title: Hypoxia injures endothelial cells by increasing endogenous xanthine oxidase activity.
abstract: Exposure to decreasing oxygen tensions progressively increased xanthine dehydrogenase (XD) and xanthine oxidase (XO) activities over 48 hr in cultured pulmonary artery endothelial cells (EC) without altering XD/XO ratios. Increases in XD and XO activity in EC induced by hypoxia were associated upon reoxygenation with increased (P less than 0.05) extracellular superoxide anion (O2-.) levels that were inhibited by treatment with XO inhibitors (tungsten, allopurinol) or an anion-channel blocker (4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid). EC monolayers subjected to hypoxia/reoxygenation also leaked more preloaded 51Cr, were more adherent to neutrophils, and permitted greater albumin transit than control monolayers. Treatment with tungsten, allopurinol, and/or superoxide dismutase decreased (P less than 0.05) 51Cr release, neutrophil adherence, and albumin transit in EC monolayers exposed to hypoxia/reoxygenation. We conclude that prolonged hypoxia increases both XO and XD activity in EC and may predispose the endothelium to oxidative and inflammatory damage.
authors.affiliation: Department of Medicine, University of Colorado Health Sciences Center, Denver.
authors.forename: L S
authors.initials: LS
authors.lastname: Terada
authors.forename: D M
authors.initials: DM
authors.lastname: Guidot
authors.forename: J A
authors.initials: JA
authors.lastname: Leff
authors.forename: I R
authors.initials: IR
authors.lastname: Willingham
authors.forename: M E
authors.initials: ME
authors.lastname: Hanley
authors.forename: D
authors.initials: D
authors.lastname: Piermattei
authors.forename: J E
authors.initials: JE
authors.lastname: Repine
mesh_terms: D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid; D012856:4-Acetamido-4'-isothiocyanatostilbene-2,2'-disulfonic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D002417:Cattle; D002448:Cell Adhesion; D015687:Cell Hypoxia / Q000502:physiology*; D002478:Cells, Cultured; D002857:Chromium / Q000378:metabolism; D046508:Culture Techniques / Q000379:methods; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology / Q000502:physiology*; D016166:Free Radical Scavengers; D007700:Kinetics; D009504:Neutrophils / Q000502:physiology*; D010100:Oxygen / Q000494:pharmacology; D011651:Pulmonary Artery; D013481:Superoxides / Q000378:metabolism*; D013997:Time Factors; D014968:Xanthine Dehydrogenase / Q000378:metabolism*; D014969:Xanthine Oxidase / Q000378:metabolism*
chemical_list: D016166:Free Radical Scavengers; D002857:Chromium; D013481:Superoxides; D012856:4-Acetamido-4'-isothiocyanatostilbene-2,2'-disulfonic Acid; D014968:Xanthine Dehydrogenase; D014969:Xanthine Oxidase; D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid; D010100:Oxygen