ENDOTHELIN-1 SYNTHESIS, RECEPTORS, AND SIGNAL-TRANSDUCTION IN ALVEOLAR EPITHELIUM - EVIDENCE FOR AN AUTOCRINE ROLE

In the lung, endothelin-1 (ET-1) is synthesized by several cell types and acts locally to cause vasoconstriction and bronchoconstriction, ac tivate alveolar macrophages, and stimulate chloride secretion. We repo rt ET-1 production, binding, and signal transduction by a previously u nrecognized site, the alvelolar epithelial cell. L2 cells, a cloned ra t alveolar epithelial cell line, secreted ET-1 and contained ET-1 mRNA . Exposure of L2 cells to lipopolysaccharide, tumor necrosis factor-al pha, interleukin-1, or transforming growth factor-beta stimulated ET-1 release, whereas interferon-gamma or platelet-derived growth factor d ecreased ET-1 secretion. I-125-ET-1 binding to L2 cells revealed a sin gle binding site with a maximal binding capacity of 22.4 fmol/mg prote in and a dissociation constant of 4.03 nM. I-125-ET-1 binding was comp letely inhibited by ET receptor A (ET(A)) blockade and by unlabeled ET -1 > > ET-3=sarafotoxin 6c, consistent with the presence of ET(A). Exo genous ET-1 increased, whereas blockade of endogenous ET-1 decreased p rostaglandin E(2) (PGE(2)) production by L2 cells; exogenous ET-1 also increased adenosine 3',5'-cyclic monophosphate (cAMP) production. We conclude that 1) cloned rat alveolar epithelial cells synthesize ET-1; 2) inflammatory mediators modulate ET-1 production; 3) L2 cells expre ss ET(A); 4) ET-1 increases PGE(2) and cAMP levels in these cells; and 5) BQ-123, an ET(A) antagonist, decreases their basal PGE(2) producti on. These studies suggest that ET-1 may function as an autocrine facto r in alveolar epithelial cells.