Endotoxin stimulates platelet-derived growth factor production from cultured human pulmonary endothelial cells

Abstract

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.

Ventilatory Response to Hypoxia during Endotoxemia in Young Rats: Role of Nitric Oxide

“…Their activation can depress respiration and change the breathing pattern during hypoxia (28 -30). Their expression is also increased during endotoxemia (7,30) and consequently could explain the observed late depression in the VRH after endotoxin administration. This possibility requires further investigation to be elucidated.…”

Eicosapentaenoic Acid Potentiates the Production of Nitric Oxide Evoked by lnterleukin-1β in Cultured Vascular Smooth Muscle Cells

“…The production of platelet-derived growth factor can be evoked in endothelial and vascular smooth muscle cells by cytokines such as tumor necrosis factor and interleu kin-ip [33], by endotoxin [36], and also by coagulation factor Xa [37] and thrombin [38,39], In contrast, the pro duction of platelet-derived growth factor in cultured en dothelial cells is inhibited by a commercial fish oil extract (MaxEPA) [40]. These observations support the idea that eicosapentaenoic acid may potentiate the production of nitric oxide in cultured vascular smooth muscle cells pos sibly by reducing the endogenous production of growth factors (e.g.…”

Lipopolysaccharide (LPS)-binding protein and soluble CD14 function as accessory molecules for LPS-induced changes in endothelial barrier function, in vitro.

“…Kinetic analysis of accessory molecule(s) regulation of LPS-induced changes in endothelial barrier function. Transendothelial "4C-BSA flux was determined across serum-starved monolayers immediately after increasing exposure times to serum-free media, LPS 100 ng/ml serum-free media, LPS with LBP (1.2 gg/ml), LPS with sCD14 (50 or 500 ng/ml), and LPS with both LBP and sCD14 (50 ng/ml certain other LPS-induced EC responses, including hyperadhesiveness for neutrophils (23), and increased expression ofplasminogen activator inhibitor 1 (24), IL-i (25), IL-6 (18, 26), IL-8 (18), and PDGF (27). The time requirements for the LPS-induced changes in endothelial barrier function are not unlike those described after either rTNFa (21 ) or rIL-1 (28) exposures.…”