Endotoxin stimulates platelet-derived growth factor production from cultured human pulmonary endothelial cells.
The interaction of Gram-negative bacterial cell wall products (endotoxins) with endothelial cells is thought to be responsible for many of the damaging manifestations of Gram-negative sepsis. Because cultured human endothelial cells are relatively resistant to the direct cytotoxic actions of endotoxin, it is possible that many of the systemic effects of endotoxin may be caused by stimulation of endothelial cells to produce biologically active mediators which could then act on targets such as smooth muscle cells, fibroblasts, and leukocytes. We hypothesized that one such endothelial cell-derived mediator could be platelet-derived growth factor (PDGF), a protein that causes proliferation of mesenchymal cells, chemotaxis of leukocytes, fibroblasts and smooth muscle cells, and vasoconstriction. We therefore examined the effect of endotoxin on PDGF-like protein production by cultured adult human pulmonary artery endothelial cells. Twenty-four hours of endotoxin exposure resulted in a threefold increase in the steady-state levels of mRNA coding for PDGF B-chain (c-sis) and a two- to threefold increase in the amount of newly synthesized PDGF released into the media, as measured by immunoprecipitation of [35S]methionine-labeled protein with anti-PDGF antiserum. We conclude that human pulmonary artery endothelial cells in culture are stimulated both to produce increased amounts of PDGF mRNA and to release PDGF-like protein after exposure to endotoxin. This increased release of PDGF-like protein by human endothelial cells may play a role in the inflammatory infiltrate, vasospasm, and fibroblast proliferation that characterize the host response to endotoxin.
Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia 19104.
S M
SM
Albelda
J A
JA
Elias
E M
EM
Levine
J A
JA
Kern
D000328:Adult; D015152:Blotting, Northern; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism*; D004731:Endotoxins / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D010982:Platelet-Derived Growth Factor / Q000096:biosynthesis* / Q000235:genetics; D011651:Pulmonary Artery / Q000187:drug effects / Q000378:metabolism; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics*
D004731:Endotoxins; D008070:Lipopolysaccharides; D010982:Platelet-Derived Growth Factor; D012333:RNA, Messenger