S -Nitroso Human Serum Albumin Treatment Reduces Ischemia/Reperfusion Injury in Skeletal Muscle via Nitric Oxide Release

Abstract

Background-Peroxynitrite generated from nitric oxide (NO) and superoxide (O 2 Ϫ ) contributes to ischemia/reperfusion (I/R) injury. Feedback inhibition of endothelial NO synthase by NO may inhibit O 2 Ϫ production generated also by endothelial NO synthase at diminished local L-arginine concentrations accompanying I/R. Methods and Results-During hindlimb I/R (2.5 hours/2 hours), in vivo NO was monitored continuously (porphyrinic sensor), and high-energy phosphates, reduced and oxidized glutathione (chromatography), and I/R injury were measured intermittently. Rabbits receiving human serum albumin (HSA) (controls) were compared with those receiving S-nitroso human serum albumin (S-NO-HSA) beginning 30 minutes before reperfusion for 1 hour or 30 minutes before ischemia for 3.5 hours (0.1 mol · kg Ϫ1 · h Ϫ1 ). The onset of ischemia led to a rapid increase of NO from its basal level (50Ϯ12 nmol/L) to 120Ϯ20 and 220Ϯ15 nmol/L in the control and S-NO-HSA-treated groups, respectively. In control animals, NO dropped below basal levels at the end of ischemia and to undetectable levels (Ͻ1 nmol/L) during reperfusion. In S-NO-HSA-treated animals, maximal NO levels never decreased below basal concentration and on reperfusion were 100Ϯ15 nmol/L (S-NO-HSA preischemia group, 175Ϯ15 nmol/L). NO supplementation by S-NO-HSA led to partial and in the preischemia group to total preservation of high-energy phosphates and glutathione status in reperfused muscle (eg, preischemia groups: ATP, 30.23Ϯ5.02 mol/g versus control, 15.75Ϯ4.33 mol/g, PϽ0.0005; % oxidized glutathione, 4.49Ϯ1.87% versus control, 22.84Ϯ6.39%, PϽ0.0001). S-NO-HSA treatment in all groups led to protection from vasoconstriction and reduced edema formation after reperfusion (eg, preischemia groups: interfiber area, 12.94Ϯ1.36% versus control, 27.83Ϯ1.95%, PϽ0.00001). Conclusions-Long

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Role of Toll-like receptors 2, 4, and 9 in mediating neutrophil dysfunction in alcoholic hepatitis

“…High-energy phosphates were measured by HPLC as previously described (8,9,22). After incubation of cells with plasma for 90 min, 10 6 cells were centrifuged, washed with 1 ml of PBS, and then deproteinized with 200 l of 0.4 mol/l perchloric acid.…”

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“…This injury is characterized by initial tissue damage during the ischemic period followed by progressive injury during the reperfusion period. Reperfusion is a trigger for the generation of reactive oxygen species, release of cytokines, induction of adhesion molecules on vascular endothelial cells, and the adhesion and extravasation of leukocytes into postischemic tissue (Hallstrom et al, 2002;Dworschak et al, 2004). Potent cytoprotection against ischemia-reperfusion liver injury in rats (Ikebe et al, 2000) and antibacterial activity in vitro against several types of bacteria (Miyamoto et al, 2000a,b) resulted after human ␣ 1 -protease inhibitor (␣ 1 -PI), an acute phase reactive protein in serum, was S-nitrosylated (SNO-␣ 1 -PI).…”