Lack of discoidin domain receptor 1 protects against lung fibrosis

Abstract

Rationale Discoidin Domain Receptor 1 (DDR1) is a tyrosine kinase activated by various types of collagen. Based on previous work showing increased DDR1 expression in bronchoalveolar lavage cells from patients with idiopathic pulmonary fibrosis, we hypothesized that DDR1 could be a key mediator during disease progression following lung injury. Objectives To investigate the response of DDR1 knockout and control mice to bleomycin-induced lung injury. Methods Age- and gender-matched C57/BL6 knockout and control mice received a single intratracheal instillation of 2U/kg bleomycin or saline, respectively. After 2 weeks, lung inflammation and fibrosis were assessed using immunohistochemistry, real time PCR, TUNEL assay, ELISA, FACS and Western blot analysis. Results Compared to control animals, DDR1-null mice were largely protected against bleomycin injury. Collagen content as well as tenascin- C and fibrillin-1 expression were significantly less increased in knockout than control mice. Myofibroblast expansion and apoptotic cell count were lower in DDR1-null than control mice. Absence of inflammation in knockout mice was confirmed by lavage cell count and cytokine ELISA. Western blot analysis of injured lung tissue revealed that DDR1-null mice failed to respond with an increase in p42/p44 and p38 MAPK pathway activation, which was observed in control mice. Conclusions Using a mouse strain lacking DDR1, our data provide compelling evidence that DDR1 expression is a prerequisite in the progression of lung inflammation and fibrosis. Blockade of DDR1 may therefore be a novel and attractive therapeutic intervention in patients with pulmonary fibrosis. Grant support: Canada Research Chair Program