PROCOAGULANT AND PROTHROMBOTIC RESPONSES OF HUMAN ENDOTHELIUM TO INDOMETHACIN AND ENDOTOXIN IN-VITRO - RELEVANCE TO NONSTEROIDAL ANTIINFLAMMATORY DRUG ENTEROPATHY

Background: In View of the association between non-steroidal, anti-inf lammatory drugs (NSAIDs) and microvascular injury in the intestine, th is study investigated the procoagulant changes in cultured human umbil ical vein endothelial cells (HUVEC) when exposed to indomethacin eithe r alone or in the presence of bacterial lipopolysaccharide (LPS). Meth ods: Confluent HUVEC cultures were cultured for 1, 6, 12, and 24 h in the presence of LPS (10 mu g/ml) with or without indomethacin (1-100 m u M). After incubation, supernatants were analysed for 6-keto-prostagl andin (PG) F-1 alpha and PGE(2) content, whereas cells were freeze-fra ctured and assayed in a one-stage clotting assay for the expression of procoagulant activity (PCA). Results: LPS induced a significant expre ssion of PCA at 6, 12, and 24 h, with a significantly increased produc tion of 6-keto-PG(1 alpha), whereas the increased PGE(2) production wa s much less pronounced. Indomethacin alone induced a time-dependent PC A response; when coincubated with LPS the PCA response was greater tha n that produced by either indomethacin or LPS alone. Indomethacin tota lly abolished the synthesis of antithrombotic eicosanoids. Conclusion: Indomethacin induces PCA in HUVEC and augments LPS-induced PCA, while it abolishes the antithrombotic prostanoid response in these cells. T hese observations may be relevant to the microvascular injury and thro mbosis observed in NSAID enteropathy.