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Iloprost inhibits superoxide formation and gp91 phox expression induced by the thromboxane A 2 analogue U46619, 8‐isoprostane F 2 α , prostaglandin F 2 α , cytokines and endotoxin in the pig pulmonary artery
Author(s) -
Muzaffar Saima,
Shukla Nilima,
Lobo Clinton,
Angelini Gianni D,
Jeremy Jamie Y
Publication year - 2004
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0705626
Subject(s) - prostacyclin , nadph oxidase , superoxide , chemistry , thromboxane , endocrinology , iloprost , medicine , superoxide dismutase , thromboxane a2 , downregulation and upregulation , thromboxane a synthase , biochemistry , reactive oxygen species , enzyme , platelet , receptor , gene
Since the roles of thromboxane A 2 (TXA 2 ), prostacyclin (PGI 2 ) and 8‐isoprostane F 2 α in mediating vascular O 2 •− formation and its relation to adult respiratory distress syndrome (ARDS) is unknown, the effects of these eicosanoids on the expression of gp91 phox (catalytic subunit of NADPH oxidase) and O 2 •− 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 TXA 2 analogue, U46619, (±LPS, tumour necrosing factor‐alpha (TNF‐ α ) or IL‐1 α ), 8‐isoprostane F 2α and±iloprost (a stable PGI 2 analogue) for 16 h. The formation of superoxide dismutase‐inhibitable O 2 •− was then measured spectrophotometrically and gp91 phox expression assessed using Western blotting. In parallel experiments, whole PA segments were treated with LPS, TNF‐ α and IL‐ α after which time TXA 2 , PGI 2 , PGF 2 α and 8‐isoprostane F 2 α formation was measured using enzyme‐linked immunoassays. U46619, PGF 2 α and 8‐isoprostane F 2 α promoted the formation of O 2 •− in PA segments, PAVSMCs and PAECs, an effect inhibited by diphenyleneiodonium and apocynin (both NADPH oxidase inhibitors) and upregulated the expression of gp91 phox in PAECs and PAVSMCs. These effects were augmented by LPS, TNF‐ α and IL‐1 α but inhibited by iloprost. Under identical incubation conditions, IL‐1 α , LPS and TNF‐ α all induced an increase in the formation of TXA 2 , PGF 2 α and 8‐isoprostane F 2 α but reduced the concomitant formation of PGI 2 . These data demonstrate that LPS and cytokines influence the relative balance of TXA 2 , PGI 2 , PGF 2 α and 8‐isoprostane F 2 α in pig PA, which in turn alter NADPH oxidase expression and O 2 •− 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