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Discoidin Domain Receptor 1–deficient Mice Are Resistant to Bleomycin-induced Lung Fibrosis

Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada

Correspondence and requests for reprints should be addressed to Wolfgang F. Vogel, Ph.D., Medical Sciences Building, Room 6342, 1 King's College Circle, Toronto, ON, M5S 1A8 Canada. E-mail: w.vogel{at}utoronto.ca

Rationale: Discoidin domain receptor 1 (DDR1) is a tyrosine kinase activated by native collagens. Based on previous findings showing increased DDR1 expression in bronchoalveolar lavage cells from patients with idiopathic pulmonary fibrosis, we hypothesized that DDR1 mediates disease progression after lung injury.

Objectives: To investigate the inflammatory and fibrotic responses of DDR1 knockout and wild-type mice to bleomycin-induced lung injury.

Methods: Age- and sex-matched DDR1 knockout and wild-type C57BL/6 mice received a single intratracheal instillation of 2 U/kg bleomycin or saline, respectively. After 2 wk, lung inflammation and fibrosis were assessed using immunohistochemistry, real-time polymerase chain reaction, TUNEL assay, ELISA, fluorescence-activated cell sorting, and Western blot analysis.

Measurements and Main Results: Compared with wild-type animals, DDR1-null mice were largely protected against bleomycin-induced injury. Bleomycin-induced increases in collagen protein levels and tenascin-C mRNA levels were abrogated in knockout animals. Furthermore, myofibroblast expansion and apoptosis were much lower in these animals compared with their wild-type counterparts. Absence of inflammation in knockout mice was confirmed by lavage cell count and a cytokine ELISA. Western blot analysis of injured lung tissue revealed that DDR1-null mice failed to respond to the bleomycin insult with p38 MAPK activation, which was readily observed in wild-type mice.

Conclusions: DDR1 expression is a prerequisite for the development of lung inflammation and fibrosis. Blockade of DDR1 may therefore be a novel therapeutic intervention in patients with pulmonary fibrosis.

Key Words: kinases/phosphatases • lung • signal transduction • transgenic/knockout mice

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