title: Endothelin-1 induces hypertrophy and inhibits apoptosis in human airway smooth muscle cells.
abstract: Endothelin-1 (ET-1), a G protein-coupled receptor-activating peptide, is increased in airway epithelium, plasma, and bronchoalveolar lavage fluid of asthmatic patients. We hypothesized that ET-1 may contribute to the increased airway smooth muscle mass found in severe asthma by inducing hypertrophy and inhibiting apoptosis of smooth muscle cells. To investigate this hypothesis, we determined that treatment of primary human bronchial smooth muscle cells with ET-1 dose dependently [10(-11)-10(-7) M] inhibited the apoptosis induced by serum withdrawal. ET-1 treatment also resulted in a significant increase in total protein synthesis, mediated through both ET(A) and ET(B) receptors, cell size, as well as increased expression of myosin heavy chain, alpha-smooth muscle actin, and calponin. ET-1-induced hypertrophy was accompanied by activation of JAK1/STAT-3 and MAPK1/2 (ERK1/2) cell signaling pathways. Inhibition of JAK1/STAT-3 pathways by piceatannol or ERK1/2 by the MAPK/ERK kinase 1/2 inhibitor U0126 blunted the increase in total protein synthesis. The hypertrophic effect of ET-1 was equivalent to that of the gp130 cytokine oncostatin M and greater than that induced by cardiotrophin-1. ET-1 induced release of IL-6 but not IL-11, leukemia inhibitory factor, oncostatin M, or cardiotrophin-1, although treatment of cells with IL-6 alone did not induce hypertrophy. These results suggest that ET-1 is a candidate mediator for the induction of increased smooth muscle mass in asthma and identify signaling pathways activated by this mediator.
authors.affiliation: James Hogg iCAPTURE Centre for Cardiovascular and Pulmonary Research, St. Paul's Hospital, University of British Columbia, 1081 Burrard St., Vancouver, BC, Canada V6Z 1Y6.
authors.forename: Ralph
authors.initials: R
authors.lastname: McWhinnie
authors.forename: Dmitri V
authors.initials: DV
authors.lastname: Pechkovsky
authors.forename: Danyi
authors.initials: D
authors.lastname: Zhou
authors.forename: David
authors.initials: D
authors.lastname: Lane
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Halayko
authors.forename: Darryl A
authors.initials: DA
authors.lastname: Knight
authors.forename: Tony R
authors.initials: TR
authors.lastname: Bai
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001980:Bronchi / Q000187:drug effects* / Q000473:pathology*; D002070:Butadienes / Q000494:pharmacology; D049108:Cell Enlargement / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000494:pharmacology; D019332:Endothelin-1 / Q000494:pharmacology*; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis / Q000494:pharmacology; D053613:Janus Kinase 1 / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D009124:Muscle Proteins / Q000378:metabolism; D009130:Muscle, Smooth / Q000187:drug effects* / Q000473:pathology*; D009570:Nitriles / Q000494:pharmacology; D053683:Oncostatin M / Q000494:pharmacology; D011994:Recombinant Proteins / Q000494:pharmacology; D050796:STAT3 Transcription Factor / Q000378:metabolism
chemical_list: D002070:Butadienes; D016207:Cytokines; D019332:Endothelin-1; C508600:IL6 protein, human; D015850:Interleukin-6; D009124:Muscle Proteins; D009570:Nitriles; D011994:Recombinant Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C113580:U 0126; D053683:Oncostatin M; C092073:cardiotrophin 1; C507904:JAK1 protein, human; D053613:Janus Kinase 1