Reperfusion Injury After Hemorrhage: A Collective Review

G D. Rushing, MD; L D. Britt, MD, MPH

Disclosures

Annals of Surgery. 2008;247(6):929-937. 

In This Article

Enzymatic Mediators of Reperfusion Injury (Xanthine Oxidase and Nitric Oxide Synthase)

Endothelium is also damaged in reperfusion injury secondary to oxidative radicals. Not only leukocytes, but also endothelial cells create oxygen radicals. Endothelial cells have an abundance of xanthine oxidoreductase, a metalloflavoprotein, which exists in 2 functional states.[64,65] Constitutively expressed as a dehydrogenase, it normally reduces nicotinamide adenine dinucleotide. Post-translational modification converts this enzyme to xanthine oxidase, which starts to reduce O2 instead of nicotinamide adenine dinucleotide during times of hypoxia. When oxygen is reintroduced into the hypoxic tissues during reperfusion, an accumulation of hypoxanthine allows for a burst of superoxide and hydrogen peroxide production. Several recent studies have looked at red wine constituents,[66] chimeric superoxide dismutases,[67] and more traditional antioxidants including allopurinol and deferoximine[68] for treatment of reperfusion with promising results.

NO and its effects on the endothelium have been prolifically investigated since the first classic studies by Pohl and Busse.[70] NO is the metabolic by-product of the conversion of l-arginine to l-citrulline by a class of enzymes dubbed nitric oxide synthases (NOS). To date, 3 isoforms of NOS have been identified. Neuronal NOS (nNOS or NOS1) is expressed constitutively by neurons in the brain and enteric nervous system, whereas endothelial NOS (eNOS or NOS3) exhibits constitutive expression that is confined to the endothelial cells lining the vasculature.[69,70] The third isoform of NOS is inducible NOS (iNOS or NOS2) and, as the name implies, is expressed only in response to certain inflammatory stimuli. Such inflammatory stimuli include bacterial products, cytokines, and lipid mediators.[71,72] Vasodilatory effects of endotoxin were shown to have an NO-derived component in studies in our laboratory.[73,74] NO induces vascular relaxation at mild hypoxic levels. However, when severe hypoxia (pO2 <65 mm Hg) is induced, NO-dependent vascular response is lost.[75] During severe ischemia (pO2 <35 mm Hg), relaxation of smooth muscle is associated with a potassium-adenosine triphosphate pump hyperpolarization.[76] Several studies have evaluated the effects of NO on adhesion molecules. In cultured endothelial cells NO down-regulates the production of endothelial adhesion molecules (ECAMs).[77,78,79] Similar results were also produced in animal models; increased ECAM expression was observed in NOS-deficient mice.[80] Formation of NO adducts with hemoglobin iron, protein thiols, and protein nitrites/nitrates have demonstrated early formation in red blood cells after hemorrhage. Results from these studies indicate this phenomenon is independent of iNOS up-regulation.[81] Bioreactive NO species could be transported by red blood cells systemically after hemorrhage or trauma. There has been extensive research into blockade of NO production with conflicting results. Inhibition of NO production, using l-N6-imivoethyl-lysine, demonstrates that iNOS is not responsible for up-regulation of the ECAMs.[82] This method reveals that iNOS is not responsible for extravasation of neutrophils in an animal model.[83] Although much has been delineated, a clear role for NO and each of the NOS enzymes in reperfusion is not fully understood. Evaluating the most current data, it seems that constitutively expressed NOS is involved with adhesion of neutrophils and endothelium, whereas inducible forms of NOS are involved in other activities, such as activation of NF-κB.[84]

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