title: Opposing effects of bone morphogenetic protein-2 and endothelin-1 on lung fibroblast chloride currents.
abstract: Alteration in the control of bone morphogenetic protein (BMP)-regulated genes and increased expression of endothelin (ET)-1 are both believed to play important roles in the still incompletely understood pathobiology of pulmonary vascular remodeling and fibrosis. Recent studies have drawn attention to the contribution of adventitial fibroblast activation in these phenomena. Because chloride channels are involved in the control of physiological function of fibroblasts, we hypothesized that these channels are differentially regulated by BMPs and ET. We measured chloride ion currents by whole-cell path-clamping in cultured primary human pulmonary fibroblasts. The application of BMP2 prevented activation of these currents by hypotonic challenge in a time- and dose-dependent manner, partially via protein kinase C signaling. Maximal inhibition was observed after 45-minute incubation of cells in the presence of 10 ng/ml of BMP2. ET-1 did not activate chloride channels acutely; however, prolonged treatment of cells with ET-1 (100 nM, 2 h) induced the appearance of lysophosphatidic acid-activated chloride currents (a marker of differentiated myofibroblasts), and this induction could be effectively blocked by BMP2 pretreatment (10 ng/ml). BMP2 also prevented stimulation of α-smooth muscle actin gene expression and cell migration of fibroblasts induced by ET-1. We conclude that ET-1 and BMP2 have opposing effects on chloride channel activity in human fibroblasts. This is a potentially relevant mechanism involved in pulmonary vascular remodeling and fibrosis.
authors.affiliation: Physiology Department, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Vadim
authors.initials: V
authors.lastname: Shlyonsky
authors.forename: Ismail Ben
authors.initials: IB
authors.lastname: Soussia
authors.forename: Robert
authors.initials: R
authors.lastname: Naeije
authors.forename: Frédérique
authors.initials: F
authors.lastname: Mies
mesh_terms: D000199:Actins / Q000096:biosynthesis; D000943:Antigens, Differentiation / Q000096:biosynthesis; D055396:Bone Morphogenetic Protein 2 / Q000378:metabolism* / Q000494:pharmacology; D002460:Cell Line; D002712:Chlorides / Q000378:metabolism*; D019332:Endothelin-1 / Q000378:metabolism* / Q000494:pharmacology; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D017136:Ion Transport / Q000187:drug effects; D011493:Protein Kinase C / Q000378:metabolism; D011658:Pulmonary Fibrosis / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000199:Actins; D000943:Antigens, Differentiation; C525718:BMP2 protein, human; D055396:Bone Morphogenetic Protein 2; D002712:Chlorides; D019332:Endothelin-1; D011493:Protein Kinase C