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, activate alveolar macrophages, and stimulate chloride secretion. We report ET-1 production, binding, and signal transduction by a previously unrecognized site, the alveolar epithelial cell. L2 cells, a cloned rat alveolar epithelial cell line, secreted ET-1 and contained ET-1 mRNA. Exposure of L2 cells to lipopolysaccharide, tumor necrosis factor-alpha, interleukin-1, or transforming growth factor-beta stimulated ET-1 release, whereas interferon-gamma or platelet-derived growth factor decreased ET-1 secretion. 125I-ET-1 binding to L2 cells revealed a single binding site with a maximal binding capacity of 22.4 fmol/mg protein and a dissociation constant of 4.03 nM. 125I-ET-1 binding was completely inhibited by ET receptor A (ETA) blockade and by unlabeled ET-1 >> ET-3 = sarafotoxin 6c, consistent with the presence of ETA. Exogenous ET-1 increased, whereas blockade of endogenous ET-1 decreased prostaglandin E2 (PGE2) 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 express ETA; 4) ET-1 increases PGE2 and cAMP levels in these cells; and 5) BQ-123, an ETA antagonist, decreases their basal PGE2 production. These studies suggest that ET-1 may function as an autocrine factor in alveolar epithelial cells.