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Background This study evaluates whether surgical strategies such as the portosystemic shunt and ischemic preconditioning can protect against hepatic and pulmonary injury associated with liver transplantation. Methods The effect of the portosystemic shunt, ischemic preconditioning, and both surgical procedures together were evaluated in rat liver transplantation. Alanine aminotransferase, hyaluronic acid levels in plasma, adenosine triphosphate and nucleotide levels in liver and edema, malondialdehyde levels, and myeloperoxidase activity were measured 24 hr posttransplantation. Plasmatic tumor necrosis factor (TNF) levels were measured as a possible proinflammatory factor responsible for hepatic and pulmonary damage associated with liver transplantation. Results Hepatocyte and cell endothelial damage were observed in liver grafts subjected to 8 hr of cold ischemia. This was associated with increased plasma TNF levels and lung inflammatory response. Portosystemic shunt application in the recipient protected endothelial cells but did not confer an effective protection from hepatocyte damage or reduce the increased plasma TNF levels and lung damage after liver transplantation. However, preconditioning of the donor liver conferred protection against both the endothelial cell and hepatocyte damage observed after liver transplantation. Preconditioning also attenuated the increased plasma TNF release and pulmonary damage. The combination of both surgical strategies resulted in levels of liver injury, TNF, and lung damage similar to those seen after liver transplantation. Conclusions These findings indicate that ischemic preconditioning could be a preferred treatment to reduce hepatic and pulmonary damage associated with liver transplantation. However, this strategy may not be effective in several clinical situations requiring a portosystemic shunt.

Background. Preconditioning protects against both liver and lung damage after hepatic ischemia-reperfusion (I/R). Xanthine and xanthine oxidase (XOD) may contribute to the development of hepatic I/R. Objective. To evaluate whether preconditioning could modulate the injurious effects of xanthine/XOD on the liver and lung after hepatic I/R. Methods. Hepatic I/R or preconditioning previous to I/R was induced in rats. Xanthine and xanthine dehydrogenase/xanthine oxidase (XDH/XOD) in liver and plasma were measured. Hepatic injury and inflammatory response in the lung was evaluated. Results. Preconditioning reduced xanthine accumulation and conversion of XDH to XOD in liver during sustained ischemia. This could reduce the generation of reactive oxygen species (ROS) from XOD, and therefore, attenuate hepatic I/R injury. Inhibition of XOD prevented postischemic ROS generation and hepatic injury. Administration of xanthine and XOD to preconditioned rats led to hepatic MDA and transaminase levels similar to those found after hepatic I/R. Preconditioning, resulting in low circulating levels of xanthine and XOD activity, reduced neutrophil accumulation, oxidative stress, and microvascular disorders seen in lung after hepatic I/R. Inhibition of XOD attenuated the inflammatory damage in lung after hepatic I/R. Administration of xanthine and XOD abolished the benefits of preconditioning on lung damage. Conclusions. Preconditioning, by blocking the xanthine/XOD pathway for ROS generation, would confer protection against the liver and lung injuries induced by hepatic I/R.

Background. Although nitric oxide (NO) is thought to be beneficial in hepatic ischemia-reperfusion (I/R), the mechanisms for this effect are not well established. Methods. To investigate the effects of endogenous NO and exogenous NO supplementation on hepatic I/R injury and their pathogenic mechanisms, serum ALT and hyaluronic acid (endothelial cell damage), and hepatic malondialdehyde and H 2O2 (oxidative stress), myeloperoxidase activity (leukocyte accumulation), and endothelin (vasoconstrictor peptide opposite to NO) were determined at different reperfusion periods in untreated rats and rats receiving L-NAME, L-NAME1L-arginine, and spermine NONOate (exogenous NO donor). Results. After reperfusion every parameter increased in untreated animals. Endogenous NO synthesis inhibition by L-NAME increased hepatocyte and endothelial damage as compared to untreated rats, which was reverted and even improved by the addition of L-arginine. Spermine NONOate also improved this damage. However, different mechanisms account for the beneficial effect of endogenous and exogenous NO. Oxidative stress decreased by both L-NAME and L-NAME1L-arginine, but remained unmodified by spermine NONOate. Myeloperoxidase increased by LNAME and this effect was reverted by the addition of L-arginine, whereas no change was observed with spermine NONOate. Endothelin levels were not modified by L-NAME and L-NAME1L-arginine, but decreased with spermine NONOate. Conclusions. These results suggest that, although both endogenous and exogenous NO exert a protective role in experimental hepatic I/R injury, the mechanisms of the beneficial effect of the two sources of NO are different.

Background. This study evaluates whether bosentan (endothelin [ET] receptor antagonist) or preconditioning (mechanism that inhibits the postischemic ET release) could reduce the microvascular disorders and the injurious effects of tumor necrosis factor (TNF) associated with hepatic ischemia-reperfusion (I/R). Methods. Hepatic I/R was induced in rats and the effects of bosentan or preconditioning on the deleterious effects of ET in hepatic I/R were evaluated. Transaminase and TNF levels in plasma; edema, vascular permeability, lactate, ET, and TNF levels in liver; and edema and myeloperoxidase activity levels in lung were measured after hepatic reperfusion. Results. The administration of bosentan or the induction of preconditioning previous to I/R attenuated the increase in vascular permeability, edema and lactate levels observed in liver after I/R. However, the addition of ET before preconditioning abolished its benefits. Preconditioning prevented both the increase in hepatic TNF and its release from the liver into the systemic circulation. This resulted in an attenuation of liver and lung damage. Addition of ET or TNF to the preconditioned group abolished the benefits of preconditioning, whereas the previous inhibition of TNF release with GdCl3 in the preconditioned group pretreated with ET did not modify the effects of preconditioning. The inhibition of ET with bosentan prevented the increase of both hepatic and plasma TNF, thus attenuating the liver and lung injury, whereas TNF addition abolished the benefits of bosentan. Conclusions. These findings suggest that both bosentan and preconditioning, by inhibition of ET could attenuate the microvascular disorders and the deleterious effect of TNF on the liver and lung elicited by hepatic I/R.

Previous studies have demonstrated that intestinal preconditioning protects the organ from ischemia reperfusion damage. Xanthine oxidase mediating free radical generation contributes to the development of injury associated to ischemia reperfusion. Thus, any process able to modulate the oxygen free radical generation system could attenuate the injury. Also, it is known that nitric oxide is implicated in the preconditioning response. The aim of this work is to determine: (1) the effect of intestinal preconditioning on the xanthine oxidase system, (2) the relevance of this system in the development of injury, and (3) its relationship with nitric oxide. For this purpose, we have determined the activity of the xanthine dehydrogenase/xanthine oxidase system, the levels of its substrate (xanthine), and end-product (uric acid) and oxidant stress status in rat small intestine subjected to ischemic pre-conditioning. The effects of nitric oxide inhibition have also been evaluated. Results show that the percentage of xanthine dehydrogenase to xanthine oxidase conversion, xanthine, uric acid concentration, lipoperoxides, and reduced glutathione were significantly reduced in preconditioned rats irrespectively of nitric oxide inhibition. In summary, this work shows that oxidative stress in intestinal preconditioning is reduced as consequence of the diminished conversion of xanthine dehydrogenase to xanthine oxidase, and also as a consequence of the reduced availability of xanthine.

Background. Previous studies have demonstrated that intestinal preconditioning is triggered by an initial increase in nitric oxide synthesis. This confers resistance to the organ in face of a subsequently sustained period of ischemia-reperfusion. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a key enzyme in the glycolytic cascade that could be modulated by nitric oxide. The purpose of the present study is to evaluate a possible inhibitory effect on intestinal GAPDH by the nitric oxide generated during preconditioning. This could lead to a reduction of lactate accumulation during subsequent ischemia. Methods. GAPDH activity was measured after intestinal preconditioning, and the effect of nitric oxide synthase inhibition was evaluated. Results. Preconditioning induced a significant, but transient, decrease in GAPDH activity. This effect appears to be correlated with a reduced amount of lactate accumulation during ischemia. Inhibition of nitric oxide synthesis reversed these changes. In addition, increased synthesis of nitric oxide was detected after preconditioning. Conclusions. In summary, this study indicates that nitric oxide generated during ischemic preconditioning could act as a glycolytic modulator during subsequent ischemia, through its effect on GAPDH activity.

The role of eicosanoid metabolism and its relationship with nitric oxide production in the ischemia-reperfusion associated with pancreas transplantation in the rat is explored in this study. Twenty-six male Sprague-Dawley rats were randomized into 3 groups, as follows: group 1, control animals not surgically manipulated; group 2, pancreas transplantation, after 12 hr of organ preservation in University of Wisconsin solution; group 3, same as group 2 but with administration of NG-nitro-L-arginine methyl ester (a nitric oxide synthase inhibitor) (10 mg/kg) before organ revascularization. The results show posttransplantation increases in edema and in 6-keto-prostaglandin F1 alpha (x1.9), thromboxane B2 (x4), and prostaglandin E2 (x5) levels in pancreatic tissue. Nitric oxide synthase inhibition reversed the increases in edema and eicosanoid production, which suggests that eicosanoid generation in the recipient rat would be mediated, in part, through a nitric oxide-dependent mechanism.

This study evaluates whether surgical strategies such as the portosystemic shunt and ischemic preconditioning can protect against hepatic and pulmonary injury associated with liver transplantation.The effect of the portosystemic shunt, ischemic preconditioning, and both surgical procedures together were evaluated in rat liver transplantation. Alanine aminotransferase, hyaluronic acid levels in plasma, adenosine triphosphate and nucleotide levels in liver and edema, malondialdehyde levels, and myeloperoxidase activity were measured 24 hr posttransplantation. Plasmatic tumor necrosis factor (TNF) levels were measured as a possible proinflammatory factor responsible for hepatic and pulmonary damage associated with liver transplantation.Hepatocyte and cell endothelial damage were observed in liver grafts subjected to 8 hr of cold ischemia. This was associated with increased plasma TNF levels and lung inflammatory response. Portosystemic shunt application in the recipient protected endothelial cells but did not confer an effective protection from hepatocyte damage or reduce the increased plasma TNF levels and lung damage after liver transplantation. However, preconditioning of the donor liver conferred protection against both the endothelial cell and hepatocyte damage observed after liver transplantation. Preconditioning also attenuated the increased plasma TNF release and pulmonary damage. The combination of both surgical strategies resulted in levels of liver injury, TNF, and lung damage similar to those seen after liver transplantation.These findings indicate that ischemic preconditioning could be a preferred treatment to reduce hepatic and pulmonary damage associated with liver transplantation. However, this strategy may not be effective in several clinical situations requiring a portosystemic shunt.

Although nitric oxide (NO) is thought to be beneficial in hepatic ischemia-reperfusion (I/R), the mechanisms for this effect are not well established.To investigate the effects of endogenous NO and exogenous NO supplementation on hepatic I/R injury and their pathogenic mechanisms, serum ALT and hyaluronic acid (endothelial cell damage), and hepatic malondialdehyde and H2O2 (oxidative stress), myeloperoxidase activity (leukocyte accumulation), and endothelin (vasoconstrictor peptide opposite to NO) were determined at different reperfusion periods in untreated rats and rats receiving L-NAME, L-NAME+L-arginine, and spermine NONOate (exogenous NO donor).After reperfusion every parameter increased in untreated animals. Endogenous NO synthesis inhibition by L-NAME increased hepatocyte and endothelial damage as compared to untreated rats, which was reverted and even improved by the addition of L-arginine. Spermine NONOate also improved this damage. However, different mechanisms account for the beneficial effect of endogenous and exogenous NO. Oxidative stress decreased by both L-NAME and L-NAME+L-arginine, but remained unmodified by spermine NONOate. Myeloperoxidase increased by L-NAME and this effect was reverted by the addition of L-arginine, whereas no change was observed with spermine NONOate. Endothelin levels were not modified by L-NAME and L-NAME+L-arginine, but decreased with spermine NONOate.These results suggest that, although both endogenous and exogenous NO exert a protective role in experimental hepatic I/R injury, the mechanisms of the beneficial effect of the two sources of NO are different.

Previous studies have demonstrated that intestinal preconditioning protects the organ from ischemia reperfusion damage. Xanthine oxidase mediating free radical generation contributes to the development of injury associated to ischemia reperfusion. Thus, any process able to modulate the oxygen free radical generation system could attenuate the injury. Also, it is known that nitric oxide is implicated in the preconditioning response. The aim of this work is to determine: (1) the effect of intestinal preconditioning on the xanthine oxidase system, (2) the relevance of this system in the development of injury, and (3) its relationship with nitric oxide. For this purpose, we have determined the activity of the xanthine dehydrogenase/xanthine oxidase system, the levels of its substrate (xanthine), and end-product (uric acid) and oxidant stress status in rat small intestine subjected to ischemic pre-conditioning. The effects of nitric oxide inhibition have also been evaluated. Results show that the percentage of xanthine dehydrogenase to xanthine oxidase conversion, xanthine, uric acid concentration, lipoperoxides, and reduced glutathione were significantly reduced in preconditioned rats irrespectively of nitric oxide inhibition. In summary, this work shows that oxidative stress in intestinal preconditioning is reduced as consequence of the diminished conversion of xanthine dehydrogenase to xanthine oxidase, and also as a consequence of the reduced availability of xanthine.

This study evaluates whether bosentan (endothelin [ET] receptor antagonist) or preconditioning (mechanism that inhibits the postischemic ET release) could reduce the microvascular disorders and the injurious effects of tumor necrosis factor (TNF) associated with hepatic ischemia-reperfusion (I/R).Hepatic I/R was induced in rats and the effects of bosentan or preconditioning on the deleterious effects of ET in hepatic I/R were evaluated. Transaminase and TNF levels in plasma; edema, vascular permeability, lactate, ET, and TNF levels in liver; and edema and myeloperoxidase activity levels in lung were measured after hepatic reperfusion.The administration of bosentan or the induction of preconditioning previous to I/R attenuated the increase in vascular permeability, edema and lactate levels observed in liver after I/R. However, the addition of ET before preconditioning abolished its benefits. Preconditioning prevented both the increase in hepatic TNF and its release from the liver into the systemic circulation. This resulted in an attenuation of liver and lung damage. Addition of ET or TNF to the preconditioned group abolished the benefits of preconditioning, whereas the previous inhibition of TNF release with GdCl3 in the preconditioned group pretreated with ET did not modify the effects of preconditioning. The inhibition of ET with bosentan prevented the increase of both hepatic and plasma TNF, thus attenuating the liver and lung injury, whereas TNF addition abolished the benefits of bosentan.These findings suggest that both bosentan and preconditioning, by inhibition of ET could attenuate the microvascular disorders and the deleterious effect of TNF on the liver and lung elicited by hepatic I/R.

Background. This study evaluates whether bosentan (endothelin [ET] receptor antagonist) or preconditioning (mechanism that inhibits the postischemic ET release) could reduce the microvascular disorders and the injurious effects of tumor necrosis factor (TNF) associated with hepatic ischemia-reperfusion (I/R). Methods. Hepatic I/R was induced in rats and the effects of bosentan or preconditioning on the deleterious effects of ET in hepatic I/R were evaluated. Transaminase and TNF levels in plasma; edema, vascular permeability, lactate, ET, and TNF levels in liver, and edema and myeloperoxidase activity levels in lung were measured after hepatic reperfusion. Results. The administration of bosentan or the induction of preconditioning previous to I/R attenuated the increase in vascular permeability, edema and lactate levels observed in liver after I/R. However, the addition of ET before preconditioning abolished its benefits. Preconditioning prevented both the increase in hepatic TNF and its release from the liver into the systemic circulation. This resulted in an attenuation of liver and lung damage. Addition of ET or TNF to the preconditioned group abolished the benefits of preconditioning, whereas the previous inhibition of TNF release with GdCl3 in the preconditioned group pretreated with ET did not modify the effects of preconditioning. The inhibition of ET with bosentan prevented the increase of both hepatic and plasma TNF, thus attenuating the liver and lung injury, whereas TNF addition abolished the benefits of bosentan. Conclusions. These findings suggest that both bosentan and preconditioning, by inhibition of ET could attenuate the microvascular disorders and the deleterious effect of TNF on the liver and lung elicited by hepatic I/R.

Previous studies have demonstrated that intestinal preconditioning protects the organ from ischemia reperfusion damage. Xanthine oxidase mediating free radical generation contributes to the development of injury associated to ischemia reperfusion. Thus, any process able to modulate the oxygen free radical generation system could attenuate the injury. Also, it is known that nitric oxide is implicated in the preconditioning response. The aim of this work is to determine: (1) the effect of intestinal preconditioning on the xanthine oxidase system, (2) the relevance of this system in the development of injury, and (3) its relationship with nitric oxide. For this purpose, we have determined the activity of the xanthine dehydrogenase/xanthine oxidase system, the levels of its substrate (xanthine), and end-product (uric acid) and oxidant stress status in rat small intestine subjected to ischemic preconditioning. The effects of nitric oxide inhibition have also been evaluated. Results show that the percentage of xanthine dehydrogenase to xanthine oxidase conversion, xanthine, uric acid concentration, lipoperoxides, and reduced glutathione were significantly reduced in preconditioned rats irrespectively of nitric oxide inhibition. In summary, this work shows that oxidative stress in intestinal preconditioning is reduced as consequence of the diminished conversion of xanthine dehydrogenase to xanthine oxidase, and also as a consequence of the reduced availability of xanthine.

Free radical species have been implicated as important agents in ischemia-reperfusion injury associated to transplantation procedures. This study was carried out to investigate the possible relationship between phospholipase A2 activity (PLA2), lipoperoxidation, and the changes in arachidonic acid metabolism during ischemia reperfusion injury in pancreas transplantation, as well as the effect of a free radical scavenger such as superoxide dismutase on these changes. For this purpose male Lewis rat groups (n = 7) were classified as follows: group I--control; group II--syngenic pancreas transplantation after 15 min preservation in Collins solution at 4 degrees C; group III--syngenic pancreas transplantation after 18 hr preservation in the same conditions; group IV--same as III but with administration of SOD (i.v.) immediately before revascularization in the recipient rat. The results indicate that significant increases in PLA2 activity and lipoperoxide levels occur concomitantly with an increase of thromboxane B2 (TXB2) and 6-keto prostaglandin F1 alpha (6-keto PGF1 alpha) in pancreatic tissue after pancreas transplantation. The counteracting effect of a free radical scavenger such as SOD supports the role of oxygen free radicals (OFR) mediating activation of PLA2 and subsequent formation of eicosanoids in pancreas transplantation.

Previous studies have demonstrated that intestinal preconditioning is triggered by an initial increase in nitric oxide synthesis. This confers resistance to the organ in face of a subsequently sustained period of ischemia-reperfusion. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a key enzyme in the glycolytic cascade that could be modulated by nitric oxide. The purpose of the present study is to evaluate a possible inhibitory effect on intestinal GAPDH by the nitric oxide generated during preconditioning. This could lead to a reduction of lactate accumulation during subsequent ischemia.GAPDH activity was measured after intestinal preconditioning, and the effect of nitric oxide synthase inhibition was evaluated.Preconditioning induced a significant, but transient, decrease in GAPDH activity. This effect appears to be correlated with a reduced amount of lactate accumulation during ischemia. Inhibition of nitric oxide synthesis reversed these changes. In addition, increased synthesis of nitric oxide was detected after preconditioning.In summary, this study indicates that nitric oxide generated during ischemic preconditioning could act as a glycolytic modulator during subsequent ischemia, through its effect on GAPDH activity.