Bucillamine, a thiol antioxidant, prevents transplantation-associated reperfusion injury

Abstract

Ischemia͞reperfusion (I͞R) injury is a serious potential threat to outcomes in organ transplantation and other clinical arenas inwhich there is temporary interruption of blood flow. I͞R is a frequent cause of primary failure in organ transplantation. We hypothesized that the antioxidant bucillamine, a potent sulfhydryl donor, would protect against I͞R injury in high-risk organ transplants. Because livers subjected to prolonged ischemia and very fatty livers are highly susceptible to severe I͞R injury, we studied the effect of bucillamine in three animal models of liver transplantation: two ex vivo models of isolated perfused livers, either normal or fatty rat livers, and an in vivo model of syngenic orthotopic liver transplants in rats. In all models, livers were deprived of oxygen for 24 h before either ex vivo reperfusion or transplantation. In the ex vivo models, bucillamine treatment significantly improved portal vein blood flow and bile production, preserved normal liver architecture, and significantly reduced liver enzyme release and indices of oxidative stress. Moreover, bucillamine treatment significantly increased levels of reduced glutathione in the liver and lowered levels of oxidized glutathione in both liver and blood. In rats subjected to liver transplants, bucillamine significantly enhanced survival and protected against hepatic injury. Possible mechanisms of this protection include prevention of excessive accumulation of toxic oxygen species, interruption of redox signaling in hepatocytes, and inhibition of macrophage activation. This study demonstrates the potential utility of bucillamine or other cysteine-derived thiol donors for improving outcomes in organ transplantation and other clinical settings involving I͞R injury.

Molecular Characterization of Rat Leukocyte P-Selectin Glycoprotein Ligand-1 and Effect of Its Blockade: Protection from Ischemia-Reperfusion Injury in Liver Transplantation

“…The perfusate was maintained at a pH of 7.4 and oxygenated with Hamilton silastic lung tubing (Fisher Scientific), which maintained the pO 2 Ͼ 250 mmHg. The livers were perfused ex vivo for 2 h, with stable temperature (37°C), pressure (13 cm of H 2 O), and pH 7.4, as described (18,19,(21)(22)(23)(24). Experimental animals were divided into two groups: anti-PSGL-1 group: blood donor animals received 1 mg/kg of anti-rat PSGL-1 Ab (Wyeth Pharmaceuticals) i.v.…”

Grape seed extract treatment reduces hepatic ischemia‐reperfusion injury in rats

“…Free radical ablation for the treatment of reperfusion injury found its first clinical application in the prevention of postischemic tissue injury after organ transplantation (Amersi et al, 2002;Seo and Lee, 2002). Thus, free radical scavengers and antioxidant agents are thought to be useful in the clinical setting of hepatic I/R damage.…”

Failure of P-selectin blockade alone to protect the liver from ischemia-reperfusion injury in the isolated blood-perfused rat liver

“…It is well documented that GSH plays a protective role in liver I/R injury [1,[53][54][55][56][57] . GSH can react with ROS such as hydrogen peroxide, peroxynitrite, and hypochlorous acid generated by KC and PMNs.…”