title: Activation of discoidin domain receptor 1 on CD14-positive bronchoalveolar lavage fluid cells induces chemokine production in idiopathic pulmonary fibrosis.
abstract: Discoidin domain receptor 1 (DDR1) is a receptor tyrosine kinase activated by collagen. We previously reported the functional expression of DDR1 on human monocyte-derived macrophages in vitro; however, information regarding its role in diseases is limited. Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease, and the lesions contain an abundance of collagen. In this study, we examined DDR1 expression on bronchoalveolar lavage fluid (BALF) cells and investigated its functionality using samples obtained from 28 IPF patients, 13 chronic obstructive pulmonary disease patients, and 14 healthy volunteers. The DDR1 expression level in CD14-positive BALF cells was higher in IPF patients than in chronic obstructive pulmonary disease patients or healthy volunteers. The predominant isoform was DDR1b in the IPF group, while DDR1a was predominant in the other two groups. Using immunohistochemical analysis, we also detected DDR1 expression on infiltrating inflammatory cells in the IPF lesion. In IPF patients, DDR1 activation induced the production of MCP-1, IL-8, MIP-1 alpha, and matrix metalloproteinase-9 (MMP-9) from CD14-positive BALF cells in a p38 MAPK-dependent manner. In contrast, DDR1 activation of CD14-positive BALF cells in the other groups did not induce the production of these chemokines or MMP-9. These chemokines and MMP-9 contribute to the development of IPF and, therefore, we suggest that DDR1 might be associated with the pathogenesis of IPF in the tissue microenvironment.
authors.affiliation: Division of Respiratory Medicine, Respiratory and Stress Care Center, Kagoshima University Hospital, Sakuragaoka, Kagoshima, Japan. vega@xa2.so-net.ne.jp
authors.forename: Wataru
authors.initials: W
authors.lastname: Matsuyama
authors.forename: Masaki
authors.initials: M
authors.lastname: Watanabe
authors.forename: Yuko
authors.initials: Y
authors.lastname: Shirahama
authors.forename: Ken-Ichi
authors.initials: K
authors.lastname: Oonakahara
authors.forename: Ikkou
authors.initials: I
authors.lastname: Higashimoto
authors.forename: Teizo
authors.initials: T
authors.lastname: Yoshimura
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Osame
authors.forename: Kimiyoshi
authors.initials: K
authors.lastname: Arimura
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000328:Adult; D000368:Aged; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology* / Q000276:immunology*; D002469:Cell Separation; D018925:Chemokines / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D003094:Collagen / Q000494:pharmacology; D000070819:Discoidin Domain Receptor 1; D000070821:Discoidins; D004357:Drug Synergism; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007106:Immune Sera / Q000494:pharmacology; D007150:Immunohistochemistry; D007527:Isoenzymes / Q000378:metabolism / Q000502:physiology; D037102:Lectins / Q000378:metabolism*; D018950:Lipopolysaccharide Receptors / Q000096:biosynthesis*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis; D008565:Membrane Proteins / Q000819:agonists / Q000096:biosynthesis / Q000276:immunology / Q000378:metabolism*; D008875:Middle Aged; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D021381:Protein Transport / Q000276:immunology; D015800:Protozoan Proteins / Q000378:metabolism*; D011658:Pulmonary Fibrosis / Q000201:enzymology* / Q000276:immunology* / Q000503:physiopathology; D011725:Pyridines / Q000494:pharmacology; D020794:Receptor Protein-Tyrosine Kinases / Q000096:biosynthesis / Q000276:immunology / Q000378:metabolism*; D055765:Shc Signaling Adaptor Proteins; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D015854:Up-Regulation / Q000276:immunology; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018925:Chemokines; D000070821:Discoidins; D007093:Imidazoles; D007106:Immune Sera; D007527:Isoenzymes; D037102:Lectins; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D015800:Protozoan Proteins; D011725:Pyridines; C528024:SHC1 protein, human; D055765:Shc Signaling Adaptor Proteins; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D003094:Collagen; C092030:DDR1 protein, human; D000070819:Discoidin Domain Receptor 1; D020794:Receptor Protein-Tyrosine Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020780:Matrix Metalloproteinase 9; C093642:SB 203580