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Previous studies indicate that ischemic preconditioning protects against lung injury resulting from hepatic ischemiareperfusion (I/R) through inhibition of tumor necrosis factor (TNF) release from Kupffer cells. The present study investigated whether this effect is limited to the lung or is a generalized systemic response and explores the molecular mechanisms involved. Hepatic I/R led to an increase in neutrophil accumulation in liver, lung, and splanchnic organs. Although preconditioning did not modify neutrophil infiltration in liver during reperfusion, it conferred protection against hepatic injury associated with I/R. In remote organs, preconditioning abrogated the increase in P-selectin up-regulation, preventing neutrophil infiltration and thus reducing the oxidative stress and microvascular disorders following hepatic I/R in these organs. Administration of Abs against P-selectin or TNF previous to ischemia had the same effects as preconditioning. The effects of preconditioning on the blockade of P-selectin up-regulation probably results from inhibition of systemic TNF release from Kupffer cells. Supplementation of TNF abolished the benefits of preconditioning, whereas the injurious effects of TNF were prevented by previous blockade of P-selectin. The results of the present study suggest that ischemic preconditioning protects the liver against I/R injury by a mechanism independent of adhesion molecule expression and neutrophil accumulation. In remote organs, however, hepatic preconditioning prevents inflammatory damage by reducing the systemic TNF release from the liver and thus preventing P-selectin up-regulation. (HEPATOLOGY 2001;33:100-113.)

The LeVeen shunt and paracentesis are equally effective in relieving refractory ascites. The former may provide better long-term control of ascites, but shunt occlusion is common and survival is not improved.

SUMMARY:Because reactive oxygen species (ROS) have been implicated as mediators of inflammatory bowel disease (IBD), the purpose of the present work was to determine the functional role of mucosal GSH in the trinitrobenzenesulfonic acid in 50% ethanol (TNBSϩethanol)-induced colitis in rats. Mucosal samples were taken to evaluate the temporal relationship between the extent of injury, the levels of glutathione (GSH) during acute colitis induced by TNBSϩethanol, and the effect of N-acetylcysteine (NAC) administration. In vitro assays revealed the interaction of TNBS with GSH leading to the almost instantaneous disappearance of GSH, while the reductive metabolism of TNBS by GSSG reductase generated ROS. Mucosal samples from TNBSϩethanol-treated rats indicated a direct correlation between GSH depletion and injury detected as soon as 30 minutes after TNBSϩethanol administration that persisted 24 hours post treatment. Although, short term depletion of mucosal GSH per se by diethylmaleate did not result in mucosal injury, the oral administration of NAC (40 mM) 4 hours after TNBSϩethanol treatment increased GSH stores (2-fold), decreasing the extent of mucosal injury (60 -70%) examined at 24 hours post treatment. However, an equimolar dose of dithiothreitol failed to increase GSH levels and protect mucosa from TNBSϩethanol-induced injury. Interestingly, GSH levels in TNBSϩethanol-treated rats recovered by 1-2 weeks, an effect that was accounted for by an increase of ␥-glutamylcysteine synthetase (␥-GCS) activity due to an induction of ␥-GCS-heavy subunit chain mRNA. Thus, TNBS promotes two independent mechanisms of injury, GSH depletion and ROS generation, both being required for the manifestation of mucosal injury as GSH limitation renders intestine susceptible to the TNBS-induced ROS overgeneration. Accordingly, in vivo administration of NAC attenuates the acute colitis through increased mucosal GSH levels, suggesting that GSH precursors may be of relevance in the acute relapse of IBD. (Lab Invest 2000, 80:735-744).I nflammatory bowel disease (IBD) is a chronic inflammatory disorder whose etiology is not completely understood. Several factors are recognized to contribute to its development including an overgeneration of reactive oxygen species (ROS). Production of ROS from several sources initiate a cytotoxic cascade of events that culminate in cell death. Thus, stimulated inflammatory cells present in the inflamed mucosa are capable of producing superoxide anion and hydrogen peroxide (Harris et al, 1992;McKenzie et al, 1996;Simmonds and Rampton, 1993).The xantine oxidase pathway and the oxidation of arachidonic acid in colonocytes constitute additional sources of ROS (Biemond et al, 1988;Markowitz et al, 1988;Sedghi et al, 1993). The interaction of these species with specific vascular or interstitial components yield potent chemoattractants for inflammatory phagocytes, establishing a self-amplifying cycle of ROS production that may overwhelm defense strategies resulting in tissue damage (Lewis et al, 1988;Shingu and ...