Effect of endothelin-1 on alpha-smooth muscle actin expression and on alveolar fibroblasts proliferation in interstitial lung diseases

Endothelin-l (ET-I) is a potent constrictor and mitogen peptide which is ex pressed in several pulmonary diseases. To elucidate the involvement of ET-1 in lung interstitial pathologic events, we assessed ET-1 secretion by alve olar macrophages (AIM) and fibroblasts recovered from the bronchoalveolar l avage (BAL) of patients with idiopathic pulmonary fibrosis (IPF), sarcoidos is (SA) and from control subjects. We characterized in vitro alveolar fibro blasts of all subjects using monoclonal antibody specific to alpha-smooth m uscle actin (alpha-SM actin) and human fibroblast marker. We also examined the effect of ET-1 on the fibroblasts' mitogenesis and on their cytoskeleta l phenotype. The AM recovered from IPF patients showed increased spontaneou s secretion of ET-1 compared with cells from SA and control subjects, The e xpression of alpha-SM actin in the fibroblasts from IPF patients was signif icantly higher than in SA fibroblasts and normal lung fibroblasts. Assessin g alveolar fibroblasts purity revealed a negative staining for alpha-SM act in in all SA acid control fibroblasts, while alveolar fibroblasts recovered from IPF were 100% positive for alpha-SM actin, a reliable differentiation marker of myofibroblastic cells. Exposure of SA alveolar fibroblasts to ET -1 resulted in an increased expression of alpha-SM actin. Addition of exoge nous ET-1 to alveolar fibroblasts culture stimulated DNA synthesis and prol iferation in all groups. Moreover, neutralization of ET-1 by monoclonal ant ibody was shown to decrease H-3-thymidine incorporation in fibroblasts cult ured with AM supernatants. These results suggest possible interactions betw een AM, myofibroblasts and fibroblasts in interstitial lung diseases (ILD). By modulating alpha-SM actin expression and exertion of the mitogenic effe ct on alveolar fibroblasts, ET-1 might play an important role in the fibrog enesis of ILD. (C) 1999 International Society for Immunopharmacology. Publi shed by Elsevier Science Ltd. All rights reserved.