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)‐ β and 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‐ β was 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‐ β in 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 ± 0.527  μg/mg vs. 1.889 ± 0.520, P = 0.028). Immunohistochemistry of Cthrc1 ^‐/‐ lung sections showed intracellular localization and activation of β‐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.