Iloprost inhibits superoxide formation and gp91phoxexpression induced by the thromboxane A2analogue U46619, 8-isoprostane F2α, prostaglandin F2α, cytokines and endotoxin in the pig pulmonary artery

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Abstract
Since the roles of thromboxane A2 (TXA2), prostacyclin (PGI2) and 8‐isoprostane F2α in mediating vascular O2•− formation and its relation to adult respiratory distress syndrome (ARDS) is unknown, the effects of these eicosanoids on the expression of gp91phox (catalytic subunit of NADPH oxidase) and O2•− release from cultured pig pulmonary artery (PA) segments, PA vascular smooth muscle cells (PAVSMCs) and PA endothelial cells (PAECs) were investigated. PA segments, PAVSMCs and PAECs were incubated with the TXA2 analogue, U46619, (±LPS, tumour necrosing factor‐alpha (TNF‐α) or IL‐1α), 8‐isoprostane F2α and±iloprost (a stable PGI2 analogue) for 16 h. The formation of superoxide dismutase‐inhibitable O2•− was then measured spectrophotometrically and gp91phox expression assessed using Western blotting. In parallel experiments, whole PA segments were treated with LPS, TNF‐α and IL‐α after which time TXA2, PGI2, PGF2α and 8‐isoprostane F2α formation was measured using enzyme‐linked immunoassays. U46619, PGF2α and 8‐isoprostane F2α promoted the formation of O2•− in PA segments, PAVSMCs and PAECs, an effect inhibited by diphenyleneiodonium and apocynin (both NADPH oxidase inhibitors) and upregulated the expression of gp91phox in PAECs and PAVSMCs. These effects were augmented by LPS, TNF‐α and IL‐1α but inhibited by iloprost. Under identical incubation conditions, IL‐1α, LPS and TNF‐α all induced an increase in the formation of TXA2, PGF2α and 8‐isoprostane F2α but reduced the concomitant formation of PGI2. These data demonstrate that LPS and cytokines influence the relative balance of TXA2, PGI2, PGF2α and 8‐isoprostane F2α in pig PA, which in turn alter NADPH oxidase expression and O2•− formation. These novel findings have implications in devising effective strategies for treating ARDS. British Journal of Pharmacology (2004) 141, 488–496. doi:10.1038/sj.bjp.0705626

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