L-Arginine treatment decreased superoxide generation by cNOS while increasing NO accumulation, leading to protection from constriction (microvessel area, 17.77+/-0.95 versus 11.66+/-2.21 microm2 untreated, P<.0005) and reduction of edema after reperfusion (interfiber area, 16.56+/-2.13% versus 27.68+/-7.70% untreated, P<.005).

No abstract

Neutrophils are primary effector cells of innate immunity and fight infection by phagocytosis and degranulation. Activated neutrophils also release neutrophil extracellular traps (NETs) in response to a variety of stimuli. These NETs are net-like complexes composed of cell-free DNA, histones and neutrophil granule proteins. Besides the evolutionarily conserved mechanism to capture and eliminate pathogens, NETs are also associated with pathophysiological processes of various diseases. Here, we elucidate the mechanisms of NET formation and their different implications in disease. We focused on autoinflammatory and cardiovascular disorders as the leading cause of death. Neutrophil extracellular traps are not only present in various cardiovascular diseases but play an essential role in atherosclerotic plaque formation, arterial and venous thrombosis, as well as in the development and progression of abdominal aortic aneurysms. Furthermore, NETosis can be considered as a source of autoantigens and maintains an inflammatory milieu promoting autoimmune diseases. Indeed, there is further need for research into the balance between NET induction, inhibition, and degradation in order to pharmacologically target NETs and their compounds without impairing the patient’s immune defense. This review may be of interest to both basic scientists and clinicians to stimulate translational research and innovative clinical approaches.

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