti_fib ID1 is highly expressed in IPF lungs; ID1 is regulated by TGF-β1 in human lung fibroblasts Lin et al 2008 18583319
Id2 ENSMUSG00000020644 C57BL/6 Overexpression of Id2 NA 6-8 wk BLM 1.5 U/kg, intratracheally single dose, follow-up 0-21 days Reduced lung fibrosis up_manip anti_fib anti_fib In vitro: Overexpression of Id2 induced AEC proliferation and suppressed AEC activation.
Id2 expression is high in lung epithelial cells during development but is low in adult AECs.
No difference in Id2 expression between IPF and normal human AECs.
However, overexpression of Id2 reduced fibrosis in BLM-treated mice through the enhanced AEC proliferation and inhibited AEC activation.
[Interesting! NB!] This suggests that induced reinitiation of Id2-mediated developmental programming could shift the lung back toward normal homeostasis after injury rather than toward fibrosis.		 Yang et al 2015 25661109
Ifngr1 ENSMUSG00000020009 C57BL/6 KO Ifngr1-/- male 8-12 wk BLM 2 U/kg, intratracheally single dose, follow-up 0-14 days Reduced lung inflammation and fibrosis down_manip anti_fib pro_fib The levels of S100a4 protein increased during the pulmonary inflammation and remained high during the fibrotic phase [See KO S100a4-/-; Li et al 2018]
They hypothesized that also in pulmonary fibrosis, M2 macrophages produce and secrete S100a4, and that secreted S100a4 induces the proliferation and activation of fibroblasts 		Zhang et al 2018 29910813
Igf1 ENSMUSG00000020053 C57B6 × C3H Overexpression of Igf1 male and female 8-12 wk BLM 4 U/kg, intratracheally single dose, follow-up 0-28 days No effect on lung fibrosis and inflammation up_manip other invalid Overexpression of human IGF-IA in alveolars did not affect the development of lung fibrosis but promotes premalignant changes in the alveolar epithelium in vivo. Frankel et al 2005 15618451
Il1rl1 ENSMUSG00000026069 C57BL/6 KO Il1rl1-/- NA NA Bleomycin sulfate 0.1 U per 25-g mouse in 30 μL of PBS, intranasally single dose, follow-up 0-14 days Reduced lung inflammation and fibrosis down_manip anti_fib pro_fib [See Fanny et al 2018; Luzina et al 2013] Li et al 2014 24985397
Il1rl1 ENSMUSG00000026069 C57BL/6J KO Il1rl1-/- male 8-14 wk Bleomycin sulfate 7.5 mg/kg on Day and 3 mg/kg daily on Day 11-14, intranasally five doses in total on Day 0 and Day 11-14;
follow-up 0-14 days		 Reduced lung inflammation and fibrosis down_manip anti_fib pro_fib [See Li et al 2014 ; Luzina et al 2013]
The ST2 cardiac biomarker is a protein biomarker of cardiac stress encoded by the IL1RL1 gene.
The increased concentration of ST2 in serum may be a biomarker of IPF
[Tajima et al 2003; PMID: 14555548]		 Fanny et al 2018 29988569
Il1rl1 MGP_BALBcJ_G0015905
ENSMUSG00000026069		 BALB/c (KO)
C57BL/6 (WT)		 KO Il1rl1-/- female 10-12 wk BLM 0.075 U, intratracheally single dose, follow-up 0-14 days Reduced lung injury, inflammation and fibrosis down_manip anti_fib pro_fib [See Li et al 2014; Fanny et al 2018]
In humans, IL33R is an ortholog of mouse Il1rl1.
Of note, the protein levels of IL-33 are elevated in patients with IPF
[Luzina et al 2012,PMID:22634619] 		Luzina et al 2013 23837438
Il2ra
(CD25, protein)		 ENSMUSG00000016529 C57BL/6 Inhibition by anti-CD25
monoclonal antibodies		 male 9 wk BLM 100 mg/kg via osmotic pumps;
anti-CD25 monoclonal antibodies 1 μl, iv 		single dose (both BLM and anti-CD25 antibodies);
anti-CD25 antibodies on Day 14 post BLM;
Follow-up 0-28 days		 Reduced lung fibrosis down_manip anti_fib pro_fib [See KO Il10; the same paper]
anti-CD25 antibodies were adminisrated for deleting Tregs (regulatory T cells) 		Kamio et al 2018 29690905
Il4ra ENSMUSG00000030748 C57BL/6 (KO)
C57BL/6 & Balb/c (WT)		 KO Il4ra-/- male 12-18 wk BLM 6 U/kg in 50 μl of saline, intradermally one dose daily for 5 days/wk, totally 4 wk Reduced lung inflammation and fibrosis down_manip anti_fib pro_fib KO inhibited MMP2 and MMP9 activity in BLM-treated mice Singh et al 2017 28775096
Il4 ENSMUSG00000000869 C57BL/6J Overexpression of Il4 male 11-12 wk BLM 0.06 mg in 0.1 ml saline intratracheally single dose, follow-up 0-21 days Reduced lung fibrosis up_manip anti_fib anti_fib
[See KO Il4; the same paper]
In vitro: in murine and human lung fibroblast lines, IL-4 was shown to enhance collagen gene expression [Gillery et al 1992; PMID:1601130]
 Izbicki et al 2002 12376365
Il4 ENSMUSG00000000869 C57BL/6J KO Il4 male 11-12 wk BLM 0.06 mg in 0.1 ml saline, intratracheally single dose, follow-up 0-21 days Promoted lung fibrosis down_manip pro_fib anti_fib [See Il4 overexpression; the same paper]
In vitro: in murine and human fibroblast lines, IL-4 was shown to enhance collagen gene expression
[Gillery et al 1992; PMID:1601130]		 Izbicki et al 2002 12376365
Il5 ENSMUSG00000036117 C57BL/6 Overexpression of Il5 NA NA BLM 0.02 or 0.05 U, intratracheally single dose, follow-up 0-28 days Promoted lung injury, inflammation, fibrosis and mortality up_manip pro_fib pro_fib [See Il5-/- KO; the same paper -- NB! The same effect as KO but via different ways]
We found that overexpression of IL-5 in transgenic mice (IL-5TG) increased BLM-induced lung injury, fibrosis, and eosinophilia. Surprisingly, BLM-treated IL-5-deficient mice also developed pronounced lung fibrosis but with marked T lymphocyte infiltration and absence of eosinophilia. We suggest that eosinophils and T cells contribute distinctly to the development of BLM-induced lung fibrosis potentially via their production of different cytokines → ultimately induce TGF-β expression → lung fibrosis.		 Huaux et al 2003 14607953
Il5 ENSMUSG00000036117 C57BL/6 KO Il5-/- NA NA BLM 0.02 or 0.05 U, intratracheally single dose, follow-up 0-28 days Reduced lung injury, inflammation but promoted lung fibrosis down_manip anti_fib pro_fib [See Il5 overexpression; the same paper -- NB! The same effect as overexpression but via different ways] Huaux et al 2003 14607953
Il6 ENSMUSG00000025746 C57BL/6 Overexpression of Il6 female 8-12 wk BLM 0.03 U/mouse, intratracheally single dose, follow-up 0-21 days Promoted lung inflammation and fibrosis up_manip pro_fib pro_fib [See KO Il6-/- -- Chen et al 2016, and Osm overexpression in Ayaub et al 2017]
IL-6 has been indicated as a putative prognostic marker for acute exacerbations in IPF (AE-IPF) [Collard et al 2010; PMID: 20418386]		 Ayaub et al 2017 29038604
Il6 ENSMUSG00000025746 C57/BL6 KO Il6-/- male 4-5 wk BLM 0.035 U/g, intraperitoneally twice a week for 4 wk Reduced lung fibrosis down_manip anti_fib pro_fib [See Il6 overexpression; Ayaub et al 2017]
Elevated IL6 transcripts in IPF lungs		 Chen et al 2016 27317687
Il9 ENSMUSG00000021538 FVB Overexpression of Il9 NA NA BLM 0.05 or 0.5 U, intratracheally single dose, follow-up 0-21 days Reduced lung injury and mortality up_manip other invalid In BLM-treated transgenic mice, TGF-β and PGE2 levels in broncho-alveolar lavage fluid were increased [See Alox5]
[with a reference to Nakao et al 1999]: In a murine model of BLM-induced lung fibrosis, inhibition of TGF-β signaling prevented fibrotic response but did not affect severety of lung inflammation		 Arras et al 2005 15632004
Il10 ENSMUSG00000016529 C57BL/6 KO Il10 male 9 wk BLM 100 mg/kg via osmotic pumps single dose, follow-up 0-28 days Reduced lung fibrosis down_manip anti_fib pro_fib [See CD25; the same paper] Kamio et al 2018 29690905
Il11 (IL-11 protein) ENSMUSG00000004371 C57BL/6 anti-IL-11 antibodies X203 male 8-10 wk BLM 1 mg /kg, oropharyngeally;
anti-IL-11 antibodies X203 20 mg /kg, intraperitoneally (to WT)		 BLM single dose, follow-up 0-21 days;
anti-IL-11 antibodies X203 only in WT mice for pereventing & therapeutic targeting of IL-11 protein:
1) prevention: injections once daily on Day 7, 9, 11, 14, 16, 18 (7 days post BLM); follow up 7-21 days
2) therapeutic: injections once daily on Day 14, 16, 18, 21, 23, 25 (14 days post BLM); follow up 0-28 days		 [see Il11ra1 KO; the same paper]
Targeting of IL-11 by anti-IL-11 antibodies X203 prevented and reversed lung fibrosis in WT mice		 down_manip_manual anti_fib pro_fib
Hydroxyproline was greatly reduced in X203-treated WT mice.
Of note, IL11 protein was up-regulated in IPF lungs
Ng et al 2019 31554736
Il13 MGP_BALBcJ_G0018241
ENSMUSG00000020383		 Balb/c (KO)
C57BL/6 & Balb/c (WT)		 KO Il13-/- male 12-18 wk BLM 6 U/kg in 50 μl of saline, intradermally one dose daily for 5 days/wk, totally 4 wk Reduced lung inflammation and fibrosis down_manip anti_fib pro_fib KO Il13 inhibited MMP2 and MMP9 activity.
The enhanced protein levels of IL-13 in IPF lungs; these levels inversely correlated with lung function [Chandriani et al 2014; PMID:24879793]		 Singh et al 2017 28775096
Il11ra1
(gene & protein)		 ENSMUSG00000073889 C57BL/6 KO Il11ra1-/-
anti-IL-11 antibodies X203		 male 8-10 wk BLM 1 mg /kg, oropharyngeally;
anti-IL-11 antibodies X203 20 mg /kg, intraperitoneally (to WT)		 BLM single dose, follow-up 0-21 days;
anti-IL-11 antibodies X203 only in WT mice for pereventing & therapeutic targeting of IL-11 protein:
1) prevention: injections once daily on Day 7, 9, 11, 14, 16, 18 (7 days post BLM); follow up 7-21 days
2) therapeutic: injections once daily on Day 14, 16, 18, 21, 23, 25 (14 days post BLM); follow up 0-28 days		 Reduced lung fibrosis;
Targeting of IL-11 by anti-IL-11 antibodies X203 prevented and reversed lung fibrosis in WT mice		 down_manip anti_fib pro_fib
[See anti-IL-11 antibodies; the same paper]
Hydroxyproline was greatly reduced in X203-treated WT mice.
Of note, IL11 protein was up-regulated in IPF lungs
Ng et al 2019 31554736
Il13ra2 ENSMUSG00000031289 C57BL/6 Overexpression of Il13ra2 NA 6-8 wk BLM 1 U/kg, intratracheally single dose, follow-up 0-14 days Reduced lung fibrosis up_manip anti_fib anti_fib In vitro: Il13ra2 overexpression inhibited the IL-13 induction of fibrotic markers Lumsden et al 2015 25659898
Il17a
(gene & protein)		 ENSMUSG00000025929 C57BL/6 KO Il17a-/-;
anti‐IL‐17A monoclonal
mouse antibody		 male 6-8 wk BLM 4 mg/kg in 40 μL saline, intratracheally;
HSV-1 (herpes simplex virus) 5x105 mixed in 40 μl DMSO → 10 μl suspension, intranasally;
TUDCA 250 mg/kg (ERS inhibitor), intraperitoneally		 BLM single dose (no separate BLM group);
HSV-1 once daily, from Day 21 to Day 24 (4 times) after BLM (BLM+HSV-1 group);
TUDCA once daily, from Day 21 to Day 28
(BLM+HSV-1+TUDCA group);
Follow-up 0-28 days		 Reduced lung inflammation and fibrosis (in both groups);
Reduced mortality in BLM+HSV-1 group 		down_manip anti_fib pro_fib Anti‐IL‐17A antibody treatment and IL‐17A gene KO alleviate UPR in lung tissue In their previous studies, they used twice intratracheal administration of BLM to successfully establish a mouse model of noninfection‐induced AE‐PF [Wei et al 2016; Chen et al 2017]. They found that IL17A levels in the BALF of mice with BLM+BLM‐induced AE‐PF were increased significantly vs the mice with stable BLM‐induced PF. Consequently, i.p. injection of anti‐IL‐17A antibody alleviated lung inflammation.
HSV-1 could promote acute lung damage via UPR, without exacerbation of BLM-induced fibrosis (UPR ‒ Unfolded Protein Response).
TUDCA ‒ Tauroursodeoxycholic acid; a classic inhibitor of Endoplasmic Reticulum Stress.
TUDCA inhibited HSV1 infection‐induced acute lung injury in a mouse model of pulmonary fibrosis.
IL‐17A may promote ERS in lung tissue. The ERS inhibitor TUDCA reduced IL‐17A production and attenuated the lung tissue damage during AE‐PF in mice		 Chen et al 2019 30378252
Il17a ENSMUSG00000025929 Balb/c (WT) C57BL/6J (WT & KO) KO Il17a-/- male 4-6 wk BLM 2 U/kg, intratracheally single dose, follow-up 0-21 days Reduced lung fibrosis down_manip anti_fib pro_fib Reduced lung fibroblast apoptosis in BLM-treated KO C57BL/6J mice In contrast to C57BL/6J WT mice, BLM-treated WT Balb mice showed minimal peripheral deposition of collagen fibers.
In IL-17 receptor A KO mice, the peripheral deposition of ECM by myofibroblasts of the fibrosis-susceptible C57BL/6J murine strain does not change in the late stage of lung fibrosis but did induce type V collagen overexpression.
IL-17A expression increased in IPF lungs [Wilson et al 2010; PMID:20176803]		 Fabro et al 2015 25172545
Il17a ENSMUSG00000025929 C57BL/6 KO Il17a-/-
anti-IL-17 mAb		 NA 8-10 wk BLM 2 mg/kg, intratracheally anti-IL-17 mAb 100 mg or 200 mg per mouse, i.p single dose, follow-up 0-21 days Promoted lung fibrosis down_manip pro_fib anti_fib BLM-induced lung fibrosis was more severe in Il17a-/- mice and in Tlr2-/- mice treated with anti-IL-17 mAb than in Tlr2-/- and WT mice untreated with anti-IL-17 mAb TLR2 signaling promotes BLM-induced lung fibrosis by inducing IL-27 and chemokine production by respiratory epithelial cells, thereby inhibiting IL-17 production and recruiting inflammatory cells into the lungs. Kim et al 2011 21930967
Inpp5d (Ship1) ENSMUSG00000026288 C57BL/6 KO Inpp5d-/- (Ship1-/-);
KO Mir155		 male and female 6-10 wk BLM 3 mg/kg, intratracheally single dose, follow-up 0-28 days Promoted lung inflammation and fibrosis down_manip pro_fib anti_fib Reduced EndoMT [See Mir155 KO; the same paper]
Deletion of Inpp5d (Ship1), a miR-155 target gene, causes spontaneous lung inflammation and fibrosis in mice		 Tang et al 2019 31907997
Irf7 ENSMUSG00000025498 C57BL/6J KO Irf7 female 8 wk BLM 0.02 units/day, subcutaneously BLM once daily, 6 days per week for 4 weeks; follow-up 0-28 days Reduced lung inflammation and fibrosis down_manip anti_fib pro_fib In KO mice, hydroxyproline content, dermal thickness as well as Col1a2, Acta2 and Il6 mRNA levels were attenuated Wu et al 2019 31439591
Itga3 ENSMUSG00000001507 C57BL6/129 KO Itga3 NA 6 wk BLM 1.3 U/kg, endotracheally (intratracheally) single dose, follow-up 0-21days Unaltered acute response to BLM, but reduced lung inflammation and fibrosis down_manip anti_fib pro_fib KO mice exhibited markedly decreased accumulation of lung myofibroblasts and type I collagen Kim Ket al 2009 19104148
Itln1
(Omentin-1;
Intelectin-1)		 ENSMUSG00000038209 C57BL/6 Overexpression of Omentin-1
(Itln1)		 female 8 wk BLM 3.5mg/kg, intratracheally single dose, follow-up 0-3 days Reduced lung inflammation and injury up_manip other invalid Zhou et al 2018 30245266
Kl (Klotho) ENSMUSG00000058488 C57BL/6 Overexpression of Kl NA 6 mo BLM 1.25 U/kg, oropharyngeally single dose, follow-up 0-21 days Reduced lung inflammation and fibrosis up_manip anti_fib anti_fib [See KO Kl+/- ; the same paper] [Klotho is longevity-associated gene (LAG) and tumor suppressor]
In IPF lungs, downregulation of Klotho may contribute to fibrosis and inflammation.
NB! FGF23 (fibroblast growth factor 23) may act as a compensatory antifibrotic and anti-inflammatory mediator via inhibition of TGF-β signaling.
Kl overexpression attenuated the IL-18-induced cellular senescence of lung fibroblasts, as indicated by the decrease in SA-β-gal-positive cells, expression of p21 and p53 and inhibition of SASP (senescence-associated secretory phenotype) (decreased content of IL-6, IL-1β, and FGF23 in supernatants of primary lung fibroblasts [Zhang et al 2019; PubMed 30870716]		 Barnes et al 2019 31042083
Kl (Klotho) ENSMUSG00000058488 S129J KO Kl+/- NA 6 mo BLM 1.25 U/kg, oropharyngeally single dose, follow-up 0-21 days Promoted lung inflammation and fibrosis down_manip pro_fib anti_fib [See Kl overexpression; the same paper] [Klotho is LAG and tumor suppressor]
In IPF lungs, downregulation of Klotho may contribute to fibrosis and inflammation.
NB! FGF23 (fibroblst growth factor 23) may act as a compensatory anti-fibrotic and anti-inflammatory mediator via inhibition of TGF-β signaling		 Barnes et al 2019 31042083
Klf4 ENSMUSG00000003032 FVB Overexpression of Klf4 male 8-11 wk BLM 5 mg/kg, intratracheally Double dose -- on Day 0 and Day 8, follow-up 0-21 days Reduced lung fibrosis up_manip anti_fib anti_fib Klf4 overexpression attenuates lung fibrosis via Inhibiting EMT [See KO Klf4; Cowan et al 2010] [See also Mir145a KO; Yang et al 2013]
The expression of KLF4 was decreased in lungs of IPF patients.
NB! Klf4 is one of the Yamanaka factors		 Lin et al 2017 29158503
Klf4 ENSMUSG00000003032 C57BL6/J KO Klf4 male and female 6-8 wk LPS 7.5 mg/kg, intratracheally single dose Follow-up 0-18 hours Promoted lung injury, edema and inflammation down_manip other invalid [See Klf4 overexpression; Lin et al 2017] [See also Mir145a KO; Yang et al 2013]
NB! One of the Yamanaka factors		 Cowan et al 2010 20724706
Lclat1 ENSMUSG00000054469 C57BL/6J Overexpression of Lclat1 male 8 wk BLM 2 U/kg, intratracheally single dose, follow-up 0-21 days Reduced lung fibrosis up_manip anti_fib anti_fib The increased Lclat1 expression in IPF lung fibroblasts and upregulation in IPF lungs.
In vitro: Overexpression of Lclat1 in human lung fibroblasts ameliorated TGF-β-mediated mitochondrial superoxide formation and fibroblast-to-myofibroblast differentiation.		 Huang et al 2017 28751023
Loxl1 ENSMUSG00000032334 B6N(Cg) KO Loxl1-/- NA 8-20 wk AdTGF-β1 (overexpression of TGF-β1 using adenoviral (Ad) gene transfer) 5x108 pfu, intratracheally single dose, follow-up 0-35 days Reduced lung fibrosis down_manip anti_fib pro_fib The inflammatory profiles were comparable between KO Loxl1-/- and WT mice Loxl1 was overexpressed in active fibrotic regions of BLM-treated mice [Ovet et al 2014; PMID 25349139]. LOXL1 was up-regulated in BLM-induced lung fibrosis, and also in human IPF lungs in areas of active fibrosis and fibroblastic foci Bellaye et al 2018 29115860
Lpar1 ENSMUSG00000038668 C57Bl/6 × 129Sv/J KO Lpar1 NA NA BLM 0.05 or 0.075 U, intratracheally single dose, follow-up 0-14 days Reduced lung injury and fibrosis down_manip anti_fib pro_fib They found that LPA levels were elevated in bronchoalveolar lavage (BAL) samples from individuals with IPF and that the fibroblast chemotactic activity present in these samples was dependent on fibroblast LPA1 Tager et al 2007 18066075
Lpar2 ENSMUSG00000031861 B6129SF2/J KO Lpar2-/- male 8-10 wk Bleomycin sulfate 1.25 - 2 U/kg, intratracheally single dose, follow-up 0-21 days Reduced lung injury, inflammation, fibrosis and mortality down_manip anti_fib pro_fib The LPA2 mRNA expression was not significantly changed in fibroblasts from patients with IPF
[Renzoni et al 2004; PMID:15571627]		 Huang et al 2013 23808384
Lrg1 ENSMUSG00000037095 C57BL/6 KO Lrg1 female 8-12 wk BLM 1.5 mg/kg, intratracheally single dose, follow-up 0-21 days Reduced lung fibrosis down_manip anti_fib pro_fib In KO mice, phosphorylation of Smad2 and expression of alpha-SMA were decreased.
LRG protein was upregulated in IPF lungs [Niu et al 2017,PMID: 28122020] 		Honda et al 2017 29279415
Lrp5 ENSMUSG00000024913 C57BL/6 KO Lrp5-/- male 8-12 wk BLM 1.5 U/kg in 50 ml saline, intratracheally;
LiCl 200 mg/kg in 200 ml of PBS, intraperitoneally		 BLM single dose;
LiCl once a day either on Day 0-6 or on Day 7-21 		Reduced lung fibrosis induced both by BLM and LiCl down_manip anti_fib pro_fib NB! LiCl was used to activate β-Catenin to promote BLM-induced lung fibrosis Sennello et al 2017 27668462
Ltbp3 ENSMUSG00000024940 NA Overexpression of Ltbp3 female 8-10 wk BLM 1.5 U/kg, intratracheally single dose, follow-up 0-28 days Reduced lung inflammation and fibrosis up_manip anti_fib anti_fib [See TGF-β1 protein inhibition; Weng et al 2018]
Ltbp3 -- Latent Transforming Growth Factor Beta Binding Protein 3 (inhibits TGF-β1 protein)		 Tang et al 2014 24885478
Ltc4s ENSMUSG00000020377 BALB/c Overexpression of Ltc4s NA NA BLM sulfate 5 mg/kg, intratracheally single dose, follow-up 0-14 days Promoted lung inflammation and fibrosis up_manip pro_fib pro_fib [See Alox5; Peters-Golden et al 2002]
Ltc4s -- Leukotriene C4 Synthase		 Hirata et al 2013 23432979
Malat1 ENSMUSG00000092341 C57BL/6 KO/KD Malat1mye-/- male 8 wk BLM 1.5 U/kg intratracheally;
LPS 5 - 10 mg/kg, intratracheally		 BLM single dose, follow-up 0-21 days;
LPS single dose, follow-up 48 hours		 Promoted BLM-induced lung inflummation and fibrosis;
Reduced LPS-induced acute lung injury and inflammation
down_manip pro_fib anti_fib Cui et al 2019 30676324
Map1lc3b ENSMUSG00000031812 B6 KO Map1lc3b-/- NA 13 wk and 42 wk BLM 1.5 U/kg, intratracheally single dose, follow-up 0-14 days Promoted lung fibrosis in middle-age (42-wk-old) mice, but not in young (13-we-old) mice down_manip pro_fib anti_fib [See Ctsa overexpression; the same paper]
[NB! Age-related differences in response to BLM]		 Kesireddy et al 2019 31431059
Map3k19 protein ENSMUSG00000051590 C57BL/6J Inhibition of MAP3K19 by Dexamethasone or Compound A female 8 wk Bleomycin sulfate 3 U/kg, intratracheally;
Dexamethasone (inhibitor of Map3k19) 3 mg/kg, intraperitoneally;
Compound A (inhibitor of Map3k19) 10 mg/kg, orally		 Bleomycin sulfate single dose;
Dexamethasone every two days from Day 6 to Day 13;
Compound A daily from Day 6 to Day 13 days;
Follow-up 0-14 days		 Reduced lung inflammation and fibrosis down_manip anti_fib pro_fib MAP3K19 is highly expressed in pulmonary macrophages isolated from human IPF patients Boehme et al 2016 27144281
Mapkapk2 ENSMUSG00000016528 C57BL/6J KO Mapkapk2-/-
(only in fibroblasts)		 NA NA BLM 3 U/kg in 50 μl saline, intratracheally single dose, follow-up 0-14 days Promoted lung fibrosis down_manip pro_fib anti_fib [See Mapkapk2 KO; Liang et al 2019] [NB! Discripancy with Liang et al 2019 -- maybe due to KO in fibroblasts only]
Higher levels of collagen in fibrotic regions in the lungs of BLM-treated KO mice		 Liu et al 2007 17600313
Mapkapk2 (Mk2) ENSMUSG00000016528 C57BL/6J KO Mapkapk2 NA NA BLM 2.5 U/kg, intratracheally;
MMI-0100 (MK2 inhibitor) 37.5 μg/kg, intraperitoneally to WT		 BLM single dose;
MMI-0100 once a day, 3-21 days after BLM -- WT only;
Follow-up 0-21 days 		Reduced lung fibrosis down_manip anti_fib pro_fib MK2 inhibition attenuated hyaluronan accumulation and reduced collagen content in
BLM-injured WT mouse lungs, and eventually reduced lung fibrosis in WT mice		 [See Mapkapk2-/- KO; Liu et al 2007] [NB! Discripancy with Liu et al 2007]
The increased levels of activated MK2 were found in IPF lungs and in the mouse BLM model of lung fibrosis		 Liang et al 2019 30130411
Mcat ENSMUSG00000048755 C57Bl/6 J Overexpression of Mcat male and female 8-10 wk BLM 0.025 units/50 μL saline, intratracheally;
Crocidolite asbestos 100 μg/50 μL saline, intratracheally 		single dose of BLM or Crocidolite asbestos (separately); Follow-up 0-21 days Reduced lung fibrosis up_manip anti_fib anti_fib Mcat overexpression reduced lung fibrosis and ROS-induced AEC mtDNA damage and apoptosis in Crocidolite-exposed mice Kim et al 2016 27840320
Mep1a ENSMUSG00000024313 NA KO Mep1a NA NA BLM 3 U/kg intratracheally single dose, follow-up 0-14 days Did not alter the inflammatory and fibrotic responses down_manip other invalid [See KO Mep1b and Mep1a+b; the same paper]
Reduced collagen deposition and tissue density in Mep1b KO, but not in Mep1a or double (Mep1a+b) KO mice.
They did not detect any substantial changes in meprins expression in IPF lung homogenates vs donor samples		 Biasin et al 2017 28059112
Mep1b ENSMUSG00000024313 NA KO Mep1b NA NA BLM 3 U/kg intratracheally single dose, follow-up 0-14 days Reduced lung fibrosis, but did not alter the inflammatory response down_manip anti_fib pro_fib [See KO Mep1b and Mep1a+b; the same paper]
Reduced collagen deposition and tissue density in Mep1b KO, but not in Mep1a or double (Mep1a+b) KO mice.
They did not detect any substantial changes in meprins expression in IPF lung homogenates vs donor samples		 Biasin et al 2017 28059112
Mfn1 ENSMUSG00000027668 C57BL/6 KO Mfn1-/- NA 12 wk BLM 0.5 - 0.75 mg/kg, intratracheally single dose, follow-up 0-14 days Promoted lung fibrosis down_manip pro_fib anti_fib [See KO Mfn2-/-; the same paper] Chung et al 2019 31358769
Mfn2 ENSMUSG00000029020 C57BL/6 KO Mfn2-/- NA 12 wk BLM 0.5 - 0.75 mg/kg, intratracheally single dose, follow-up 0-14 days Promoted lung fibrosis down_manip pro_fib anti_fib [See KO Mfn1-/-; the same paper] Chung et al 2019 31358769
Mir29b ENSMUSG00000065604 C57BL/6J Overexpression of Mir29b in
the lungs		 female 8-10 wk BLM 1.5 U/kg, intratracheally single dose, follow-up 0-28 days Reduced lung inflammation and fibrosis up_manip anti_fib anti_fib [See Smad3 KO; Gu et al 2007 and Zhao et al 2002; and Smad3 protein inhibition -- Shou et al 2018]
Gene transfer of miR-29 inhibits BLM-induced lung fibrosis by suppressing TGF-β/Smad3.
miR-29 family members are downregulated in BLM-treated lungs (Cushing et al 2011).
Delivery of miR-29 mimics during BLM-induced lung fibrosis restored endogenous miR-29 function whereby decreasing collagen expression and blocking and reversing lung fibrosis (Montgomery et al 2014).
miR-29a and miR-29c is downregulated in lung fibroblasts from patient with IPF and IPF lungs (Miao et al 2018)		 Xiao et al 2012 22395530
Mir34a ENSMUSG00000065493 C57BL/6 KO Mir34a male or female 11-12 wk BLM 1.5 U/kg in 0.1 mL saline, oropharyngeally single dose, follow-up 0-56 days Promoted lung injury and fibrosis down_manip pro_fib anti_fib [See Mir34a-/- KO; Cui et al 2017a,b; PMID 27635790 and 27979858]
[See alo Cflar (C-Flip) overexpression; Golan-Gerstl et al 2012]
Forced upregulation of miR-34 with miR-34 mimic in human IPF fibrotic-lung myofibroblasts decreased cell survival through downregulation of FLIP (FLICE-like inhibitory protein).
Inverse correlation between miR-34a levels and its target protein FLIP (FLICE-like inhibitory protein) in human IPF lung myofibroblasts and BLM model → the more FLIP, the more severe lung fibrosis.
In vitro: IPF lung fibroblasts transfected with mimic-miR34a substantially reduced FLIP protein levels and decreased cell survival (the latter was suggested to be attributed to FLIP).
miR-34a is upregulated in AECs from the lungs of IPF patients and IPF model mice (Miao et al 2018)		 Bulvik et al 2020 32210149
Mir34a ENSMUSG00000065493 C57BL/6 KO Mir34a-/- male 10-12 wk BLM 1.5 U/kg in 50 μl saline, intratracheally single dose, follow-up 0-21 days Promoted lung fibrosis down_manip pro_fib anti_fib signaling [NB on possible age-related effects! See Cui et al 2017b, PMID 27979858 and Bulvik et al 2020]
[See Cflar (C-Flip) overexpression; Golan-Gerstl et al 2012]
miR34a targets multiple genes that regulate cellular senescence markers: SA-β-gal, p21 and pai1 (plasminogen activator inhibitor 1);
20 months vs 10-12 wk -- antagonictic pleiotropy?!
Greater expression of miR-34a in IPF lungs.
[See Cflar (C-Flip) overexpression; Golan-Gerstl et al 2012] 		Cui et al 2017a 27635790
Mir34a ENSMUSG00000065493 C57BL/6 KO Mir34a-/- male 20 months BLM 1.5 U/kg in 50 μl saline, intratracheally single dose, follow-up 0-21 days Reduced lung fibrosis down_manip anti_fib pro_fib Reduced senescent phenotype in alveolar epithelial cells of BLM-treated aged KO mice [NB on possible age-related effects! See Cui et al 2017a, PMID 27635790 and Bulvik et al 2020]
[See Cflar (C-Flip) overexpression; Golan-Gerstl et al 2012]
miR34a targeted Sirt1, a master anti-aging regulator, and multiple genes that regulate cellular senescence (CS markers: SA-β-gal, p21 and pai1 (plasminogen activator inhibitor 1);
20 months vs 10-12 wk -- antagonictic pleiotropy?!
Greater expression of miR-34a in IPF lungs.
[See Cflar (C-Flip) overexpression; Golan-Gerstl et al 2012]		 Cui et al 2017b 27979858
miR-34b-5p [?] C57BL/6 miR-34b-5p knockdown;
KO Timp3-/-		 male 6-8 wk BLM 1 - 1.5 U/kg, intratracheally;
Antagomir (anti-miR-34b-5p oligonucleotide)		 single dose, follow-up 0-18 days Reduced lung fibrosis down_manip anti_fib pro_fib [see Timp3; the same paper]
miR-34b-5p knockdown appears to enhance the resistance to BLM-induced lung fibrosis through enhancing the mRNA (qPCR) and protein (Western blotting) levels of its target gene Timp3		 Hu et al 2019 30915776
Mir145a ENSMUSG00000065592 C57BL/6 KO Mir145a-/- NA NA BLM 1 U/kg in 40 μL of saline, intratracheally single dose, follow-up 0-14 days Reduced lung fibrosis down_manip anti_fib pro_fib miR-145 target gene KLF4 is a known negative regulator of α-SMA expression.
NB! Klf4 is one of the Yamanaka factors. [See KO Klf4; Cowan et al 2010; Lin et al 2017]
miR-145 was expressed at higher levels in IPF lungs.
In vitro: Overexpression of miR-145 in human lung fibroblasts increased α-SMA expression, enhanced contractility, and promoted formation of focal and fibrillar adhesions.
In contrast, miR-145 deficiency diminished TGF-β1 induced α-SMA expression.
miR-145 did not affect the activity of TGF-β1, but promoted the activation of latent TGF-β1.		 Yang et al 2013 23457217
Mir155 ENSMUSG00000065397 C57BL/6 KO Mir155-/-
LXRα antagonist
[LXRα -- the target gene of miR-155]		 NA NA BLM 0.06 U/25 g in 30 μl, intranasally;
LXRα antagonist 22(S) hydroxycholesterol [22(S)HC] 30 mg/kg, i.p. (was dissolved in a 40% solution of 2-hydroxypropyl-β
cyclodextrin in water)
[LXRα -- the target gene of miR-155]
 BLM single dose;
LXRα antagonist 22(S)HC started 2 days before BLM and continued one dose daily, 20 days in total;
Follow-up 0-18 days		 Promoted lung inflammation and fibrosis down_manip pro_fib anti_fib LXR antagonist 22(S)HC reduced BLM-induced lung inflammation and fibrosis
in miR-155-/- mice 		[NB! Contradictory effects with Tang et al 2019] [!See Nr1h3 (Lxra) antagonist; the same paper]
miR155 KO enhanced the mRNA (qPCR) and protein (Western blotting) levels of its target gene LXRα → enhanced collagen 1 and 3 deposition in lungs, TGF-β1 production, and enhanced the alternative activation of macrophages.
In vitro: human primary IPF or normal fibroblasts were transfected with miR-155 mimic or treated with synthetic LXRα agonist GW3965 or antagonist 22(S)HC → (i) LXRα exacerbated fibrotic phenotype of IPF fibroblasts; (ii) LXRα antagonist reduced IPF fibroblast proliferation and migration; (iii) Primary IPF lung fibroblasts had constitutively raised LXRα, deregulated from miR-155, and their pro-fibrotic phenotype was inhibited by LXRα antagonist, LXRα gene silencing or exogenous miR-155 mimic.
They suggested that manipulation of the miR-155/LXR pathway may have therapeutic potential for IPF. 		Kurowska-Stolarska et al 2016 27746237
Mir155 ENSMUSG00000065397 C57BL/6 KO Mir155;
KO Inpp5d-/- (Ship1-/-)		 male and female 6-10 wk BLM 3 mg/kg, intratracheally single dose, follow-up 0-28 days Reduced lung inflammation and fibrosis down_manip anti_fib pro_fib Reduced EndoMT [NB! Contradictory effects with Kurowska-Stolarska et al 2016]
[See also KO Inpp5d (Ship1); the same paper]
Deletion of Inpp5d (Ship1), a miR-155 target gene, causes spontaneous lung inflammation and fibrosis in mice [see Inpp5d (Ship1)]		 Tang et al 2019 31907997
Mmp7 ENSMUSG00000018623 C57BL/6
129Sv		 KO Mmp7-/- male 8-16 wk 129Sv and
14-23 wk C57BL/6		 BLM 0.05–0.08 U, intratracheally single dose, follow-up 0-21 days Reduced lung fibrosis down_manip anti_fib pro_fib [See KO Mmp7; Nareznoi et al 2020]
In both mouse strains, hydroxyproline content in lungs was lower in KO vs WT		 Zuo et al 2015 11983918
Mmp7 ENSMUSG00000018623 C57BL/6 KO Mmp7 male 11-12 wk BLM 0.08 U, oropharyngeally single dose, follow-up 0-14 days Reduced lung fibrosis down_manip anti_fib pro_fib [See KO Mmp7; Zuo et al 2015]
MMP-7 expression is elevated in human IPF lungs [Cosgrove et al 2002; PMID:11893661]		 Nareznoi et al 2020 32053892
Mmp9 ENSMUSG00000017737 C57BL/6 Overexpression of Mmp9 NA 8-10 wk BLM 0.13 U/ 10 g in 50 μl saline, intratracheally single dose, follow-up 0-16 wk Reduced lung inflammation and fibrosis up_manip anti_fib anti_fib TG mice expressed Mmp9 in alveolar macrophages.
In IPF, MMP9 was highly expressed in the lungs and BAL fluids and localized mainly to epithelial cells, neutrophils, and alveolar macrophages [Selman et al 2000,PMID:10956632]		 Cabrera et al 2007 17702637
Mmp19 ENSMUSG00000025355 C57BL/6/ × 129O1 KO Mmp19-/- NA NA BLM 0.05 U/10 g, intratracheally single dose, follow-up 0-21 days Reduced lung inflammation and promoted lung fibrosis down_manip anti_fib pro_fib [Unusial response!]
They discovered that MMP-19 was significantly increased in hyperplastic epithelial cells adjacent to fibrotic regions in IPF lungs		 Yu et al 2012 22859522
Mmp28 ENSMUSG00000020682 C57BL/6 KO Mmp28-/- male 8-12 wk BLM 0.0017 - 0.0025 U/g, intratracheally single dose, follow-up 0-28 days Reduced lung fibrosis down_manip anti_fib pro_fib Gharib et al 2013 23964118
MTOR (protein) ENSMUSG00000028991 PVB Inhibition of MTOR protein
by Rapamycin		 male 8-11 wk BLM 5 mg/kg, intratracheally;
Rapamycin 4 mg/kg, intraperitoneally 		BLM single dose;
Rapamycin once daily, two days before BLM;
Follow-up 0-21 days 		Reduced lung fibrosis down_manip anti_fib pro_fib Rapamycin suppressed EMT both in vitro and in vivo Rapamycin effect on EMT -- suggested as a novel mechanism by which MTOR inhibitor
ameliorates lung fibrosis		 Han et al 2018 29704504
Muc5b ENSMUSG00000066108 C57BL/6J Overexpression of Muc5b male and female 8-12 wk BLM 1.0 - 1.5 - 2.5 U/kg at different time points, intratracheally Three groups:
- BLM single dose of 2.5 U/kg on D0; Follow-up 0-70 days;
- BLM three administrations: 2.5 U/kg on D0, 1.5 U/kg on D14 and 1.5 U/kg on D28; Follow-up 0-49 days;
- BLM three administrations: 2.0 U/kg on D0, 1.0 U/kg on D14 and 1.0 U/kg D28; Follow-up 0-49 days		 Promoted lung fibrosis up_manip pro_fib pro_fib [See KO Muc5b; the same paper]
Muc5b is overexpressed in IPF lungs		 Hancock et al 2018 30560893
Muc5b ENSMUSG00000066108 C57BL/6J KO Muc5b+/- or Muc5b-/- male and female 8-12 wk BLM 1.0 - 1.5 - 2.5 U/kg at different time points, intratracheally Three groups:
- BLM single dose of 2.5 U/kg on D0; Follow-up 0-70 days;
- BLM three administrations: 2.5 U/kg on D0, 1.5 U/kg on D14 and 1.5 U/kg on D28; Follow-up 0-49 days;
- BLM three administrations: 2.0 U/kg on D0, 1.0 U/kg on D14 and 1.0 U/kg D28; Follow-up 0-49 days		 Reduced lung fibrosis down_manip anti_fib pro_fib [See Muc5b overexpression; the same paper]
Muc5b is overexpressed in IPF lungs		 Hancock et al 2018 30560893
Myd88 ENSMUSG00000032508 C57BL/6J KO Myd88 female 8-11 wk BLM sulfate 0.06 mg in 50 μL PBS per mouse, intratracheally single dose, follow-up 0-28 days Reduced lung inflammation and fibrosis down_manip anti_fib pro_fib KO Myd88 reduced the TGF-β1 protein level in pulmonary cells Li et al 2017 28662409
Ncf1 ENSMUSG00000015950 C57BL/6J KO Ncf1-/- NA 10 wk Bleomycin sulfate 50 μL/mouse, intranasally single dose, follow-up 0-14 days Promoted acute inflammatory response but did not develop lung fibrosis down_manip pro_fib anti_fib The absence of collagen deposition in KO mice seems to be associated with an elevated MMP-9/TIMP-1 ratio in the lungs [see Timp1, Mmp7 & Mmp19] Manoury et al 2005 15663794
Neu3 ENSMUSG00000035239 C57BL/6 KO Neu3-/- male and female 7-9 wk and 18 wk BLM 3 U/kg, oropharyngeally single dose, follow-up 0-21 days Reduced lung fibrosis down_manip anti_fib pro_fib They consistently found elevated levels of NEU3 protein in the fibrotic lesions in human (IPF) and mouse lungs [Karhadkar et al 2017; PMID: 29118338] Karhadkar et al 2019 31617733
Nfe2l2 (Nrf2) ENSMUSG00000015839 C57BL/6 KO Nfe2l2-/- NA NA BLM 4.5 mg/kg, intratracheally single dose, follow-up 0-28 days Promoted lung fibrosis down_manip pro_fib anti_fib Activating Nrf2 antioxidant pathway could effectively alleviate the EMT by increasing
the level of Numb protein → inhibits E-cadherin		 Zhang et al 2018 29362432
Nfe2l2 (Nrf2) ENSMUSG00000015839 C57BL/6 KO Nfe2l2-/- NA NA BLM 4.5 mg/kg, intratracheally single dose, follow-up 0-28 days Promoted lung fibrosis down_manip pro_fib anti_fib KO Nrf2 promoted EMT by activating Snail expression Zhou et al 2016 27982105
Ninj1 ENSMUSG00000037966 C57BL/6J KO Ninj1-/- male 8-10 wk BLM 1 mg/kg, intratracheally
single dose, follow-up 0-14 days Reduced lung inflammation and fibrosis down_manip anti_fib pro_fib Ninj1 expression increased in BLM-treated WT macrophages and alveolar epithelial cells (AECs).
Ninj1 gene expression level was increaseded in IPF lungs		 Choi et al 2018 30510259
Nos1 ENSMUSG00000029361 C57BL/6 triple & single KO Nos-/- or n/i/eNos-/- or eNos-/- male 7-8 wk BLM 8 mg/kg, intraperitoneally one dose daily for 10 consecutive days;
follow-up 0-10 days		 Promoted lung fibrosis: fibrotic changes were the greatest in the n/i/eNOS-/- mice and the lowest in the single Nos-/- mice down_manip pro_fib anti_fib Noguchi et al 2014 25092105
Nos2 ENSMUSG00000020826 C57 BL6/J KO Nos2-/- male 10 wk Bleomycin sulfate 3.0 U/kg in 50 μl saline, intratracheally single dose, follow-up 0-21 days Reduced early stage of inflammation, but promoted
long-term inflammation and lung fibrosis 		down_manip pro_fib anti_fib Guo et al 2016 26526764
Nos2
(gene and protein)		 ENSMUSG00000020826 CD KO Nos2
Inhibition of Nos2 protein		 NA NA Bleomycin sulfate 1 mg/kg, intratracheally;
GW274150 (inhibitor of Nos2) 5 mg/kg, intraperitoneally 		Bleomycin sulfate single dose;
GW274150 once a day, Day 1-15 (only to WT);
Follow-up 0-15 days 		Reduced lung inflammation, fibrosis and mortality;
GW274150 prevented lung inflammation and reduced collagen production in BLM-treated WT mice 		down_manip anti_fib pro_fib Genovese et al 2005 15955252
Nos3 ENSMUSG00000028978 C57/BL6 Overexpression of Nos3 NA NA Bleomycin hydrochloride 1 U/body/day in 200 µL of PBS, intraperitoneally Every other day, four doses in total, started on Day 0;
follow-up 0-14 days		 Reduced lung inflammation and fibrosis up_manip anti_fib anti_fib Overexpression of Nos3 by the endothelium impairs MMP-9/ TIMP-1 balance Yoshimura et al 2006 16916326
Nox4 ENSMUSG00000030562 NA Overexpression of Nox4 NA NA BLM 5 mg/kg, intratracheally;
Schizandrin B (Sch B) 100 mg/kg (10 mL/kg), orally;
Glycyrrhizic acid (GA) 75 mg/kg (10 mL/kg), orally;
Schizandrin B + Glycyrrhizic acid 100 mg/kg + 75 mg/kg, orally		 BLM single dose;
Schizandrin B once a day, 1-28 days;
Glycyrrhizic acid once a day, 1-28 days;
Schizandrin B + Glycyrrhizic acid once a day, 1-28 days;
Follow-up 0-28 days		 Promoted lung fibrosis up_manip pro_fib pro_fib Sch B and GA ameliorated the BLM-induced overexpression of Nox4 in both transgenic and WT mice NOX4 was expressed in thickened pulmonary arteries in IPF [Pache et al 2011; PMID: 21217672] Zhang et al 2017 28476015
Nppc ENSMUSG00000026241 C57BL/6N Overexpression of Nppc
Exogenous CNP		 male 6 wk BLM 1 mg/kg in 80 μl of saline, oropharyngeally;
CNP (C-type natriuretic peptide) 2.5 μg/kg/min, subcutaneously via an osmotic mini-pump		 BLM single dose;
CNP 24 h before BLM;
Follow-up 0-14 days		 Reduced lung inflammation and fibrosis up_manip anti_fib anti_fib CNP reduced BLM-induced lung fibrosis and inflammation in mice by suppressing
TGF-β signaling and myofibroblastic differentiation in lung fibroblasts 		In vitro: human IPF lung fibroblasts, CNP attenuated TGF-β-induced phosphorylation of Smad2 → suppresses fibroblast differentiation into myofibroblasts Kimura et al 2016 26895702
Npr1 ENSMUSG00000027931 C57BL/6 Overexpression of Npr1
Exogenous ANP		 male 7 wk BLM 1 mg/kg in 80 μl of saline, oropharyngeally;
ANP (Atrial natriuretic peptide) 0.5 μg/kg/min, subcutaneously, infused via an osmotic mini-pump		 BLM single dose;
ANP 72 h before BLM;
Follow-up 0-21 days		 Reduced lung inflammation and fibrosis;
ANP also reduced lung inflammation and fibrosis in both transgenic and WT mice		 up_manip anti_fib anti_fib [See KO Npr1; Baliga et al 2014 ]
This study is the first to show that ANP exerts anti-fibrotic and anti-inflammatory effects in
BLM-induced pulmonary fibrosis in mice via vascular endothelial cells, possibly by attenuating
the phosphorylation of Smad2 in TGF-β signaling
Okamoto et al 2017 28049526
Npr1 (NprA, Npr-A) ENSMUSG00000027931 C57BL/6 KO Npr1 male NA BLM 25 IU, oropharyngeally;
Enhance the levels of natriuretic peptide protein [see Comments]:
Ecadotril 0.3 mL
Sildenafil 30 mg/kg (both in drinking water)		 Four groups (follow-up 0-14 days):
BLM single dose (to KO & WT);
To WT only:
BLM+Ecadotril (daily), Day 0-14;
BLM+Sildenafil (daily), Day 0-14;
BML+Ecadotril+Sildenafil (daily), Day 0-14		 Promoted lung inflammation and fibrosis;
Ecadotril+Sildenafil (but not each drug alone) prevented and reversed BLM-induced fibrosis in WT mice 		down_manip pro_fib anti_fib [See Npr1 overexpression; Okamoto et al 2017]
Npr1 = Natriuretic Peptide Receptor 1.
Ecadotril & Sildenafil inhibit Neutral endopeptidase (NEP) which degrades the natriuretic peptide.
Mice receiving sildenafil+ecadotril following BML showed a clear reduction in the incidence of fibrotic damage and inflammation mediated by TGFβ, IL-1β, IL-13, and iNOS.
Not only does augmentation of natriuretic peptide signalling represent reduced disease severity, but also endogenous release of natriuretic peptide represents an intrinsic defence mechanism counteracting the progression of lung fibrosis. 		Baliga et al 2014 24641440
Nr1h3 (Lxra) ENSMUSG00000025434 C57BL/6 LXRα antagonist to Mir155 KO mice [LXRα -- the target gene of miR-155];
KO Mir155 		NA NA BLM 0.06 U/25 g in 30 μl, intranasally;
LXRα antagonist 22(S) hydroxycholesterol [22(S)HC] 30 mg/kg, i.p. (was dissolved in a 40% solution of 2-hydroxypropyl-β cyclodextrin in water)
[LXRα -- the target gene of miR155]		 BLM single dose;
LXRα antagonist 22(S)HC started 2 days before BLM and continued one dose daily, 20 days in total;
Follow-up 0-18 days		 Reduced BLM-induced lung inflammation and fibrosis in miR-155-/-
mice		 up_manip_manual anti_fib anti_fib Mir-155-/- KO promoted BLM-induced lung inflammation and fibrosis [NB! Contradictory effects with Tang et al 2019] [!See Mir155-/- KO; the same paper]
miR155 KO enhanced the mRNA (qPCR) and protein (Western blotting) levels of its target gene LXRα → enhanced collagen 1 and 3 deposition in lungs, TGF-β1 production, and enhanced the alternative activation of macrophages.
In vitro: human primary IPF or normal fibroblasts were transfected with miR-155 mimic or treated with synthetic LXRα agonist GW3965 or antagonist 22(S)HC → (i) LXRα exacerbated fibrotic phenotype of IPF fibroblasts; (ii) LXRα antagonist reduced IPF fibroblast proliferation and migration; (iii) Primary IPF lung fibroblasts had constitutively raised LXRα, deregulated from miR-155, and their pro-fibrotic phenotype was inhibited by LXRα antagonist, LXRα gene silencing or exogenous miR-155 mimic.
They suggested that manipulation of the miR-155/LXR pathway may have therapeutic potential for IPF.		 Kurowska-Stolarska et al 2016 27746237
Nrep ENSMUSG00000042834 C57BL/6 KO Nrep male 7-9 wk Bleomycin sulfate 2 U/kg, intratracheally single dose, follow-up 0-14 days Reduced lung fibrosis down_manip anti_fib pro_fib Decreased collagen deposition in lungs.
NREP expression increased TGF-β concentration/activity in mouse and human lung fibroblasts, thereby leading to an activated phenotype with increased collagen production, as seen in IPF		 Duan et al 2019 30230348
Ntn1 ENSMUSG00000020902 C57/BL6 KO Ntn1+/- NA 8 wk BLM 2.5 U/kg, orotracheally single dose, follow-up 0-14 days Reduced lung inflammation and fibrosis down_manip anti_fib pro_fib Netrins are also expressed outside the nervous system, e.g. in human leukocytes [Mirakaj et al 2014; PMID: 24863066] and together with differential expression of several Netrin-1 receptors may predict reduced event-free survival in IPF [Herazo-Maya et al 2013; PMID: 24089408] and control the development of experimentally induced lung fibrosis in mice [Karmouty-Quintana et al 2015; PMID: 25318478] Sun et al 2016 26749424
Nudt21 ENSMUSG00000031754 C57BL/6 KO Nudt21 male and female 4-7 wk BLM 0.035 U/g intraperitoneally (male);
BLM 2.5 μ/kg, oropharyngeally (female)		 BLM i.p twice a week for 4 weeks (male);
BLM o.p. single dose (female);
Follow-up 0-21 days		 Promoted lung inflammation and fibrosis in female and promoted late stages of lung fibrosis without affecting inflammation in male down_manip pro_fib anti_fib [NB! Sex-dependent changes?]
NB! Not formal coincedence with the effect of Nudt21 KO in mice and Nudt21 overexpression suppressed the expression of key profibrotic factors in IPF lung fibroblasts in vivo		 Weng et al 2019 30830875
Ogg1 ENSMUSG00000030271 C57BL/6J (WT)
C57Bl/6J × FV6 (OE)		 Overexpression of Ogg1 male or female 8-10 wk BLM 0.025 U in 50 μL normal saline, intratracheally;
Crocidolite asbestos 100-200 μg suspended in 50 μL PBS, intratracheally 		BLM single dose;
Crocidolite asbestos single dose (separately from BLM);
Follow-up 0-21 days		 Reduced lung fibrosis in both asbestos and BLM models;
Reduced mitochondrial DNA damage in both models		 up_manip anti_fib anti_fib [See Pink1 in the same paper]
Oxidative stress induces alveolar epithelial cell (AECs) Pink1 deficiency, mitochondrial DNA damage, and apoptosis of AECs -- that can be all reduced by Ogg1 overexpression.
mtDNA damage in lungs and AT2 cells is reduced in mtOgg1tg mice following asbestos exposure and lung mtDNA damage is augmented in IPF		 Kim et al 2020 32209025
Osm ENSMUSG00000058755 C57BL/6 Overexpression of Osm female 8-12 wk BLM 0.03 U/mouse, intratracheally single dose, follow-up 0-21 days Promoted lung inflammation and fibrosis up_manip pro_fib pro_fib [See IL-6 in the same paper]
Both IL-6 and OSM levels were undetectable in BALF (broncheoalveolar lavage fluid) during the fibrotic phase (day 21) of the BLM-induced model 		Ayaub et al 2017 29038604
Parp1 ENSMUSG00000026496 C57BL/6 KO Parp1-/- male 8-9 wk BLM 0.05 IU in 50 μl of saline, intratrachealy single dose, follow-up 0-21 days Reduced lung inflammation and fibrosis down_manip anti_fib pro_fib [See Parp1 KO in Hu et al 2013] Durante et al 2019 31164820
Parp1 ENSMUSG00000026496 C57/BL6 KO Parp1 NA 7-8 wk BLM 1.5 U/kg, intratracheally single dose, follow-up 0-21 days Reduced lung fibrosis down_manip anti_fib pro_fib [See Parp1 KO in Durante et al 2019]
The increased levels of PARP-1 and α-SMA mRNAs in lung cells from IPF patients 		Hu et al 2013 23260200
Pgam5 ENSMUSG00000029500 C57BL/6 KO Pgam5-/- NA NA BLM 3 mg/kg, intranasally single dose, follow-up 0-21 days Reduced lung inflammation and fibrosis down_manip anti_fib pro_fib Ganzleben et al 2019 31168659
Pik3cg (Pi3kg) ENSMUSG00000020573 C57Bl/6J KO Pik3cg male 8-10 wk Bleomycin sulfate 5 mg/kg, intratracheally single dose, follow-up 0-16 days Reduced lung inflammation, fibrosis and mortality down_manip anti_fib pro_fib In KO mice, decreased production of TGF-β1 and CCL2 and increased production of IFN-γ and IL-10 In vitro: treatment of human endothelial cells with the PI3Kγ inhibitor AS605240 decreased proliferation, migration, and angeogenesis (formation of capillary) Russo et al 2011 21048214
Pink1 ENSMUSG00000028756 C57BL/6 & BALB/c KO Pink1-/- or Pink1+/- male 2–3 mo and ≥18 mo BLM 2 U/kg, intratracheally single dose, follow-up 0-15 days Promoted lung inflammation and fibrosis;
impaired mitochondrial homeostasis		 down_manip pro_fib anti_fib [See Ppargc1a]
[NB! Two different age groups]
Impaired mitochondria in IPF and aging lungs were associated with low expression of PTEN-induced putative kinase 1 (PINK1)		 Bueno et al 2014 25562319
Pink1 ENSMUSG00000028756 C57Bl/6 KO Pink1 female 9-12 wk BLM 1.5 U/kg, intratracheally single dose, follow-up 0-21 days Promoted lung fibrosis;
impaired mitochondrial homeostasis 		down_manip pro_fib anti_fib KO Pink1 led to inability to process dysfunctional mitochondria through mitophagy Yu et al 2018 29200204
Pink1 ENSMUSG00000028756 C57BL/6J KO Pink1 male or female 8-10 wk BLM 0.025 units in 50 μL normal saline, intratracheally
Crocidolite asbestos 100–200 μg suspended in 50 μL PBS, intratracheally 		BLM single dose;
Crocidolite asbestos single dose (separately from BLM);
Follow-up 0-21 days		 Promoted lung fibrosis in both asbestos and BLM models down_manip pro_fib anti_fib [See OGG1 in the same paper] Kim et al 2020 32209025
Pirb ENSMUSG00000058818 C57BL/6 KO Pirb-/- male 6-8 wk Bleomycin sulfate 0.03–0.1 U/mouse, intratracheally single dose, follow-up 0-28 days Promoted lung inflammation and fibrosis down_manip pro_fib anti_fib Expression of PIR-B human orthologue LILRB3/ILT-5 is higher in lung biopsies from patients
with IPF		 Karo-Atar et al 2014 23258232
Pla2g4a ENSMUSG00000056220 C57BL/6J × 129/Ola KO Pla2g4a-/- NA NA BLM 5 mg/kg, intratracheally single dose, follow-up 0-14 days Reduced lung inflammation and fibrosis down_manip anti_fib pro_fib BLM-induced overproduction of thromboxanes and leukotrienes in the lungs was significantly reduced in Pla2g4a KO mice Nagase et al 2002 11984592
Plau ENSMUSG00000021822 C57BL/6 Overexpression of Plau NA 6-8 wk BLM 1.15 U/kg in 50 μL in PBS, intratracheally
Doxycycline 0.5 mg/mL in 1% ethanol in drinking water		 BLM single dose, follow-up 0-28 days;
Doxycycline 3 regimens:
- prevention study, 1-28 days after BLM
- late inflammatory and early fibrotic phase study, 9-28
or 14-28 days after BLM
- reversal study, 21-42 days after BLM		 Reduced lung fibrosis but did not alter lung inflammation up_manip anti_fib anti_fib [NB! Skin wound healing in αMUPA transgenic mice; Yanai et al 2015]
The increased uPA expression in the epithelium and myofibroblasts of IPF lungs, increased uPA in the serum of IPF patients, and an inverse correlation between serum uPA and lung function in patients with IPF [Schuliga et al 2017,PMID:28139758]		 Horowitz et al 2019 31705517
Plxnc1 ENSMUSG00000074785 C57BL/6 KO Plxnc1-/- NA 8 wk BLM 0.8 U/kg, orotracheally single dose, follow-up 0-14 days Promoted lung inflammation and fibrosis down_manip pro_fib anti_fib [See also KO Syt7; the same paper]
Both Plxnc1 and Syt1 are involved in the regulation of monocyte-macrophage migration.
PLXNC1 is under-expressed and SYT1 is over-expressed in IPF lungs 		Peng et al 2016 27609773
Postn ENSMUSG00000027750 C57BL/6 KO Postn-/- NA NA BLM 0.025 U, intratracheally single dose, follow-up 0-21 days Reduced lung fibrosis down_manip anti_fib pro_fib [See also KO Elk1!]
αvβ6 is an epithelial-specific integrin that is a receptor for the extracellular matrix (ECM) proteins fibronectin, vitronectin, tenascin and the latency associated peptide (LAP) of TGF-β.
The increased Periostin expression in IPF lungs was localized to active areas of fibrosis. IPF patients also showed increased percentages of Periostin-expressing fibrocytes and monocytes in the blood [Naik et al 2012; PMID: 23043074] 		Ashley et al 2016 27435108
Pou2af1 ENSMUSG00000032053 C57BL/6 KO Pou2af1-/- female 8-12 wk BLM 3 U/kg, intratracheally single dose, follow-up 0-14 days Reduced lung fibrosis down_manip anti_fib pro_fib Expression of POU2AF1 is increased in B lymphocytes in IPF lungs McDonough et al 2019 31600171
Ppara
(gene and protein)		 ENSMUSG00000022383 NA KO Pparα
WY-14643 (PPAR-α ligand) 		NA 4-5 wk Bleomycin sulfate 1 mg/kg intratracheally;
WY-14643 (a potent exogenous PPAR-α ligand) 6 μL/day, subcutaneously (to WT) 		BLM sulfate single dose Follow-up 0-15 days
WY-14643 once daily, 3 hours post BLM for 15 days (to WT)		 Promoted lung injury and inflammation;
WY-14643 reduced lung injury and inflammation in WT mice 		down_manip other invalid They suggested to use WY-14643 for anti-fibrotic therapy in humans Genovese et al 2005 16317386
Pparg ENSMUSG00000000440 C57BL /6 KO Pparg-/- male 6-8 wk Bleomycin sulfate 0.025 U in 50 μl of saline, intratracheally single dose, follow-up 0-21 days Promoted lung fibrosis down_manip pro_fib anti_fib Promoted TGF-β effects In vitro: Genetic KO or KD of Pparg (PPARɤ) in otherwise normal murine or human lung fibroblasts directly elicits a profibrotic phenotype encompassing both enhanced TGF-β signaling and transdifferentiation into myofibroblasts Reddy et al 2014 25252739
Ppargc1a ENSMUSG00000029167 C57Bl/6 KO Ppargc1a female 9-12 wk BLM 1.5 U/kg, intratracheally single dose, follow-up 0-21 days Reduced lung fibrosis down_manip anti_fib pro_fib [See Pink1; 3 papers]
The expression of PPARGC1A and PINK1 is decreased in IPF lungs. Yet, it is unclear whether directly overexpressing either of the molecules will have any antifibrotic effect		 Yu et al 2018 29200204
Ppl ENSMUSG00000039457 C57BL/6J KO Ppl-/- male NA Bleomycin hydrochloride 55 μg, intratracheally single dose, follow-up 0-14 days Reduced lung inflammation and fibrosis down_manip anti_fib pro_fib PPL is expressed (immunohistochemistry) in the normal and fibrotic human lungs (IPF)
[Taillé et al 2011; PMID: 20935114]		 Besnard et al 2018 29515024
Prdx4 ENSMUSG00000025289 C57BL/6 Overexpression of Prdx4 male 10 wk BLM 2 mg/kg, intratracheally single dose, follow-up 0-21 days Promoted lung inflammation and fibrosis up_manip pro_fib pro_fib In human study, the patients with AE-IPF (acute exacerbation of IPF) had higher serum PRDX4 protein levels than those with S-IPF (stable IPF) Hanaka et al 2019 31888585
Prkaa1 ENSMUSG00000050697 C57BL/6 KO Prkaɑ1 male 8-10 wk BLM 1.25 U/kg, intratracheally;
Metformin 65 mg/kg, intraperitoneally 		BLM single dose;
Metformin (AMPK activator) every-other-day for a total of 18 days, starting on Day 10 post BLM;
Follow-up 0-28 days		 Promoted lung injury and fibrosis down_manip pro_fib anti_fib Metformin reduced several BLM-induced pro-fibrotic markers, including total lung hydroxyproline and the expression of α-SMA, in WT mice but not in KO mice [NB!]
Prkaa1 encodes 5'-AMP-activated protein kinase catalytic subunit alpha-1 (AMPK enzyme).
Metformin is a longevity-promoting drug (used for treatments of type 2 diabetes).
AMPK activity is lower in fibrotic regions of IPF lungs (as well as in BLM mouse model of of lung fibrosis) with metabolically active and apoptosis-resistant myofibroblasts 		Rangarajan et al 2018 29967351
Pros1 (Protein S) ENSMUSG00000022912 C57BL/6J Overexpression of Pros1
Exogenous hPS (Protein S)		 male 8-12 wk BLM 100 mg/kg, subcutaneously via osmotic minipumps;
Exogenous hPS (Protein S) 1 mg/kg, intranasally 		BLM continuously during 7 days
Exogenous hPS on Day 4, 6, 8, 10, 17 and 19 after BLM		 Reduced lung inflammation and fibrosis up_manip anti_fib anti_fib Exogenous hPS in WT mice → Ameliorated BLM-induced lung fibrosis.
Exogenous hPS in hPS-TG mice → Less apoptosis in lung tissue and inhibition of alveolar epithelial cell apoptosis		 Pros1 expression was significantly reduced in IPF lungs Urawa et al 2016 27172994
Psmd11 ENSMUSG00000017428 C57BL/6 Overexpression of Psmd11 female 10-12 wk BLM 3 U/kg, intratracheally single dose, follow-up 0-56 days Promoted lung fibrosis up_manip pro_fib pro_fib Psmd11 is overexpressed in myofibroblasts and basal cells of the bronchiolar epithelium in lungs of IPF patients Semren et al 2015 26207697
Ptger4 ENSMUSG00000039942 C57BL/6 Overexpression of Ptger4 male 7-9 wk BLM sulfate 2.5 U/kg, intratracheally BLM sulfate single dose, follow-up 0-14 days Reduced lung inflammation up_manip other invalid [See Ptger4 KO; the same paper and Alox5, Peters-Golden et al 2002]
Ptger4 -- Prostaglandin E Receptor 4.
Macrophage-specific Eprap overexpression reduces BLM-induced pulmonary inflammation		 Higuchi et al 2016 27799315
Ptger4 (EP4) ENSMUSG00000039942 C57BL/6 KO Ptger4
EP4 agonist		 male 7-9 wk BLM sulfate 2.5 U/kg, intratracheally;
ONO-AE1-329 (selective EP4 agonist) 0.3 mg/kg, subcutaneously		 Bleomycin sulfate single dose, follow-up 0-14 days
ONO-AE1-329 twice a day from the day before BLM (to KO and WT mice)		 Promoted lung inflammation and fibrosis down_manip pro_fib anti_fib ONO-AE1-329 ameliorates BLM-induced lung injury and inflammatory responses in WT mice, but not in KO mice [See Ptger4 overexpression; the same paper and Alox5, Peters-Golden et al 2002]
Ptger4 -- Prostaglandin E Receptor 4.		 Higuchi et al 2016 27799315
Ptges ENSMUSG00000050737 C57BL/6 KO Ptges-/- or Ptges+/- male 6-8 wk BLM 5 mg/kg, intratracheally single dose, follow-up 0-28 days Promoted lung inflammation and fibrosis down_manip pro_fib anti_fib [See Ptgs1 & 2 (COX-1 & 2); Card et al 2007]
Ptges -- Prostaglandin E Synthase.
PGE2 production was decreased in lung fibroblasts isolated from IPF patients [Wilborn et al 1995;
PMID: 7706493], so they hypothesize that mPGES-1, one of PGE synthases, may play an essential role in IPF development and progression 		Wei et al 2014 24756129
Ptgis ENSMUSG00000017969 FVB Overexpression of Ptgis female 10-14 wk BLM 0.08 U/mouse, intranasally single dose, follow-up 0-14 days Reduced lung inflammation and mortality up_manip other invalid TG mice reduced BLM-induced apoptosis in the lungs In vivo and in vitro experiments: PGI2 induced NADP(H): quinoneoxidoreductase 1 (Nqo 1), an enzyme that prevents the generation of ROS Zhou et al 2011 21764988
Ptgs2 ENSMUSG00000032487 C57BL/6 × SvEv KO Ptgs2-/- female 3-6 mo BLM 1.0 mg/kg, intratracheally single dose, follow-up 0-21 days Promoted lung dysfunction but not fibrosis down_manip pro_fib anti_fib [See Ptgs1 (COX-1) -- the same paper, and Ptges; Wei et al 2014; Wilborn et al 1995]
Cyclooxygenase 2 (COX-2), also known as prostaglandin G/H synthase 2.
Fibroblasts isolated from IPF lungs express less COX-2 and produce less of the antifibrotic PGE2 than nonfibrotic fibroblasts [Keerthisingam et al 2001; PMID: 11290559] 		Card et al 2007 17496151
Ptpn13 ENSMUSG00000034573 C57BL/6J KO Ptpn13-/- or Ptpn13+/- male 8-10 wk BLM 2.5 U/kg, intratracheally single dose, follow-up 0-14 days Reduced lung inflammation and fibrosis down_manip anti_fib pro_fib In WT, Ptpn13 promotes resistance of myofibroblasts to apoptosis in lung fibrosis.
PTPN13 protein was constitutively expressed by (myo)fibroblasts in the fibroblastic foci of patients with IPF. Human lung (myo)fibroblasts, which are resistant to Fas-induced apoptosis, basally expressed PTPN13 in vitro		 Bamberg et al 2018 29727583
Rac2 ENSMUSG00000033220 C57BL/6 KO Rac2-/- male 10-14 wk Bleomycin sulfate 0.125 U/100 g single dose, follow-up 0-21 days Reduced lung inflammation, fibrosis and mortality down_manip anti_fib pro_fib Arizmendi et al 2014 24970330
Rac2 ENSMUSG00000033220 C57BL/6J KO Rac2-/- female 8-10 wk Bleomycin sulfate 3 U/kg, intratracheally single dose, follow-up 0-28 days Reduced lung inflammation and fibrosis down_manip anti_fib pro_fib Diminished collagen deposition in association with lower expression of alternatively activated profibrotic macrophage markers Joshi et al 2017 28817691
Rag1 ENSMUSG00000061311 C57BL/6 KO Rag1-/- female 10 wk BLM 40 μL, intratracheally;
IL-2 complex 6 μg (anti-IL-2 antibody [JES6-1] 5 μg & mouse recombinant IL-2 protein 1 μg), intraperitoneally		 BLM single dose;
IL-2 complex one dose daily for 3 consecutive days before BLM administration;
Follow-up 0-14 days		 Promoted lung fibrosis and mortality;
IL-2 complex did not alter the BLM-induced lung fibrosis in KO mice, but did exacerbate in WT mice
down_manip pro_fib anti_fib Tregs promote BLM-induced lung fibrosis.
IL-2 complex was used to expand the CD4+CD25hiFoxp3+ cells (Tregs) in the lung during BLM treatment		 Birjandi et al 2016 27317904
Ramp2 ENSMUSG00000001240 C57BL/6 Overexpression of Ramp2 male 8-10 wk BLM 1 U/kg, intratracheally single dose, follow-up 0-21 days Reduced lung fibrosis and and enhanced survival up_manip anti_fib anti_fib RAMP activates cAMP/PKA signaling Kach et al 2012 23585227
Retnla (Fizz1) ENSMUSG00000061100 NA Overexpression of Retnla NA NA BLM sulfate 0.15 U, intratracheally;
Crystalline silica 3 mg (of 5 μm size) per mouse in 50 μl saline, intratracheally		 BLM single dose, follow-up 0-10 days;
Crystalline silica single dose, follow-up 0-28 days		 No effect on inflammation and fibrosis in BLM or Crystalline silica model up_manip other invalid [See Retnla KO and overexpression; Liu et al 2014]
[NB! Low dose of BLM and relatively short BLM follow-up]		 Madala et al 2014 22726462
Retnla (Fizz1) ENSMUSG00000061100 C57BL/6 Overexpression of Retnla male 8-10 wk BLM 2 U/kg, endotracheally (intratracheally) single dose, follow-up 0-21 days Promoted lung inflammation and fibrosis up_manip pro_fib pro_fib [See Retnla KO; the same paper, and Retnla overexpression -- Madala et al 2014]
In vitro: Retnlα was shown to have chemoattractant activity for bone marrow cells, including bone marrow-derived dendritic cells.
Human FIZZ2 may present the human counterpart of rodent Fizz1, especially at the functional level [Renigunta et al 2006; PMID: 16427636]. Human FIZZ2 is highly induced in the IPF lungs, and could be up-regulated in human small airway epithelial cell line by Th2 cytokines [Liu et al 2011; PMID: 21602491 ) → suggests a potential role for FIZZ2 in pathogenesis of IPF		 Liu et al 2014 24516640
Retnla (Fizz1) ENSMUSG00000061100 C57BL/6 KO Retnla NA 8-10 wk BLM 2 U/kg, endotracheally (intratracheally) single dose, follow-up 0-21 days Reduced lung inflammation and fibrosis down_manip anti_fib pro_fib [See Retnla overexpression; the same paper and Madala et al 2014]
Human FIZZ2 may present the human counterpart of rodent Fizz1, especially at the functional level [Renigunta et al 2006; PMID: 16427636]. Human FIZZ2 is highly induced in the IPF lungs, and could be up-regulated in human small airway epithelial cell line by Th2 cytokines [Liu et al 2011; PMID: 21602491 ) → suggests a potential role for FIZZ2 in pathogenesis of IPF		 Liu et al 2014 24516640
Rgs2 ENSMUSG00000026360 C57BL/6 J KO Rgs2-/-
Rgs2 agonist (Pirfenidone)		 male 11 wk Bleomycin sulfate 1.0 - 1.5 - 2.0 U/kg, intratracheally;
Pirfenidone 0.35 mg/kg, intranasally [see Comments]		 BLM single dose;
Pirfenidone one dose daily from Day 0 to Day 14;
Follow-up 0-14 days		 Promoted lung fibrosis and mortality down_manip pro_fib anti_fib Pirfenidone reduced BLM-induced lung fibrosis in WT mice but not in KO mice Pirfenidone -- antifibrotic drug; causes rapid upregulation of Rgs2.
RGS2 mRNA and protein levels were increased by Pirfenidone in HFL1 (human fetal lung fibroblast cell line) and primary human lung fibroblasts isolated from patients without or with IPF		 Xie et al 2016 27549302
Rock1 ENSMUSG00000024290 C57BL/6 KO Rock1+/- male 8-12 wk BLM 1.2 U/kg, intratracheally single dose, follow-up 0-14 days Reduced lung fibrosis down_manip anti_fib pro_fib Rock1 KO mice displayed greater attenuation of BLM-induced AEC apoptosis,
vascular permeability and αSMA1 		[See Rock2 KO; the same paper]
Rock1 and Rock2 KO mice displayed similar protection from BLM-induced AEC apoptosis, vascular leak, and myofibroblast differentiation.
Partial reduction of ROCK activity (perhaps even normalization of the increased activity reported in IPF) → has the potential to be an effective therapeutic strategy for IPF because it permits the remaining ROCK activity to participate in nonfibrotic functions necessary for homeostasis [?] 		Knipe et al 2018 29211497
Rock2 ENSMUSG00000020580 C57BL/6 KO Rock2+/- male 8–12 wk BLM 1.2 U/kg, intratracheally single dose, follow-up 0-14 days Reduced lung fibrosis down_manip anti_fib pro_fib Rock2 KO mice displayed greater attenuation of BLM-induced AEC apoptosis,
vascular permeability and αSMA1 		[See Rock1 KO; the same paper]
Rock1 and Rock2 KO mice displayed similar protection from BLM-induced AEC apoptosis, vascular leak, and myofibroblast differentiation.
Partial reduction of ROCK activity (perhaps even normalization of the increased activity reported in IPF) → has the potential to be an effective therapeutic strategy for IPF because it permits the remaining ROCK activity to participate in nonfibrotic functions necessary for homeostasis [?] 		Knipe et al 2018 29211497
S100a4 ENSMUSG00000001020 C57BL/6 KO S100a4-/- male NA BLM 5 mg/kg, intratracheally single dose, follow-up 0-28 days Reduced lung fibrosis down_manip anti_fib pro_fib [See KO Ifngr1; Zhang et al 2018]
Macrophages expressed S100A4 in lung sections of both a control and an IPF patients; also, S100A4 was detected in BAL fluids of both control and IPF patients. However, no difference
between the two groups was observed, which may be because of the very limited number of samples studied so far		 Li et al 2018 30127784
S1pr2 ENSMUSG00000043895 Balb/c KO S1pr2 male 8 wk BLM 50 mg/kg, intratrachealy single dose, follow-up 0-28 days Reduced lung inflammation and fibrosis down_manip anti_fib pro_fib [See KO S1pr2; Zhao et al 2018]
[NB! Mouse strains with different susceptibility to BLM]
S1P levels were elevated in bronchoalveolar lavage fluids (BALFs) of IPF patients, and correlated with poor lung prognosis in IPF patients [Milara et al 2012; PMID: 22106015]		 Park et al 2019 30293251
S1pr2 ENSMUSG00000043895 C57BL/6J KO S1pr2-/- male 8-10 wk BLM 0.035 U/g, intraperitoneally twice a week dose for 4 weeks Reduced lung inflammation and fibrosis down_manip anti_fib pro_fib [See KO S1pr2;Park et al 2019]
[NB! Mouse strains with different susceptibility to BLM]
In WT mice, the mechanisms of fibrotic response involved augmentation of IL-13
expression in lung macrophages		 Zhao et al 2018 29782549
S1pr3 ENSMUSG00000067586 C57 BL6/J KO S1pr3-/- male 7-10 wk Bleomycin hydrochloride 2.15 U/kg, intratracheally single dose, follow-up 0-28 days Reduced lung inflammation and fibrosis down_manip anti_fib pro_fib [See KO S1pr2; Park et al 2019 and Zhao et al 2018] Murakami et al 2014 25198418
Scgb1a1 ENSMUSG00000024653 C57BL/6 KO Scgb1a1 NA NA BLM 0.0075 - 0.0375 - 0.075 U/mouse in 50 μl saline, intratracheally single dose, follow-up 0-28 days Promoted lung inflammation, fibrosis and mortality down_manip pro_fib anti_fib Encoded Uteroglobin protein; has potent antiinflammatory and antichemotactic properties Lee et al 2006 16872605
Sdc1 ENSMUSG00000020592 C57BL/6 Overexpression of Sdc1 NA 8-12 wk BLM 0.25 - 0.75 U/kg, intratracheally single dose, follow-up 0-21 days Promoted lung fibrosis up_manip pro_fib pro_fib [See Sdc1 KO; the same paper]
Sdc1 is overexpressed in AEC type 2 in IPF lungs.
Syndecan-1 overexpression augments Wnt/β-catenin signaling in ATII cells during lung fibrosis. They suggest that their data support the concept that syndecan-1 overexpression promotes lung fibrosis by facilitating a pathological reprogramming of ATII cells in vivo through modulation of fibrogenic pathways, such as TGF-β and Wnt/β-catenin		 Parimon et al 2019 31393853
Sdc1 ENSMUSG00000020592 C57BL/6 KO Sdc1-/- NA 8-12 wk BLM 0.25 - 0.75 units/kg, intratracheally single dose, follow-up 0-21 days Reduced lung fibrosis down_manip anti_fib pro_fib [See Sdc1 overexpression; the same paper]
Sdc1 is overexpressed in AEC type 2 in IPF lungs		 Parimon et al 2019 31393853
Sdc2 ENSMUSG00000022261 C57BL6 Overexpression of Sdc2 NA 8 wk BLM 0.15 U/mouse by aspiration single dose, follow-up 0-28 days Reduced lung fibrosis (no difference in inflammation between TG and WT) up_manip anti_fib anti_fib Macrophage-specific overexpression of human syndecan-2 in transgenic mice conferred antifibrotic effects after lung injury by inhibiting
TGF-b1 signaling and downstream expression of TGF-b1 target genes, reducing extracellular matrix production and alveolar epithelial cell apoptosis.		 Elevation in alveolar macrophage Sdc2 levels in IPF patients.
In vitro (IPF cells): Sdc2 promoted caveolin-1-dependent internalization of TGF-β1 and TβRI in AECs → inhibited TGF-β1 signaling and AEC apoptosis 		Shi et al 2013 23924348
Sdc4 ENSMUSG00000017009 C57BL/6 KO Sdc4 NA NA BLM 2.5 µg/g, intratracheally single dose, follow-up 0-21 days Promoted lung inflammation and fibrosis down_manip pro_fib anti_fib In WT lung fibroblasts, Sdc4 reduced the fibrotic activity of TGF-β in vitro Tanino et al 2019 31600983
Serpine1 ENSMUSG00000037411 C57BL/6 Overexpression of Serpine1 male and female 4-6 wk BLM 0.075 or 0.15 U in a final volume of 50 μl, intratracheally single dose, follow-up 0-21 days Promoted lung inflammation and fibrosis up_manip pro_fib pro_fib [See Serpine1 KO; the same paper] Eitzman et al 1996 8550840
Serpine1 ENSMUSG00000037411 C57BL/6 KO Serpine1+/- or Serpine1-/- male and female 4-6 wk BLM 0.075 or 0.15 U in a final volume of 50 μl, intratracheally single dose, follow-up 0-21 days Reduced lung fibrosis down_manip anti_fib pro_fib [See Serpine1 overexpression; the same paper]
3 weeks after BLM, the lung hydroxyproline content of Serpine1-null mice did not differ from the control (receiving saline) WT mice. In contrast, the hydroxyproline content was significantly increased in heterozygote and WT 		Eitzman et al 1996 8550840
Serpine1 (PAI-1) ENSMUSG00000037411 C57BL/6J KO Serpine1fl/fl male 8-10 wk BLM 2 U/kg, oropharyngeally single dose, follow-up 0-14 days Reduced lung fibrosis down_manip anti_fib pro_fib [See also Serpine 1/2; Shioya et al 2018; François et al 2018]
ATII (alveolar type 2) cells in IPF lungs express higher level of Serpine 1 and cellular senescence markers p16 and p21. They suggest that Serpine 1 contributes importantly to cellular senescence of ATII.
In vitro: Inhibition of PAI-1 activity with a small molecular PAI-1 inhibitor TM5275 attenuates BLM-induced p53 expression and cellular senescence in L2 (alveolar type 2) rat cells 		Jiang et al 2017 28722352
Serpine1 (PAI-1) ENSMUSG00000037411 C57BL/6 KO Serpine1‑/‑ (PAI‑/‑) male NA 15 Gy irradiation delivered to the thorax with an X-ray irradiator single dose, follow-up 0-24 weeks Reduced lung inflammation and fibrosis down_manip anti_fib pro_fib [See also Serpine 1/2; Jiang et al 2017; François et al 2018] Shioya et al 2018 30214528
Serpine2 ENSMUSG00000026249 C57Bl/6 KO Serpine2-/- male 8-10 wk BLM 2 mg/kg, intratracheally single dose, follow-up 0-14 days Promoted lung inflammation, fibrosis and mortality down_manip pro_fib anti_fib [See also Serpine 1; Jiang et al 2017; Shioya et al 2018]
SERPINE2 expression is upregulated in lung tissue, bronchoalveolar lavage fluid (BALF), and lung fibroblasts from IPF patients (François et al 2014; PMID: 25199049		 François et al 2018 30254103
Serpinb3d ENSMUSG00000058017 C57BL/6 Overexpression of Serpinb3d NA 12-14 wk BLM 2.5 U/kg, intratracheally single dose, follow-up 0-20 days and 0-48 h Promoted lung fibrosis and reduced inflammation up_manip pro_fib pro_fib Serpinb3d reduced inflammation, influencing epithelial proliferation/apoptosis imbalance and likely favoring fibrogenesis (IPF). This experimental scenario looks like an advanced form of human IPF in which fibrotic remodeling is associated with uncontrolled epithelial proliferation.
The higher SERPIN B3/B4 expression, the more extensive fibrosis in IPF lungs (Calabrese et al 2008; PMID: 18344408]		 Lunardi et al 2011 21403642
Setd7 ENSMUSG00000037111 C57BL/6 × CBA KO Setd7 male 12 wk BLM 0.033 U/mouse, intratracheally single dose, follow-up 0-15 days Promoted lung fibrosis down_manip pro_fib anti_fib Elkouris et al 2016 27292644
Sftpd ENSMUSG00000021795 C57/BL6 Overexpression of Sftpd male and female 8-10 wk BLM sulfate 1.0 - 2.0 - 3.0 U/kg, intratracheally
single dose, follow-up 0-21 days Reduced lung injury and mortality (no difference in inflammation between TG and WT) up_manip other invalid [See Sftpd KO; the same paper] Casey et al 2005 15994463
Sftpd ENSMUSG00000021795 C57/BL6 KO Sftpd-/- male and female 8-10 wk BLM sulfate 1.0 - 2.0 - 3.0 U/kg, intratracheally
single dose, follow-up 0-21 days Promoted lung injury, inflammation, fibrosis and mortality down_manip pro_fib anti_fib [See Sftpd overexpression; the same paper] Casey et al 2005 15994463
Sgpl1 ENSMUSG00000020097 129SV KO Sgpl1+/- male 8 wk BLM sulfate 2 U/kg, intratracheally single dose, follow-up 0-21 days Promoted lung inflammation and fibrosis down_manip pro_fib anti_fib [See Sgpl1 KO; Huang et al 2015 but PMID 25446881]
BLM-induced infiltration of macrophages and lymphocytes, but not neutrophils, into alveolar space was higher in Sgpl1+/- mice compared with wild-type mice (at day 14 post BLM).
NB! IPF patients with lower Sgpl1 mRNA expression in PBMCs → higher severity of fibrosis and lower survival rate		 Huang et al 2015 26286721
Sgpl1 ENSMUSG00000020097 C57BL/6J KO Sgpl1+/- NA NA BLM 2 U/kg, intratracheally single dose, follow-up 0-21 days Promoted lung fibrosis down_manip pro_fib anti_fib [See Sgpl1 KO; Huang et al 2015 but PMID 26286721]
In vitro: Sgpl1 overexpression attenuated BML-induced TGF-β secretion and S1P-mediated differentiation of human lung fibroblasts.
NB! IPF patients with lower Sgpl1 mRNA expression in PBMCs → higher severity of fibrosis and lower survival rate		 Huang et al 2015 25446881
Shh ENSMUSG00000002633 C57BL/6J Overexpression of Shh NA 8-10 wk BLM 1.3 U/kg, intratracheally single dose, follow-up 0-21 days Promoted lung fibrosis up_manip pro_fib pro_fib SHH is expressed in lung epithelium in IPF [Stewart et al 2003; PMID: 12635140] Liu et al 2013 23371063
Sirt1 ENSMUSG00000020063 C57BL/6 Overexpression of Sirt1
Upregulation of Sirt1		 NA 8 wk BLM 0.5 mg/kg, intratracheally;
RSV (Resveratrol, a natural activator of Sirt1) 20 mg/kg, i.p.		 BLM single dose;
RSV single dose immediately after BLM to WT only;
Follow-up 0-14 days		 Reduced lung fibrosis up_manip anti_fib anti_fib Resveratrol (RSV), a natural activator of Sirt1, prevented or ameliorated BLM-induced lung injury or fibrosis. Altogether, activation or overexpression of Sirt1 reduced lung fibrosis Sirt1 was upregulated and overexpressed in lungs of BLM-treated WT mice and IPF patients.
NB! BLM → stimulation of TGF-β1 → upregulation of Sirt1 → reduced lung fibrosis: represents
a negative feedback to limit TGF-β1 signaling in lung fibroblasts		 Zeng et al 2017 28365154
Sirt3 ENSMUSG00000025486 129Sv Overexpression of Sirt3 male 10-12 wk BLM 1 U/kg, intratracheally single dose, follow-up 0-21 days Reduced lung fibrosis up_manip anti_fib anti_fib [See KO Sirt3-/-; the same paper + Jablonski et al 2017] Bindu S et al 2017 27815257
Sirt3 ENSMUSG00000025486 129Sv KO Sirt3-/- male 10-12 wk BLM 1 U/kg, intratracheally single dose, follow-up 0-21 days Promoted lung fibrosis down_manip pro_fib anti_fib [See Sirt3 overexpression -- the same paper, and KO Sirt3-/- -- Jablonski et al 2017]
KO Sirt3 promoted TGF-β1-induced myofibroblast differentiation;
KO Sirt3 promoted mitochondrial DNA damage		 Bindu et al 2017 27815257
Sirt3 ENSMUSG00000025486 129SJ KO Sirt3-/- male and female 8-10 wk BLM 0.25 U in 50 μl of saline, intratracheally single dose, follow-up 0-21 days Promoted lung fibrosis
down_manip pro_fib anti_fib [See Sirt3 overexpression; Bindu et al 2017]
KO Sirt3 augmented alveolar epithelial cell mitochondrial DNA damage and apoptosis.
An increased acetylation of key SIRT3 target MnSODK68 in IPF lungs, including in AT2 (alveolar type 2) cells, which is consistent with deficient AEC SIRT3 activity in IPF		 Jablonski et al 2017 28258190
Skp2
(gene & protein)		 ENSMUSG00000054115 C57BL/6 KO Skp2-/- or Skp2+/-
Inhibition of Skp2 protein
by SZL-P1-41		 male 10 wk BLM 2 mg/kg, intratracheally;
SZL-P1-41 (inhibitor of Skp2) 80 mg/kg, intraperitoneally (i.p.)		 BLM single dose;
SZL-P1-41 once daily from Day 1 to Day 14;
Follow-up 0-15 days		 Reduced lung inflammation and fibrosis down_manip anti_fib pro_fib Inhibition of Skp2 by SZL-P1-41 suppressed the accumulation of fibrosis markers
(collagen type 1, fibronectine) 		They speculated that Skp2 might also contribute to pulmonary fibrosis and be a potential molecular target for IPF therapy Mikamo el al 2018 29415439
Smad3 ENSMUSG00000032402 C57BL/6 KO Smad3-/- female 9 wk BLM sulfate 0.1 mg/g mouse, subcutaneously via osmotic minipumps single dose, follow-up 0-28 days Reduced lung fibrosis down_manip anti_fib pro_fib [See Smad3 KO -- Gu et al 2007; and Smad3 protein inhibition -- Shou et al 2018] [See also Mir29b OE in lungs; Xiao et al 2012] Zhao et al 2002 11839555
Smad3 ENSMUSG00000032402 NA KO Smad3 NA NA BLM 0.15 mg/g, subcutaneously via osmotic mini-pump single dose, follow-up 0-28 days Reduced lung fibrosis down_manip anti_fib pro_fib [See Smad3 KO -- Zhao et al 2002; and Smad3 protein inhibition -- Shou et al 2018] [See also Mir29b OE in lungs; Xiao et al 2012]
Differentiated myofibroblasts are significantly reduced in the lungs of BLM-treated Smad3 KO mice.
In vitro: Increased production of Smad3 protein (but not Smad2) markedly increased TGF-β1-induced α-SMA promoter activity and α-SMA protein levels in normal human lung fibroblasts.		 Gu et al 2007 17303001
Smad3 (protein) ENSMUSG00000032402 C57BL/6J Inhibition of Smad3
protein by SIS3		 male 7-8 wk BLM 1.5 mg/kg, intratracheally;
SIS3 2 mg/kg, intraperitoneally 		BLM single dose;
SIS3 every-other-day;
Follow-up 0-21 days 		Reduced lung inflammation and fibrosis down_manip anti_fib pro_fib [See Smad3 KO; Gu et al 2007 and Zhao et al 2002] [See also Mir29b OE in lungs; Xiao et al 2012]
The beneficial effect of SIS3 was possibly related to the decreased synthesis of collagen and inhibition of acute lung inflammation		 Shou et al 2018 29913150
Sod3 ENSMUSG00000072941 C57BL/6 Overexpression of Sod3 NA 8 wk Bleomycine sulfate 0.2 U/20 g, intratracheally single dose, follow-up 0-14 days Reduced lung injury and fibrosis up_manip anti_fib anti_fib [See other KO Sod3] Bowler et al 2001 11880297
Sod3 ENSMUSG00000072941 C57BL/6 KO Sod3 male 6-8 wk BLM 5 U/kg in 20-25 μl saline, intratracheally single dose, follow-up 0-7 days Promoted lung injury down_manip other invalid [See Sod3 overexpression and other KO Sod3]
Enhanced the accumulation of hyaluronan in the lungs after BLM-induced oxidative stress 		Zelko et al 2010 20493858
Sod3 ENSMUSG00000072941 C57BL/6 KO Sod3 male 8-10 wk Сrocidolite asbestos 0.1 mg, intratracheally single dose, follow-up 0-14 days Promoted lung inflammation and fibrosis down_manip pro_fib anti_fib [See Sod3 overexpression and other KO Sod3]
Asbestos-induced Hyaluronan accumulation was greater in Sod3 KO than in WT mice 		Gao et al 2008 18165226
Sphk1 ENSMUSG00000061878 C57BL/6J KO Sphk1+/- NA NA BLM 2 U/kg, intratracheally single dose, follow-up 0-21 days Reduced lung fibrosis down_manip anti_fib pro_fib The expression levels of SPHK1 and SPHK2 negatively correlated with the lung function and survival in patients with IPF [Huang et al 2013, PMID 23315259] Huang et al 2015 25446881
Sphk2 ENSMUSG00000057342 C57BL/6J KO Sphk2+/- NA NA BLM 2 U/kg, intratracheally single dose, follow-up 0-21 days No effect on lung fibrosis down_manip other invalid The expression levels of SPHK1 and SPHK2 negatively correlated with the lung function and survival in patients with IPF [Huang et al 2013, PMID 23315259] Huang et al 2015 25446881
Spp1 (Osteopontin) ENSMUSG00000029304 C57BL/6 KO Spp1 female 6-8 wk [in vitro -- BLM 0.1 μg/ml to RAW 264.7 murine macrophage cells and MLE-15 cells; SWCNT 6 μg/cm2 of monolayer surface];
Single-walled carbon nanotubes (SWCNT) 40 μg/mouse, pharyngeal aspiration		 SWCNT single dose, follow-up 0-28 days Reduced lung inflammation and fibrosis in SWCNT model down_manip anti_fib pro_fib In vitro: Reduced the levels of TGF-β1 in RAW 264.7 but not MLE-15 cells exposed to SWCNT or BLM in the presence of Osteopontin-blocking antibody [See KO Spp1; Berman et al 2004]
SWCNT induced lung fibrogenic response via osteopontin and TGF-β1.
They suggest that Osteopontin is important in initiating the response to SWCNT and it may act upstream of TGFβ 1 		Khaliullin et al 2017 29140132
Spp1 (Osteopontin) ENSMUSG00000029304 129SVJ KO Spp1-/- male and female 10-12 wk Bleomycin sulfate from 0.03 to 0.1 U, intratracheally single dose, follow-up 0-16 days Reduced lung fibrosis but did not affect inflammatory cells
(vs BLM-treated WT) 		down_manip anti_fib pro_fib [See KO Spp1; Khaliullin et al 2017]
[See also Nakama et al 1998 -- coincedes well with Tnf overexpression]
SPP1 is abundantly expressed in both human (IPF) and mouse lung fibrosis.
Osteopontin deficiency is associated with abnormal wound repair in the heart and skin.
Osteopontin-null mice develop abnormal postinflammatory repair and fibrosis in the heart, kidney, and skin. Here -- in the lung -- in contrast to WT mice, in response to BLM, osteopontin-null mice accumulated less collagen type 1 and developed cystic lung fibrosis + showed the reduced expression and activation of MMP-2 and expression of active TGF-β1 in osteopontin-null mice		 Berman et al 2004 14977630
Sulf2 ENSMUSG00000006800 C57BL/6 Overexpression of Sulf2 male 8-10 wk BLM 0.3 - 0.5 - 0.7 - 1 U/kg, intratracheally single dose, follow-up 0-14 days Reduced lung injury, inflammation and mortality up_manip other invalid [KO Sulf2; the same paper]
Increased levels of SULF2 in the hyperplastic type II alveolar epithelial cells (AECs) in the IPF lungs		 Yue et al 2017 28657777
Sulf2 ENSMUSG00000006800 C57BL/6 KO Sulf2 male 8-10 wk BLM 0.3 - 0.5 - 0.7 - 1 U/kg, intratracheally single dose, follow-up 0-14 days Promoted lung injury, inflammation and mortality down_manip other invalid [Sulf2 overexpression; the same paper]
Increased levels of SULF2 in the hyperplastic type II alveolar epithelial cells (AECs) in the IPF lungs		 Yue et al 2017 28657777
Syt7 ENSMUSG00000024743 C57BL/6 KO Syt7-/- NA 8 wk BLM 0.8 U/kg, orotracheally single dose, follow-up 0-14 days Reduced lung inflammation and fibrosis down_manip anti_fib pro_fib [See also KO Plxnc1; the same paper]
Both Plxnc1 and Syt1 are involved in the regulation of monocyte-macrophage migration.
PLXNC1 is under-expressed and SYT1 is over-expressed in IPF lungs.
Synaptotagmin-7 (Syt7) mediates fibrosis in other tissues as well; involved in multiple
processes that are potentially related to lung fibrosis, including cell (macrophage) migration, phagocytosis, and surfactant recycling 		Peng et al 2016 27609773
Tcrb NA [there are ENSEMBL IDs for Tcrbc1 & Tcrbc2] C57BL/6 KO Tcrb-/- male 6-8 wk BLM 2 U/kg in 100 μl PBS, oropharyngeally single dose, follow-up 0-45 days Promoted lung injury and fibrosis down_manip pro_fib anti_fib [See Cxcl10 KO; the same paper]
Tcrb -- T cell receptor beta chain		 Pociask et al 2011 21356368
Terc ENSMUSG00000064796 C57BL/6 KO Terc+/- or Terc -/- male and female 8-12 wk BLM 0.3 mg/kg, intratracheally;
LPS 5 mg/kg, intratracheally		 single dose, follow-up 0-14 days Telomere shortening promoted LPS- or BLM-induced
lung inflammation and fibrosis [see Tert] 		down_manip other invalid [see Tert] Liu et al 2018 29925920
Tert ENSMUSG00000021611 C57BL/6 KO Tert-/- NA NA BLM 1.5 U/kg, endotracheally (intratracheally) single dose, follow-up 0-21days Reduced lung fibrosis down_manip anti_fib pro_fib [see Terc -- NB possible discrepancy!]
Telomere length was not measured.
Reduced expression of lung alpha-SMA, a marker of myofibroblast differentiation		 Liu et al 2007 18008008
Tgfb1 ENSMUSG00000002603 C57BL/6 × CBA Overexpression of Tgfb1 male 3 mo BLM 1500 IU or 4500 IU in 0.5 ml PBS, intraperitoneally in three divided doses over a course of 5 days,
follow-up 0-42 days		 Promoted lung inflammation and fibrosis up_manip pro_fib pro_fib [See Tgfb1 overexpression -- Herrmann et al 2017; and TGF-β1 protein inhibition -- Weng et al 2018]
An increased TGFβ1 production, or a locally induced TGFβ1 increase may only be sufficient to cause a fibrotic injury when acting in concert with other factors, thus reinforcing the hypothesis that IPF development is due to the interplay of a number of factors		 Haider et al 2007 17883846
Tgfb1 ENSMUSG00000002603 C57BL/6 Overexpression of Tgfb1 male 10-12 wk BLM 0.5 mg/kg, intratracheally;
Olodaterol (anti-fibrotic drug) 10 nM, inhalation 		BLM single dose;
Olodaterol once a day after BLM 1-20 days;
Follow-up 0-21 days		 Promoted lung fibrosis up_manip pro_fib pro_fib Olodaterol reduced BLM-induced lung fibrosis in WT and Tgfb1 transgenic mice [See Tgfb1 overexpression -- Haider et al 2007; and TGF-β1 protein inhibition; Weng et al 2018]
Olodaterol (anti-fibrotic drug) reduces TGF-β1-induced lung fibrosis in a murine model and IPF 		Herrmann et al 2017 28810065
TGF-β1 (protein) ENSMUSG00000002603 C57BL/6 Inhibition of TGF-β1 protein by 2-aminopurine female 6-8 wk BLM 2.5 mg/kg, intratracheally;
2-aminopurine (2-AP) 2 mg/kg, intraperitoneally		 Single dose, follow-up 0-21 days Reduced lung inflammation and fibrosis down_manip anti_fib pro_fib [See Tgfb1 overexpression -- Haider et al 2007; Herrmann et al 2017]
[See also Ltbp3 overexpression; Tang et al 2014]		 Weng et al 2018 29531814
Tgm2 ENSMUSG00000037820 C57Bl/6J KO Tgm2 NA 8 wk Bleomycin sulfate 2.5 U/kg, oropharyngeally single dose, follow-up 0-21days Reduced lung fibrosis down_manip anti_fib pro_fib TG2 was overexpressed in lung biopsies from IPF.
In vitro: Overexpression of TG2 (encoded for transglutaminase) → increased fibronectin deposition, whereas TG2 knockdown strongly inhibited collagen gel contraction and cell adhesion in human lung fibroblasts		 Olsen et al 2011 21700912
Tiam1 ENSMUSG00000002489 C57BL/6J Overexpression of Tiam1 male 8-10 wk BLM 2U/kg, intratracheally single dose, follow-up 0-21 days Reduced lung fibrosis up_manip anti_fib anti_fib In vitro: Tiam1 KD increased the TGF-β‑induced expression of α‑SMA in normal human lung fibroblasts while Tiam1 overexpression resulted in an opposite effect → fibroblast differentiation Huang et al 2017 29067109
Timp1 ENSMUSG00000001131 C57BL/6J KO Timp1 male 8-10 wk MWCNT (multi-walled carbon nanotube) 50 µl, pharyngeally single dose, follow-up 0-14 days Reduced lung fibrosis down_manip anti_fib pro_fib [See also miR-34b-5p Knockdown; Hu et al 2019]
MWCNTs may cause lung fibrosis.
KO Timp1 reduced fibrotic focus formation, collagen fiber deposition, recruitment of fibroblasts and differentiation of fibroblasts into myofibroblasts in the lungs.
Timp1 is highly induced during fibrosis in a number of animal models, including BLM- and paraquat-induced lung fibrosis. TIMP1 is also highly induced in fibrosing diseases in humans, such as IPF and liver cirrhosis, implicating dysregulation of TIMP1 expression in the development of fibrosis
[Dong et al 2016; PMID: 26345256]		 Dong et al 2016 27852133
Timp3 ENSMUSG00000020044 C57BL/6 KO Timp3-/-;
miR-34b-5p knockdown		 male 6-8 wk BLM 1 - 1.5 U/kg, intratracheally single dose, follow-up 0-18 days Promoted lung fibrosis down_manip pro_fib anti_fib miR-34b-5p knockdown appears to enhance the resistance to BLM-induced lung fibrosis by regulating its target gene Timp3 [see miR-34b-5p; the same paper] Hu et al 2019 30915776
Tlr2 ENSMUSG00000027995 C57BL/6 KO Tlr2-/- male 6-8 wk BLM 5 mg/kg, intratracheally;
Phycocyanin 50 mg/kg, intratracheally		 single dose, follow-up 0-28 days Reduced lung fibrosis down_manip anti_fib pro_fib Hydroxyproline was used to measure collagen deposition/fibrosis in lung tissues.
Phycocyanin has both anti-oxidant and anti-inflammatory properties and partially depends
on TLR2 protein to alleviate the lung inflammation in BLM-treated mice.
TLR2 played an important role in the development of IPF 		Li et al 2017 28725012
Tlr2
(gene & protein)		 ENSMUSG00000027995 C57BL/6 KO Tlr2-/-
Tlr2 agonists (LTA or Pam3csk4)		 NA 8-10 wk BLM 2 mg/kg, intratracheally;
TLR2 agonists in vivo:
LTA or Pam3csk4 (Tlr2 agonists) 5 μg, i.p. immediately after BLM 		BLM single dose;
LTA or Pam3csk4 (Tlr2 agonists) single dose, immediately after BLM;
Follow-up 0-21 days		 Reduced lung fibrosis down_manip anti_fib pro_fib Tlr2 agonists (LTA or Pam3csk4) promote lung fibrosis in WT mice TLR2 signaling promotes BLM-induced lung fibrosis by inducing IL-27 and chemokine production by respiratory epithelial cells, thereby inhibiting IL-17 production and recruiting inflammatory cells into the lungs. Kim et al 2011 21930967
Tlr4 ENSMUSG00000039005 C57Bl/6J KO Tlr4-/- male and female 8-12 wk BLM 1.25 - 5 U/kg, intratracheally single dose, follow-up 0-21 days Promoted lung fibrosis even at low doses of BLM down_manip pro_fib anti_fib No significant difference in cell surface TLR4 protein expression between AEC2s from patients with IPF and healthy donors Liang et al 2016 27694932
Tmprss4 ENSMUSG00000032091 C57BL/6 KO Tmprss4-/- or Tmprss4+/- NA 8-12 wk Bleomycin sulfate 7 U/kg in 50 μl saline/mouse, intratracheally single dose, follow-up 0-28 days Reduced lung fibrosis down_manip anti_fib pro_fib TMPRSS4 is upregulated in IPF lungs Valero-Jiménez et al 2018 29529050
Tnf ENSMUSG00000024401 C57BL/6 Overexpression of Tnf female 4 wk BLM 150 mg/kg, intravenously single dose, follow-up 0-6 wk Promote lung fibrosis up_manip pro_fib pro_fib [See Tnf overexpression -- Fujita et al 2003, and Tnf KO -- Redente et al 2014]
BLM-treated TG mice showed an enhanced expression of interleukin (IL)-2 and osteopontin (Spp1) mRNA in the lungs [See also Spp1 KO -- coincedes well with Tnf overexpression]		 Nakama et al 1998 9457469
Tnf ENSMUSG00000024401 C57BL/6 Overexpression of Tnf NA NA BLM 0.2 U in 50 μl saline, intratracheally single dose, follow-up 0-14 days Reduced lung fibrosis up_manip anti_fib anti_fib "Large" lungs w/o fibrosis in BLM-treated TG mice [See Tnf overexpression -- Nakama et al 1998, and Tnf KO -- Redente et al 2014]
In vitro: The increased TNF-α protein levels in human IPF alveolar epithelial cells type II [Miyazaki et al 1995; PMID 7542280]
BLM-treated TNF-α TG mice: an increase in PGE2 levels and downregulation of TNF receptor I 		Fujita et al 2003 12816730
Tnf ENSMUSG00000024401 C57BL/6J KO Tnf-/- male 6-8 wk BLM 3 U/kg, intratracheally single dose, follow-up 0-21 days Reduced lung fibrosis down_manip anti_fib pro_fib [See Tnf overexpression -- Fujita et al 2003, and Nakama et al 1998] Redente et al 2014 24325577
Tnfrsf1a ENSMUSG00000030341 C57BL/6, BALB/c or 129/J KO Tnfrsf1a-/- female 6-10 wk BLM 4 U/kg, intratracheally
Silica 0.2 g/kg, intratracheally (separately from BLM)		 BLM single dose, follow-up 0-14 days;
Silica single dose, follow-up 0-28 days 		Reduced lung injury, inflammation and fibrosis after BLM;
Reduced lung injury and inflammation, but similar fibrotic response after Silica		 down_manip anti_fib pro_fib No evidence of collagen deposition and parenchymal and subpleural inflammation in lungs of BLM-treated KO mice.
No significant diffirence in hydroxyproline content after Silica between KO and WT mice		 Ortiz et al 1999 10101016
Tnfrsf1b ENSMUSG00000028599 C57BL/6, BALB/c or 129/J KO Tnfrsf1b-/- female 6-10 wk BLM 4 U/kg, intratracheally
Silica 0.2 g/kg, intratracheally (separately from BLM)		 BLM single dose, follow-up 0-14 days;
Silica single dose, follow-up 0-28 days 		Reduced lung injury, inflammation and fibrosis after BLM;
Reduced lung injury and inflammation, but similar fibrotic response after Silica		 down_manip anti_fib pro_fib Enhaced expression of Tnfrsf1b mRNA after BLM and Silica in WT mice (in all three strains) Ortiz et al 1999 10101016
Tnfsf10 ENSMUSG00000039304 BALB/c KO Tnfsf10-/- male 6-14 wk BLM 2 mg/kg, intratrachealy single dose, follow-up 0-21 days Reduced lung fibrosis down_manip anti_fib pro_fib In humans: Tnfsf10 plays pro-inflammatory role in allergic airway disease and COPD through upregulation of the E3 through the ubiquitin ligase MID1 with subsequent deactivation of PP2A (protein phophatase 2A). In support to human studies, BLM upregulated MID1 in WT mice and downregulated PP2A. KO mice were protected from upregulation of MID1 and deactivation of PP2A Collison et al 2019 30732588
Tph1 ENSMUSG00000040046 C57BL/6 KO Tph1 male 4–5 wk Bleomycin hydrochloride 2 UI/kg in 0.5 ml saline, intratracheally
single dose, follow-up 0-21 days Promoted lung fibrosis down_manip pro_fib anti_fib 5-HT (synthesized by Tph1 protein) could facilitate collagen deposition, inflammation, and
oxidative stress in BLM-induced lung fibrosis. 5-HT could be a biomarker of BLM lung fibrosis		 Zhang et al 2018 29849496
Trib3 ENSMUSG00000032715 C57BL/6 Overexpression of Trib3 male 6-8 wk BLM 3.5 mg/kg, intratracheally single dose, follow-up 0-28 days Promoted lung fibrosis up_manip pro_fib pro_fib Trib3 overexpression in BLM-treated mouse lungs → increased the expression of MAPK pathway-related and EMT-related genes and proteins Yu et al 2019 31934168
Trim16 ENSMUSG00000047821 B6.Blmpf2C3H subcongenic mice Overexpression of Trim16 NA 8-10 wk BLM 100-125 units/kg via minipump, subcutaneously continuous dose for 8 days, follow-up 0-7 wk Promoted lung inflammation and fibrosis up_manip pro_fib pro_fib NB! BLM induces lung fibrosis in susceptible C57BL/6J mice but not in mice of the C3H/HeJ strain. This differential strain response has been used in prior studies to map BKM-induced
lungt fibrosis susceptibility loci named Blmpf1 and Blmpf2. Trim16 was identified to have strain-dependent expression in the lung		 Stefanov et al 2013 23341783
Trim33 ENSMUSG00000033014 SV129 KO Trim33-/- NA NA BLM 1.5 mg/kg, intratracheally single dose, follow-up 0-21 days Promoted lung fibrosis down_manip pro_fib anti_fib TRIM33 is overexpressed in alveolar macrophages of IPF patients Boutanquoi et al 2020 32184320
Trpm2 ENSMUSG00000009292 C57BL/6J KO Trpm2 male 6-10 wk BLM 1 mg/kg, intratracheally
LPS 2.5 μg/body or 50 μg/body, intratracheally
PARP inhibitors (PJ34 or 3-aminobezamide) 50 μl/10g, intraperitoneally		 BLM and LPS single dose;
PARP inhibitors single dose of each one, 1 h before injection of BLM;
Follow-up 0-24 hours 		Reduced BLM-induced lung inflammation;
No significant differences in the severity of LPS-induced lung inflammation between KO and WT mice		 down_manip other invalid PARP induces ROS-mediated activation of Trpm protein activity.
The expression of Trpm2 mRNA (qPCR) and Trpm2 protein (Western blotting) were observed in WT mice, but not in KO mice.
PARP inhibitors markedly reduced BLM-induced recruitment of inflammatory cells and MIP-2 secretion in WT mice, but not in KO mice.		 Yonezawa et al 2015 26600069
Tsc22d3 ENSMUSG00000031431 NA Overexpression of Tsc22d3 NA 6-10 wk BLM 1 U/kg, intratracheally three doses weekly , follow-up 0-21 days Promoted lung injury, inflammation and fibrosis up_manip pro_fib pro_fib Tsc22d3 is involved in control of T lymphocytes activation and apoptosis.
In vitro: After stimulation by CD3/CD28 antibodies, peripheral naive CD4 T cells from TG mice secreted more Th-2 cytokines such as IL-4, IL-5, IL-13, and IL-10, and produce less Th-1 cytokines such as interferon-γ (IFN-γ ) than WT		 Cannarile et al 2006 16204313
Txn1 ENSMUSG00000028367 C57/BL6 Overexpression of Txn1 NA 3 mo BLM 2 units/kg, intratracheally;
Alcohol starting at 5% of alcohol, ramping up over 2 weeks by
5% every 3 to 4 days to the final concentration of 20% in water		 BLM single dose, follow-up 0-14 days
Alcohol for 8 wk + BLM (single dose), follow-up 8 wk		 Reduced lung injury up_manip other invalid Txn1 overexpression reduced TGF-β1 expression induced by chronic alcohol ingestion following BLM-induced lung injury Sueblinvong et al 2016 27436123
Vegfa ENSMUSG00000023951 C57BL/6 Overexpression of Vegfa male and female NA BLM 0.15 U/kg, intratracheally single dose, follow-up 0-14 days Reduced lung fibrosis and mortality up_manip anti_fib anti_fib Vegfa expression is decreased in IPF lungs Murray et al 2017 28814671
Vhl ENSMUSG00000033933 C57BL/6 Overexpression of Vhl NA 6-8 wk BLM 0.05 U in PBS (50 μl) instilled in 2 aliquots (25 μl each), intratracheally single dose, follow-up 0-21 days Promoted lung fibrosis up_manip pro_fib pro_fib Higher levels of pVHL mRNA and protein in IPF vs control lungs Zhou et al 2011 21642472
Vhl ENSMUSG00000033933 NA KO Vhl+/- or Vhl-/- NA NA BLM 0.045 U, intratracheally single dose, follow-up 0-21 days Reduced lung fibrosis down_manip anti_fib pro_fib Increased levels of Vhl in fibroblastic foci in the lungs from IPF patients.
BLM also induced Vhl in mouse lung fibroblasts (MLFs), but not in alveolar type II cells [Frew et al 2007, PMID 18006292]		 Zhou et al 2016 26488390
Wnt10a ENSMUSG00000026167 C57BL/6J Overexpression of Wnt10a male 8 wk BLM 2.0 mg/kg, intratracheally single dose, follow-up 0-14 days Promoted lung inflammation and fibrosis up_manip pro_fib pro_fib Wnt10a overexpression promoted fibroproliferation via the TGF-β signaling, as observed in AE-IPF Oda et al 2016 27071460
Yy1 ENSMUSG00000021264 C57BL/6 KO Yy1+/-or Yy1f/f NA 6-12 wk BLM 3 U/kg, intratracheally to WT only (examined fibroblasts isolated from the lungs);
Silica 200-300 μg, intratracheally 		BLM and silica separately, single dose, follow-up 0-21days Reduced lung inflammation and fibrosis (in Silica model only; after in vivo administration of BLM to WT → investigation in vitro down_manip anti_fib pro_fib Yy1 protein levels in lung fibroblasts isolated from BLM-treated WT mice were dramatically increased compared with those of control (PBS-treated) mice In vitro: The levels of YY1 protein were significantly higher in human IPF lung fibroblasts and murine models of lung fibrosis, including the aggregated pulmonary fibroblasts of fibrotic foci Lin et al 2011 21169469
Zmpste24 ENSMUSG00000043207 C57BL/6 KO Zmpste24-/- male WT 4 wk and 79 wk;
KO 4 wk and 13 wk (progeroid mice) 		BLM 0.1 U in 50 μl saline, oropharyngeally single dose, follow-up 0-21 days Young WT and KO mice developed a similar fibrotic response. Old WT mice developed severe lung fibrosis, while Zmpste24‐/‐ progeroid mice displayed a much lower fibrotic response down_manip anti_fib pro_fib Zmpste24‐/‐ mice display accelerated aging: lack of Zmpste24 causes progeroid phenotypes in mice and humans.
Protection of KO lungs against BLM was apperantly attributed to the upregulation of fibrosis‐related miRNAs (miR23a, 27a, 29a, 145a).
NB! Aging is not only a major risk factor for the development of IPF but also worsens the fibrotic response and outcome in human and experimental fibrotic lung diseases [Sueblinvong et al 2014; PMID: 24596659]		 Calyeca et al 2018 30530916
Contact: Vadim E. Fraifeld, MD, PhD
Head: Lab for the Biology of Aging, The Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev
P.O. Box 653, Beer-Sheva 8410501, Israel
Email:
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If you would like to cite this database please use:
Yanai H, Budovsky A, Tacutu R, Barzilay T, Abramovich A, Ziesche R, Fraifeld VE. Tissue repair genes: the TiRe database and its implication for skin wound healing. Oncotarget. 2016; 7:21145-55.