Modulation of the endothelial procoagulant response to lipopolysaccharide and tumour necrosis factor-alpha in-vitro: the effects of dexamethasone, pentoxifylline, iloprost and a polyclonal anti-human IL-1 alpha antibody.
Endothelial expression of tissue factor (TF), a potent procoagulant molecule, is increased in response to inflammatory mediators such as lipopolysaccharide (LPS), tumour necrosis factor (TNF) and interleukin-1 (IL-1). We have examined the effects of three antiinflammatory agents and a polyclonal anti-human IL-1 alpha antibody on the human endothelial TF response to E. coli 0111:B4 LPS and recombinant TNF alpha (rTNF alpha) in vitro. In contrast to the expected inhibitory effect, dexamethasone, pentoxyfilline and iloprost failed to block TF expression when administered simultaneously or 30 minutes prior to stimulation with either LPS or rTNF alpha. Inhibition of procoagulant activity was demonstrated with the anti-IL-1 alpha antibody, suggesting that endothelial derived IL-1 alpha is partially responsible for the TF response to the agonists employed. The failure of the antiinflammatory agents to inhibit endothelial TF expression highlights the possibility that therapeutic agents that modulate the circulating monocyte response to LPS and TNF alpha may not ameliorate the endothelial dysfunction that is also induced by these inflammatory mediators.
Heyderman
R S
RS
Department of Paediatrics, St. Mary's Hospital Medical School, London, UK.
Klein
N J
NJ
Daramola
O A
OA
Levin
M
M
D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D000906:Antibodies / Q000494:pharmacology*; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D004926:Escherichia coli / Q000378:metabolism; D006801:Humans; D016285:Iloprost / Q000494:pharmacology; D007375:Interleukin-1 / Q000276:immunology; D008070:Lipopolysaccharides / Q000633:toxicity; D010431:Pentoxifylline / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000633:toxicity; D013925:Thromboplastin / Q000096:biosynthesis; D014409:Tumor Necrosis Factor-alpha / Q000633:toxicity; D014471:Umbilical Veins / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D014665:Vasodilator Agents / Q000494:pharmacology*
D000276:Adjuvants, Immunologic; D000893:Anti-Inflammatory Agents; D000906:Antibodies; D007375:Interleukin-1; D008070:Lipopolysaccharides; D010726:Phosphodiesterase Inhibitors; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D014665:Vasodilator Agents; D003907:Dexamethasone; D013925:Thromboplastin; D016285:Iloprost; D010431:Pentoxifylline