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.
Markewitz
B A
BA
Department of Medicine, Veterans Administration Medical Center, Salt Lake City, Utah.
Kohan
D E
DE
Michael
J R
JR
D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D000242:Cyclic AMP / Q000378:metabolism; D015232:Dinoprostone / Q000037:antagonists & inhibitors / Q000378:metabolism; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000096:biosynthesis* / Q000494:pharmacology; D004847:Epithelial Cells; D004848:Epithelium / Q000502:physiology; D015335:Molecular Probes / Q000235:genetics; D008969:Molecular Sequence Data; D010456:Peptides, Cyclic / Q000494:pharmacology; D011650:Pulmonary Alveoli / Q000166:cytology / Q000502:physiology*; D051381:Rats; D017466:Receptors, Endothelin / Q000378:metabolism*; D015398:Signal Transduction
D065128:Endothelin Receptor Antagonists; D016232:Endothelins; D015335:Molecular Probes; D010456:Peptides, Cyclic; D017466:Receptors, Endothelin; D000242:Cyclic AMP; D015232:Dinoprostone; C072247:cyclo(Trp-Asp-Pro-Val-Leu)