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John D Lang,
Xinjun Teng, Phillip Chumley,
Jack H Crawford,
T Scott Isbell,
Balu K Chacko,
Yuliang Liu,
Nirag Jhala,
D Ralph Crowe,
Alvin B Smith,
Richard C Cross,
Luc Frenette,
Eric E Kelley,
Diana W Wilhite,
Cheryl R Hall,
Grier P Page,
Michael B Fallon,
J Steven Bynon,
Devin E Eckhoff,
Rakesh P Patel
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ABSTRACT: Ischemia/reperfusion (IR) injury in transplanted livers contributes to organ dysfunction and failure and is characterized in part by loss of NO bioavailability. Inhalation of NO is nontoxic and at high concentrations (80 ppm) inhibits IR injury in extrapulmonary tissues. In this prospective, blinded, placebo-controlled study, we evaluated the hypothesis that administration of inhaled NO (iNO; 80 ppm) to patients undergoing orthotopic liver transplantation inhibits hepatic IR injury, resulting in improved liver function. Patients were randomized to receive either placebo or iNO (n = 10 per group) during the operative period only. When results were adjusted for cold ischemia time and sex, iNO significantly decreased hospital length of stay, and evaluation of serum transaminases (alanine transaminase, aspartate aminotransferase) and coagulation times (prothrombin time, partial thromboplastin time) indicated that iNO improved the rate at which liver function was restored after transplantation. iNO did not significantly affect changes in inflammatory markers in liver tissue 1 hour after reperfusion but significantly lowered hepatocyte apoptosis. Evaluation of circulating NO metabolites indicated that the most likely candidate transducer of extrapulmonary effects of iNO was nitrite. In summary, this study supports the clinical use of iNO as an extrapulmonary therapeutic to improve organ function following transplantation.
Journal of Clinical Investigation 10/2007; 117(9):2583-91. · 15.39 Impact Factor
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Stephan Baldus,
Ralf Köster, Phillip Chumley,
Thomas Heitzer,
Volker Rudolph,
Mir Abolfazl Ostad,
Ascan Warnholtz,
Hans-Jürgen Staude,
Felix Thuneke,
Klaus Koss,
Jürgen Berger,
Thomas Meinertz,
Bruce A Freeman,
Thomas Münzel
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ABSTRACT: Coronary endothelial dysfunction is a powerful prognostic marker in patients with coronary artery disease (CAD) that is centrally related to oxidative inhibition of nitric oxide (NO)-dependent vascular cell signaling. Xanthine oxidase (XO), which both binds to and is expressed by endothelial cells, generates superoxide and hydrogen peroxide upon oxidation of purines. Whether inhibition of xanthine oxidase activity results in improved coronary vasomotor function in patients with CAD, however, remains unknown. We assessed coronary and peripheral (brachial artery) endothelial function in 18 patients (pts; 65+/-8 years, 86% male) with angiographically documented CAD, preserved left ventricular function, and non-elevated uric acid levels (233+/-10 microM). Patients received incremental doses of intracoronary acetylcholine (ACh; 10(-7) to 10(-5) microM), and minimal lumen diameter (MLD) and coronary blood flow (CBF) were assessed before and after intravenous administration of oxypurinol (200 mg). Oxypurinol inhibited plasma XO activity 63% (0.051+/- 0.001 vs 0.019+/- 0.005 microU/mg protein; p<0.01). In pts who displayed endothelial dysfunction as evidenced by coronary vasoconstriction in response to ACh (n=13), oxypurinol markedly attenuated ACh-induced vasoconstriction (-23+/- 4 vs -15+/- 4% at ACh 10(-5) microM, p<0.05) and significantly increased CBF (16+/-17 vs 62+/-18% at ACh 10(-5) microM, p<0.05), whereas in patients with preserved coronary endothelial function, oxypurinol had no effect on ACh-dependent changes in MLD (+2.8+/- 4.2 vs 5.2+/- 0.7%, p>0.05) or CBF (135+/-75 vs 154+/-61%, p>0.05). Flow-mediated dilation of the brachial artery, assessed in eight consecutive patients, increased from 5.1+/-1.5 before to 7.6+/-1.5% after oxypurinol administration (p < 0.05). Oxypurinol inhibition of XO improves coronary vascular endothelial dysfunction, a hallmark of patients with CAD. These observations reveal that XO-derived reactive oxygen species significantly contribute to impaired coronary NO bioavailability in CAD and that XO inhibition represents an additional treatment concept for inflammatory vascular diseases that deserves further investigation.
Free Radical Biology and Medicine 11/2005; 39(9):1184-90. · 5.42 Impact Factor
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ABSTRACT: Appreciating that CO2 modifies the chemical reactivity of nitric oxide (NO)-derived inflammatory oxidants, we investigated whether hypercapnia would modulate pulmonary inflammatory responses. Rabbits (n = 72) were ventilated with approximately 7-ml/kg tidal volume for 6 hours. Animals were randomized to one of the following conditions: eucapnia (Pa(CO2) at approximately 35-40 mm Hg), eucapnia + lipopolysaccharide (LPS), eucapnia + LPS + inhaled NO (iNO delivered at approximately 20 ppm), hypercapnia (Pa(CO2) at approximately 60 mm Hg), hypercapnia + LPS, and hypercapnia + LPS + iNO. The hypercapnia + LPS groups compared with groups exposed to eucapnia + LPS displayed significantly increased bronchoalveolar lavage fluid protein concentrations (p < 0.05), lung wet-to-dry ratios (p < 0.05), bronchoalveolar lavage fluid cell counts (p < 0.05), and lung histologic alterations consistent with greater injury. Furthermore, expression of inducible nitric oxide synthase (p < 0.05), tissue myeloperoxidase content (p < 0.05), and formation of lung protein 3-nitrotyrosine derivatives (p < 0.05) was greatest under conditions of hypercapnia + LPS. Groups exposed to hypercapnic conditions without LPS did not manifest these changes. The inhalation of iNO attenuated selected indices of lung injury. We conclude that hypercapnia induced by means of reduced rate and tidal volume amplifies pulmonary inflammatory responses.
American Journal of Respiratory and Critical Care Medicine 02/2005; 171(2):147-57. · 11.08 Impact Factor
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ABSTRACT: Human serum albumin is used clinically to maintain colloid osmotic pressure and is viewed to serve an antioxidant role in the vascular compartment via binding of redox-active metal complexes, transport of nitric oxide, and the oxidant-scavenging reactions of the single thiol of human serum albumin, cys34. Because of these potentially desirable adjunctive actions, we evaluated the purity and thiol redox state and compared the relative effects of clinically available 25% human serum albumin preparations with a starch-derived colloid, 6% hydroxyethyl starch, in in vitro models of inflammatory vascular injury.
Bovine aortic endothelial cell responses to chemical, enzymatic, and cell-derived reactive inflammatory mediators in the presence of human serum albumin or hydroxyethyl starch were assessed.
The cys34 thiol of fresh human serum albumin preparations was 70-85% oxidized and contained a population of human serum albumin (approximately 25% of total) having the cys34 resistant to reduction by 2-mercaptoethanol and NaBH4. Treatment of bovine aortic endothelial cells with human serum albumin dose-dependently protected from HOCl-mediated 14C-adenine release, with this protective effect of human serum albumin not dependent on protein thiol status. Addition of human serum albumin to cell media provided no protection from the cytotoxic actions of peroxynitrite and xanthine oxidase-derived reactive species. Binding of activated polymorphonuclear leukocytes to bovine aortic endothelial cells was significantly amplified by hydroxyethyl starch and inhibited by human serum albumin administration. The binding of neutrophil-derived myeloperoxidase to bovine aortic endothelial cells, a mediator of multiple oxidative and nitric oxide-consuming reactions, was also inhibited by human serum albumin and enhanced by hydroxyethyl starch.
Clinical human serum albumin preparations show modest intrinsic non-thiol-dependent antiinflammatory properties in vitro, a phenomenon that was not observed with hydroxyethyl starch.
Anesthesiology 02/2004; 100(1):51-8. · 5.36 Impact Factor
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ABSTRACT: Background: Human serum albumin is used clinically to maintain colloid osmotic pressure and is viewed to serve an antioxidant role in the vascular compartment via binding of redox-active metal complexes, transport of nitric oxide, and the oxidant-scavenging reactions of the single thiol of human serum albumin, cys34. Because of these potentially desirable adjunctive actions, we evaluated the purity and thiol redox state and compared the relative effects of clinically available 25% human serum albumin preparations with a starch-derived colloid, 6% hydroxyethyl starch, in in vitro models of inflammatory vascular injury.
Anesthesiology 12/2003; 100(1):51-58. · 5.36 Impact Factor
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Stephan Baldus,
Jason P Eiserich,
Alireza Mani,
Laura Castro,
Mario Figueroa, Phillip Chumley,
Wenxin Ma,
Albert Tousson,
C Roger White,
Daniel C. Bullard,
Marie-Luise Brennan,
Aldons J Lusis,
Kevin P. Moore,
Bruce A Freeman
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ABSTRACT: Nitrotyrosine formation is a hallmark of vascular inflammation, with polymorphonuclear neutrophil–derived (PMN-derived) and monocyte-derived myeloperoxidase (MPO) being shown to catalyze this posttranslational protein modification via oxidation of nitrite (NO2–) to nitrogen dioxide (NO2•). Herein, we show that MPO concentrates in the subendothelial matrix of vascular tissues by a transcytotic mechanism and serves as a catalyst of ECM protein tyrosine nitration. Purified MPO and MPO released by intraluminal degranulation of activated human PMNs avidly bound to aortic endothelial cell glycosaminoglycans in both cell monolayer and isolated vessel models. Cell-bound MPO rapidly transcytosed intact endothelium and colocalized abluminally with the ECM protein fibronectin. In the presence of the substrates hydrogen peroxide (H2O2) and NO2–, cell and vessel wall–associated MPO catalyzed nitration of ECM protein tyrosine residues, with fibronectin identified as a major target protein. Both heparin and the low–molecular weight heparin enoxaparin significantly inhibited MPO binding and protein nitrotyrosine (NO2Tyr) formation in both cultured endothelial cells and rat aortic tissues. MPO–/– mice treated with intraperitoneal zymosan had lower hepatic NO2Tyr/tyrosine ratios than did zymosan-treated wild-type mice. These data indicate that MPO significantly contributes to NO2Tyr formation in vivo. Moreover, transcytosis of MPO, occurring independently of leukocyte emigration, confers specificity to nitration of vascular matrix proteins.
Journal of Clinical Investigation 01/2002; · 15.39 Impact Factor
