Discoidin domain receptor 1-deficient mice are resistant to bleomycin-induced lung fibrosis.
BACKGROUND
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.


OBJECTIVE
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.


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.
Avivi-Green
Carmel
C
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
Singal
Mayank
M
Vogel
Wolfgang F
WF
D000818:Animals; D001761:Bleomycin / Q000009:adverse effects; D015153:Blotting, Western; D001992:Bronchoalveolar Lavage Fluid; D000070818:Discoidin Domain Receptors; D018450:Disease Progression; D005260:Female; D005355:Fibrosis; D008168:Lung / Q000187:drug effects / Q000473:pathology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D011975:Receptors, Mitogen / Q000235:genetics / Q000378:metabolism*
D011975:Receptors, Mitogen; D001761:Bleomycin; D000070818:Discoidin Domain Receptors; D020794:Receptor Protein-Tyrosine Kinases