Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0242706 (hyperoxia)
 5,219 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Infection during the neonatal period commonly induces apnea episodes, and the proinflammatory cytokine IL-1beta may serve as a critical mediator between these events. To determine the mechanism by which IL-1beta depresses respiration, we examined a prostaglandin E(2) (PGE(2))-dependent pathway in newborn mice and human neonates. IL-1beta and transient anoxia rapidly induced brainstem-specific microsomal prostaglandin E synthase-1 (mPGES-1) activity in neonatal mice. Furthermore, IL-1beta reduced respiratory frequency during hyperoxia and depressed hypoxic gasping and autoresuscitation in mPGES-1 wild-type mice, but not in mPGES-1 knockout mice. In wild-type mice, PGE(2) induced apnea and irregular breathing patterns in vivo and inhibited brainstem respiratory rhythm generation in vitro. Mice lacking the EP3 receptor (EP3R) for PGE(2) exhibited fewer apneas and sustained brainstem respiratory activity, demonstrating that PGE(2) exerts its respiratory effects via EP3R. In human neonates, the infectious marker C-reactive protein was correlated with elevated PGE(2) in the cerebrospinal fluid, and elevated central PGE(2) was associated with an increased apnea frequency. We conclude that IL-1beta adversely affects breathing and its control by mPGES-1 activation and PGE(2) binding to brainstem EP3 receptors, resulting in increased apnea frequency and hypoxia-induced mortality.
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PMID:The induced prostaglandin E2 pathway is a key regulator of the respiratory response to infection and hypoxia in neonates. 1753

Phosphatidic acid generated by the activation of phospholipase D (PLD) functions as a second messenger and plays a vital role in cell signaling. Here we demonstrate that PLD-dependent generation of phosphatidic acid is critical for Rac1/IQGAP1 signal transduction, translocation of p47(phox) to cell periphery, and ROS production. Exposure of [(32)P]orthophosphate-labeled human pulmonary artery endothelial cells (HPAECs) to hyperoxia (95% O(2) and 5% CO(2)) in the presence of 0.05% 1-butanol, but not tertiary-butanol, stimulated PLD as evidenced by accumulation of [(32)P]phosphatidylbutanol. Infection of HPAECs with adenoviral constructs of PLD1 and PLD2 wild-type potentiated hyperoxia-induced PLD activation and accumulation of O(2)(.)/reactive oxygen species (ROS). Conversely, overexpression of catalytically inactive mutants of PLD (hPLD1-K898R or mPLD2-K758R) or down-regulation of expression of PLD with PLD1 or PLD2 siRNA did not augment hyperoxia-induced [(32)P]phosphatidylbutanol accumulation and ROS generation. Hyperoxia caused rapid activation and redistribution of Rac1, and IQGAP1 to cell periphery, and down-regulation of Rac1, and IQGAP1 attenuated hyperoxia-induced tyrosine phosphorylation of Src and cortactin and ROS generation. Further, hyperoxia-mediated redistribution of Rac1, and IQGAP1 to membrane ruffles, was attenuated by PLD1 or PLD2 small interference RNA, suggesting that PLD is upstream of the Rac1/IQGAP1 signaling cascade. Finally, small interference RNA for PLD1 or PLD2 attenuated hyperoxia-induced cortactin tyrosine phosphorylation and abolished Src, cortactin, and p47(phox) redistribution to cell periphery. These results demonstrate a role of PLD in hyperoxia-mediated IQGAP1 activation through Rac1 in tyrosine phosphorylation of Src and cortactin, as well as in p47(phox) translocation and ROS formation in human lung endothelial cells.
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PMID:Phospholipase D-mediated activation of IQGAP1 through Rac1 regulates hyperoxia-induced p47phox translocation and reactive oxygen species generation in lung endothelial cells. 1936 6