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Endothelin-1 and Transforming Growth Factor-β1 Independently Induce Fibroblast Resistance to Apoptosis via AKT Activation

¹ Department of Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan Medical Center, Ann Arbor, Michigan

Correspondence and requests for reprints should be addressed to Jeffrey C. Horowitz, M.D., University of Michigan Medical Center, 6301 MSRB III, 1150 W. Medical Center Dr., Ann Arbor, MI 48109-5642. E-mail: jchorow{at}umich.edu

Myofibroblast apoptosis is critical for the normal resolution of wound repair responses, and impaired myofibroblast apoptosis is associated with tissue fibrosis. Lung expression of endothelin (ET)-1, a soluble peptide implicated in fibrogenesis, is increased in murine models of pulmonary fibrosis and in the lungs of humans with pulmonary fibrosis. Mechanistically, ET-1 has been shown to induce fibroblast proliferation, differentiation, contraction, and collagen synthesis. In this study, we examined the role ET-1 in the regulation of lung fibroblast survival and apoptosis. ET-1 rapidly activates the prosurvival phosphatidylinositol 3'-OH kinase (PI3K)/AKT signaling pathway in normal and fibrotic human lung fibroblasts. ET-1–induced activation of PI3K/AKT is dependent on p38 mitogen-activated protein kinase (MAPK), but not extracellular signal-regulated kinase (ERK) 1/2, JNK, or transforming growth factor (TGF)-β1. Activation of the PI3K/AKT pathway by ET-1 inhibits fibroblast apoptosis, and this inhibition is reversed by blockade of p38 MAPK or PI3K. TGF-β1 has been shown to attenuate myofibroblast apoptosis through the p38 MAPK–dependent secretion of a soluble factor, which activates PI3K/AKT. In this study, we show that, although TGF-β1 induces fibroblast synthesis and secretion of ET-1, TGF-β1 activation of PI3K/AKT is not dependent on ET-1. We conclude that ET-1 and TGF-β1 independently promote fibroblast resistance to apoptosis through signaling pathways involving p38 MAPK and PI3K/AKT. These findings suggest the potential for novel therapies targeting the convergence of prosurvival signaling pathways activated by these two profibrotic mediators.

Key Words: myofibroblast • fibrosis • Fas • p38 mitogen-activated protein kinase • mesenchymal cells

CLINICAL RELEVANCE The primary finding of this study is that two fibrogenic growth factors, endothelin (ET)-1 and transforming growth factor (TGF)-β1 independently activate antiapoptotic signaling mechanisms in human lung fibroblasts by p38 mitogen-activated protein kinase–dependent activation of phosphatidylinositol 3'-OH kinase/AKT. These results provide important insights into the mechanisms regulating fibroblast survival and apoptosis, with broad implications in the regulation of lung injury and repair processes. The convergence antiapoptotic signaling pathways mediated by ET-1 and TGF-β1 may represent novel therapeutic targets for the treatment of pulmonary fibrosis.