Washed human platelets prevent ischemia-reperfusion edema in isolated rabbit lungs

1991 ◽  
Vol 70 (3) ◽  
pp. 1075-1084 ◽  
Author(s):  
C. A. Zamora ◽  
D. Baron ◽  
J. E. Heffner
Keyword(s):  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Human Platelets ◽  
Lung Edema ◽  
Redox Cycle ◽  
Lung Weight ◽  
Edema Formation ◽  
Glutathione Redox Cycle ◽  
Isolated Lungs ◽  
Glutathione Redox

Washed human platelets prevent edema formation in isolated rabbit lungs infused with xanthine oxidase, an enzyme that injures endothelial membranes by generating extracellular oxidants. We hypothesized that platelets would similarly preserve membrane permeability in isolated lungs exposed to ischemia-reperfusion injury, a model that perturbs endothelial cells by the generation of intracellular oxidants. Isolated perfused rabbit lungs (IPL) were exposed to warm ischemia-reperfusion to cause lung edema. The infusion of washed human platelets (1.05 +/- 0.02 x 10(10) cells) prevented edema formation as measured by lung weight gain, wet-to-dry lung weight ratios, histological edema, and preservation of paraendothelial cell tight junctions. Inhibition of the platelet glutathione redox cycle with 1,3-bis(2-chloroethyl)-1-nitrosourea, dehydroepiandrosterone, or 1-chloro-2,4-dinitrobenzene interfered with platelet protective effects. In contrast, inhibition of platelet catalase with aminotriazole and H2O2 had no effect on platelet protection. Lung tissue malonyldialdehyde concentrations were similar in isolated lungs exposed to ischemia-reperfusion with or without the infusion of platelets. These results indicate that platelet attenuation of ischemia-reperfusion lung edema depends on platelet glutathione redox cycle antioxidants but not platelet catalase.

Human platelets attenuate oxidant injury in isolated rabbit lungs

1988 ◽  
Vol 65 (3) ◽  
pp. 1258-1266 ◽  
Author(s):  
J. E. Heffner ◽  
S. A. Katz ◽  
P. V. Halushka ◽  
J. A. Cook
Keyword(s):  
Lung Injury ◽  
Xanthine Oxidase ◽  
Human Platelets ◽  
Antioxidant Systems ◽  
Albumin Concentration ◽  
Redox Cycle ◽  
Lung Weight ◽  
Edema Formation ◽  
Glutathione Redox Cycle ◽  
Glutathione Redox

Because platelets contain active antioxidant systems, the capacity of platelets to attenuate oxidant lung injury was investigated. Purine and xanthine oxidase were infused into isolated perfused rabbit lungs (IPL) to generate H2O2, thereby causing increased membrane permeability edema. The coinfusion of washed human platelets (1.20 +/- 0.07 x 10(10) cells) attenuated the degree of edema formation as measured by lung weight gain and lung lavage albumin concentration. Electron microscopy of lung preparations demonstrated platelet adherence to capillary endothelial luminal surfaces of oxidant-injured lungs, but there was no evidence of vascular plugging with platelet macroaggregates. The platelet glutathione redox cycle or platelet catalase were inhibited before infusion of platelets into the IPL with purine and xanthine oxidase. Inhibition of the glutathione redox cycle with 1,3-bis(2-chloroethyl)-1-nitrosourea, 1-chloro-2,4-dinitrobenzene, or buthionine sulfoximine prevented platelet attenuation of lung injury. Inactivation of platelet catalase with 3-amino-1,2,4-triazole, however, did not significantly reduce the platelet-induced lung protection. We conclude that the platelet glutathione redox cycle plays a major role in reducing enzymatically generated toxic O2 metabolites and attenuating lung injury.

Hypoxia increases glutathione redox cycle and protects rat lungs against oxidants

1988 ◽  
Vol 65 (6) ◽  
pp. 2607-2616 ◽  
Author(s):  
C. W. White ◽  
J. H. Jackson ◽  
I. F. McMurtry ◽  
J. E. Repine
Keyword(s):  
Glutathione Reductase ◽  
Left Atrial ◽  
Reduced Glutathione ◽  
Lung Lavage ◽  
Redox Cycle ◽  
Lung Weight ◽  
Glutathione Redox Cycle ◽  
Isolated Lungs ◽  
Glucose 6 Phosphate Dehydrogenase ◽  
Glutathione Redox

Preexposure to hypoxia increased survival and lung reduced glutathione-to-oxidized glutathione ratios (GSH/GSSG) and decreased pleural effusions in rats subsequently exposed to continuous hyperoxia. In addition, lungs from hypoxia-preexposed rats developed less acute edematous injury (decreased lung weight gains and lung lavage albumin concentrations) than lungs from normoxia-preexposed rats when isolated and perfused with hydrogen peroxide (H2O2) generated by xanthine oxidase (XO) or glucose oxidase (GO). In contrast, when perfused with elastase or exposed to a hydrostatic left atrial pressure challenge, lungs isolated from hypoxia-preexposed rats developed the same acute edematous injury as lungs from normoxia-preexposed rats. The mechanism by which hypoxia preexposure conferred protection against H2O2 appeared to depend on hexose monophosphate shunt (HMPS)-dependent increases in lung glutathione redox cycle activity. First, before perfusion with GO, lungs from hypoxia-preexposed rats had increased glutathione peroxidase and glucose 6-phosphate dehydrogenase (but not catalase or glutathione reductase) activities compared with lungs from normoxia-preexposed rats. Second, after perfusion with GO, lungs from hypoxia-preexposed rats had increased H2O2 reducing equivalents, as reflected by increased GSH/GSSG and NADPH/NADPH+, compared with lungs from normoxia-preexposed rats. Third, pretreatment of rats with an HMPS inhibitor, (6-aminonicotinamide) or a glutathione reductase inhibitor, [1,3-bis(2-chloroethyl)-1-nitrosourea] prevented hypoxia-conferred protection against H2O2-mediated acute edematous injury in isolated lungs. These findings suggest that increased detoxification of H2O2 by glutathione redox cycle and HMPS-dependent mechanisms contributes to tolerance to hyperoxia and resistance to H2O2 of lungs from hypoxia-preexposed rats.

Platelets attenuate oxidant-induced permeability in endothelial monolayers: glutathione-dependent mechanisms

1996 ◽  
Vol 81 (4) ◽  
pp. 1701-1706 ◽  
Author(s):  
Charlie Strange ◽  
Andrew Gottehrer ◽  
Karen Birmingham ◽  
John E. Heffner
Keyword(s):  
Glucose Oxidase ◽  
Oxidant Stress ◽  
Buthionine Sulfoximine ◽  
Human Platelets ◽  
Protective Effects ◽  
Redox Cycle ◽  
Endothelial Monolayers ◽  
Glutathione Redox Cycle ◽  
Monolayer Permeability ◽  
Glutathione Redox

Strange, Charlie, Andrew Gottehrer, Karen Birmingham, and John E. Heffner. Platelets attenuate oxidant-induced permeability in endothelial monolayers: glutathione-dependent mechanisms. J. Appl. Physiol. 81(4): 1701–1706, 1996.—We studied the effects of adding washed human platelets or platelets with nonintact glutathione redox cycles to endothelial cell monolayers treated with glucose oxidase to initiate oxidant stress and increase permeability. Changes in125I-labeled albumin transmonolayer movement were used as the index of monolayer permeability. Washed human platelets attenuated oxidant-induced increases in albumin flux. Platelets treated with 1,3-bis(2-chloroethyl)-1-nitrosurea, 1-chloro-2,4-dinitrobenzene, or buthionine sulfoximine to inhibit selective enzymatic steps in the glutathione redox cycle decreased permeability to a lesser degree. We conclude that 1) washed human platelets attenuate monolayer permeability defects in aortic endothelial monolayers exposed to glucose oxidase and 2) the protective effects of platelets are partially dependent on an intact platelet glutathione redox cycle.

Hypoxia compared with normoxia alters the effects of nitric oxide in ischemia-reperfusion lung injury

1997 ◽  
Vol 273 (3) ◽  
pp. L504-L512 ◽  
Author(s):  
Y. C. Huang ◽  
P. W. Fisher ◽  
E. Nozik-Grayck ◽  
C. A. Piantadosi
Keyword(s):  
Nitric Oxide ◽  
Lung Injury ◽  
Average Rate ◽  
Ischemia Reperfusion ◽  
Oxidant Stress ◽  
No Production ◽  
Protective Effects ◽  
Lung Weight ◽  
Edema Formation ◽  
No Donors

Because both the biosynthesis of nitric oxide (NO.) and its metabolic fate are related to molecular O2, we hypothesized that hypoxia would alter the effects of NO. during ischemia-reperfusion (IR) in the lung. In this study, buffer-perfused lungs from rabbits underwent either normoxic IR (AI), in which lungs were ventilated with 21% O2 during ischemia and reperfusion, or hypoxic IR (NI), in which lungs were ventilated with 95% N2 during ischemia followed by reoxygenation with 21% O2. Lung weight gain (WG) and pulmonary artery pressure (Ppa) were monitored continuously, and microvascular pressure (Pmv) was measured after reperfusion to calculate pulmonary vascular resistance. We found that both AI and NI produced acute lung injury, as shown by increased WG and Ppa during reperfusion. In AI, where perfusate PO2 was > 100 mmHg, the administration of the NO. synthase inhibitor N-nitro-L-arginine methyl ester (L-NAME) before ischemia worsened WG and Ppa. Pmv also increased, suggesting a hydrostatic mechanism involved in edema formation. The effects of L-NAME could be attenuated by giving L-arginine and exogenous NO. donors before ischemia or before reperfusion. Partial protection was also provided by superoxide dismutase. In contrast, lung injury in NI at perfusate PO2 of 25-30 mmHg was attenuated by L-NAME; this effect could be reversed by L-arginine. Exogenous NO. donors given either before ischemia or before reperfusion, however, did not increase lung injury. NO. production was measured by quantifying the total nitrogen oxides (NOx) accumulating in the perfusate. The average rate of NOx accumulation was greater in AI than in NI. We conclude that hypoxia prevented the protective effects of NO on AI lung injury. The effects of hypoxia may be related to lower NO. production relative to oxidant stress during IR and/or altered metabolic fates of NO.-mediated production of peroxynitrite by hypoxic ischemia.

Role of glutathione redox cycle in TNF-α-mediated endothelial cell dysfunction

1995 ◽  
Vol 117 (2) ◽  
pp. 179-188 ◽  
Author(s):  
Michal Toborek ◽  
Steven W. Barger ◽  
Mark P. Mattson ◽  
Craig J. McClain ◽  
Bernhard Hennig
Keyword(s):  
Endothelial Cell ◽  
Redox Cycle ◽  
Endothelial Cell Dysfunction ◽  
Cell Dysfunction ◽  
Glutathione Redox Cycle ◽  
Tnf Α ◽  
Glutathione Redox

scholarly journals Tumor cell anti-oxidant defenses. Inhibition of the glutathione redox cycle enhances macrophage-mediated cytolysis

1981 ◽  
Vol 153 (4) ◽  
pp. 766-782 ◽  
Author(s):  
CF Nathan ◽  
BA Arrick ◽  
HW Murray ◽  
NM DeSantis ◽  
ZA Cohm
Keyword(s):  
Tumor Cell ◽  
Tumor Cells ◽  
Defense Mechanisms ◽  
Specific Activity ◽  
Protective Role ◽  
Target Cells ◽  
Redox Cycle ◽  
Oxidation Reduction ◽  
Glutathione Redox Cycle ◽  
Glutathione Redox

The basis of resistance to oxidative injury was studied in six murine tumor cell lines that differed 54-fold in their resistance to enzymatically generated H(2)0(2). The tumors varied 56.7-fold in their specific activity of catalase, 5.3-fold in glutathione peroxidase (GPO), 3.3-fold in glutathione reductase (GR), and 2.7-fold in glutathione. There was no correlation among the levels of the three enzymes, and tumor cell resistance to lysis by H(2)0(2). However, the logarithm of the flux of H(2)0(2) necessary to cause 50 percent lysis of the tumor cells correlated with their content of glutathione (r = 0.91). The protective role of glutathione was analyzed by blocking GR and GPO, the catalysts of the glutathione redox cycle. This was facilitated by the demonstration that the anti-neoplastic agent 1,3-bis-(2- chloroethyl)-l-nitrosourea (BCNU) was a potent inhibitor of GR in intact tumor cells. BCNU inactivated tumor cell GR with a 50 percent inhibitory dose of 11 μM and a t(l/2) of inhibition of 30 s. Complete inhibition of GR was attained with no effect on GPO or catalase. Tumor cells whose GR was inactivated by BCNU could be lysed by fluxes of H(2)0(2) to which they were otherwise completely resistant. They could be killed by phorbol myristate acetate (PMA)-stimulated, bacilli Calmette-Guerin-activated macrophages in numbers which were otherwise insufficient, and by nonactivated macrophages, which otherwise were ineffective. BCNU-treated target cells were also much more sensitive to antibody-dependent, macrophage-mediated cytolysis. However, such tumor cells were no more sensitive than controls to lysis by alloreactive T cells or by antibody plus complement. Next, we deprived tumor cells of selenium by passage in selenium-deficient mice. GPO was inhibited 85 percent in such cells, with no effect on GR or catalase. Tumor cells with reduced GPO activity were markedly sensitized to lysis by small fluxes of H(2)0(2) or by PMA-stimulated macrophages or granulocytes. In contrast, inhibition of catalase with aminotriazole had no effect on the sensitivity of three tumors to peroxide-mediated lysis, and had modest effects with two others. Thus, the oxidation-reduction cycle of glutathione serves as one of the major defense mechanisms of tumor cells against three related forms of oxidant injury: lysis by fluxes of H(2)0(2), by PMA-triggered macrophages, and by macrophages in the presence of anti-tumor antibody.

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