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.

• Authors: Andrew P Binks, Megyn Beyer, Ryan Miller, Renee J LeClair
• Journal: Physiological reports (Physiol Rep) Vol. 5 Issue 5 (Mar 2017) ISSN: 2051-817X [Electronic] United States
• PMID: 28292882 (Publication Type: Journal Article)
• Copyright: © 2017 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.

Chemical References

• Cthrc1 protein, mouse
• Extracellular Matrix Proteins
• Bleomycin
• Collagen

Topics

• Animals
• Bleomycin
• Cells, Cultured
• Collagen (genetics, metabolism)
• Disease Models, Animal
• Extracellular Matrix Proteins (genetics, metabolism)
• Fibroblasts (metabolism, pathology)
• Lung (metabolism, pathology)
• Male
• Mice
• Mice, Knockout
• Pulmonary Fibrosis (chemically induced, genetics, metabolism, pathology)
• Respiration
• Signal Transduction (genetics)