title: Cthrc1 lowers pulmonary collagen associated with bleomycin-induced fibrosis and protects lung function.
abstract: Idiopathic pulmonary fibrosis (IPF) involves collagen deposition that results in a progressive decline in lung function. This process involves activation of Smad2/3 by transforming growth factor (TGF)-βand Wnt signaling pathways. Collagen Triple Helix Repeat-Containing-1 (Cthrc1) protein inhibits Smad2/3 activation. To test the hypothesis that Cthrc1 limits collagen deposition and the decline of lung function, Cthrc1 knockout (Cthrc1-/-) and wild-type mice (WT) received intratracheal injections of 2.5 U/kg bleomycin or saline. Lungs were harvested after 14 days and Bronchoalveolar lavage (BAL) TGF-β, IL1-β, hydroxyproline and lung compliance were assessed. TGF-βwas significantly higher in Cthrc1-/-compared to WT (53.45 ± 6.15 ng/mL vs. 34.48 ± 11.05) after saline injection. Bleomycin injection increased TGF-βin both Cthrc1-/-(66.37 ± 8.54 ng/mL) and WT (63.64 ± 8.09 ng/mL). Hydroxyproline was significantly higher in Cthrc1-/-compared to WT after bleomycin-injection (2.676 ± 0.527μg/mg vs. 1.889 ± 0.520,P= 0.028). Immunohistochemistry of Cthrc1-/-lung sections showed intracellular localization and activation ofβ-catenin Y654 in areas of tissue remodeling that was not evident in WT Lung compliance was significantly reduced by bleomycin in Cthrc1-/-but there was no effect in WT animals. These data suggest Cthrc1 reduces fibrotic tissue formation in bleomycin-induced lung fibrosis and the effect is potent enough to limit the decline in lung function. We conclude that Cthrc1 plays a protective role, limiting collagen deposition and could form the basis of a novel therapy for pulmonary fibrosis.
authors.affiliation: Department of Biomedical Sciences, School of Medicine, Greenville, University of South Carolina, Greenville, South Carolina.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Binks
authors.affiliation: Department of Biomedical Sciences, College of Osteopathic Medicine, University of New England, Biddeford, Maine.
authors.forename: Megyn
authors.initials: M
authors.lastname: Beyer
authors.affiliation: Department of Biomedical Sciences, School of Medicine, Greenville, University of South Carolina, Greenville, South Carolina.|Department of Biomedical Sciences, College of Osteopathic Medicine, University of New England, Biddeford, Maine.
authors.forename: Ryan
authors.initials: R
authors.lastname: Miller
authors.affiliation: Department of Biomedical Sciences, School of Medicine, Greenville, University of South Carolina, Greenville, South Carolina leclairr@greenvillemed.sc.edu.
authors.forename: Renee J
authors.initials: RJ
authors.lastname: LeClair
mesh_terms: D000818:Animals; D001761:Bleomycin; D002478:Cells, Cultured; D003094:Collagen / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D008168:Lung / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D012119:Respiration; D015398:Signal Transduction / Q000235:genetics
chemical_list: C530500:Cthrc1 protein, mouse; D016326:Extracellular Matrix Proteins; D001761:Bleomycin; D003094:Collagen
keywords: Collagen; Cthrc1; interstitial lung disease; lung fibrosis