Published ahead of print on May 11, 2006, doi:10.1164/rccm.200603-333OC Am. J. Respir. Crit. Care Med., Volume 174, Number 4, August 2006, 420-427 A more recent version of this article appeared on August 15, 2006
Submitted on March 7, 2006 Discoidin Domain Receptor 1 Deficient Mice are Resistant to Bleomycin-induced Lung FibrosisCarmel Avivi-Green1,1 Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada * To whom correspondence should be addressed. 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 gender-matched DDR1 knockout and wild type C57BL/6 mice received a single intratracheal instillation of 2 U/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. Measurements and Main Results: Compared to 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 to 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, Signal Transduction, Lung fibrosis, Transgenic/Knockout Mice
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