title: Discoidin domain receptor 1 contributes to the survival of lung fibroblast in idiopathic pulmonary fibrosis.
abstract: Idiopathic pulmonary fibrosis (IPF), characterized by fibroblast proliferation and accumulation of extracellular matrix, including collagen, is a chronic progressive disorder that results in lung remodeling and fibrosis. However, the cellular mechanisms that may make fibroblasts resistant to apoptosis have not been completely elucidated. Discoidin domain receptor 1 (DDR1), a receptor tyrosine kinase whose ligand is collagen, is expressed in vivo and contributes in vitro to leukocyte differentiation and nuclear factor (NF)-kappaB activation, which may play an important role in fibroblast survival. In this study, we examined in vivo and in vitro DDR1 expression and its role in cell survival using fibroblasts obtained from IPF and non-IPF patients. Immunohistochemically, fibroblasts present in fibroblastic foci expressed endogenous DDR1. The DDR1 expression level was significantly higher in fibroblasts from IPF patients, and the predominant isoform was DDR1b. In IPF patients, DDR1 activation in fibroblasts inhibited Fas ligand-induced apoptosis and resulted in NF-kappaB nuclear translocation. Suppression of DDR1 expression in fibroblasts by siRNA abolished these effects, and an NF-kappaB inhibitor abrogated the anti-apoptotic effect of DDR1 activation. We propose that DDR1 contributes to fibroblast survival in the tissue microenvironment of IPF and that DDR1 up-regulation may occur in other fibroproliferative lung diseases as well.
authors.affiliation: Division of Respiratory Medicine, Respiratory and Stress Care Center, Kagoshima University Hospital, Sakuragaoka 8-35-1, Kagoshima 890-8520, 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: Hideo
authors.initials: H
authors.lastname: Mitsuyama
authors.forename: Ikkou
authors.initials: I
authors.lastname: Higashimoto
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Osame
authors.forename: Kimiyoshi
authors.initials: K
authors.lastname: Arimura
mesh_terms: D000199:Actins / Q000032:analysis / Q000378:metabolism; D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000906:Antibodies / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002470:Cell Survival; D003094:Collagen / Q000494:pharmacology; D000070818:Discoidin Domain Receptors; D053222:Fas Ligand Protein; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D008168:Lung / Q000201:enzymology* / Q000473:pathology; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000494:pharmacology; D009130:Muscle, Smooth / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D011658:Pulmonary Fibrosis / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D034741:RNA, Small Interfering / Q000494:pharmacology; D020794:Receptor Protein-Tyrosine Kinases / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D011975:Receptors, Mitogen / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D000079424:Tumor Necrosis Factor Inhibitors; D048069:Tumor Necrosis Factors / Q000494:pharmacology
chemical_list: D000199:Actins; D000906:Antibodies; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D034741:RNA, Small Interfering; D011975:Receptors, Mitogen; D000079424:Tumor Necrosis Factor Inhibitors; D048069:Tumor Necrosis Factors; D003094:Collagen; D000070818:Discoidin Domain Receptors; D020794:Receptor Protein-Tyrosine Kinases