Suppression of discoidin domain receptor 1 by RNA interference attenuates lung inflammation.
Discoidin domain receptor 1 (DDR1) is a receptor tyrosine kinase whose ligand is collagen. Recently, we have reported the association of DDR1 in the cytokine production of human leukocytes in in vitro and in vivo expression in idiopathic pulmonary fibrosis. However, its role in in vivo inflammation has not been fully elucidated. Small interference RNA (siRNA) can induce specific suppression of in vitro and in vivo gene expression. In this study, using a bleomycin-induced pulmonary fibrosis mouse model, we administered siRNA against DDR1 transnasally and evaluated histological changes, cytokine expression, and signaling molecule activation in the lungs. Histologically, siRNA against DDR1 successfully reduced in vivo DDR1 expression and attenuated bleomycin-induced infiltration of inflammatory cells. Furthermore, it significantly reduced inflammatory cell counts and concentrations of cytokines such as MCP-1, MIP-1alpha, and MIP-2 in bronchoalveolar lavage fluid. Subsequently, bleomycin-induced up-regulation of TGF-beta in bronchoalveolar lavage fluid was significantly inhibited, and collagen deposition in the lungs was reduced. Furthermore, siRNA against DDR1 significantly inhibited bleomycin-induced P38 MAPK activation in the lungs. Considered together, we propose that DDR1 contributes to the development of bleomycin-induced pulmonary inflammation and fibrosis.
Matsuyama
Wataru
W
Division of Respiratory Medicine, Respiratory and Stress Care Center, Kagoshima University Hospital, Kagoshima, Japan. vega@xa2.so-net.ne.jp
Watanabe
Masaki
M
Shirahama
Yuko
Y
Hirano
Ryuki
R
Mitsuyama
Hideo
H
Higashimoto
Ikkou
I
Osame
Mistuhiro
M
Arimura
Kimiyoshi
K
D000281:Administration, Intranasal; D000818:Animals; D001761:Bleomycin / Q000633:toxicity; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D000070818:Discoidin Domain Receptors; D005260:Female; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology; D034741:RNA, Small Interfering / Q000008:administration & dosage*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics*; D011975:Receptors, Mitogen / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
D016207:Cytokines; D034741:RNA, Small Interfering; D011975:Receptors, Mitogen; D001761:Bleomycin; D000070818:Discoidin Domain Receptors; D020794:Receptor Protein-Tyrosine Kinases; D048051:p38 Mitogen-Activated Protein Kinases