Hypoxia injures endothelial cells by increasing endogenous xanthine oxidase activity.
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.
Terada
L S
LS
Department of Medicine, University of Colorado Health Sciences Center, Denver.
Guidot
D M
DM
Leff
J A
JA
Willingham
I R
IR
Hanley
M E
ME
Piermattei
D
D
Repine
J E
JE
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*
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