Ischemic preconditioning and intermittent clamping confer protection against ischemic injury in the cirrhotic mouse liver

Abstract

Surgery on cirrhotic livers is fraught with complications, and many surgeons refrain from operating on patients with cirrhosis. Surgical procedures include temporal occlusion of blood flow resulting in ischemia. The mechanisms of protective strategies to prevent ischemic injury in patients with cirrhosis are not fully understood. The aim of this study was to evaluate how the cirrhotic liver tolerates an ischemic insult, whether mechanisms other than those observed in the normal liver are active, and whether intermittent clamping and preconditioning, which are known as safe surgical strategies in normal and steatotic livers, confer protection to the cirrhotic liver. We applied partial hepatic inflow occlusion to cirrhotic mice fed carbon tetrachloride according to different vascular occlusion protocols: intermittent clamping with 15 or 30 minute cycles of ischemia or ischemic preconditioning prior to 60 or 75 minutes of ischemia. Continuous ischemia (60 or 75 minutes) served as controls. The results showed that the cirrhotic liver was significantly more susceptible to 60 minutes of ischemia than the normal liver. Apoptosis was higher in the normal liver, whereas necrosis was a predominant feature in the cirrhotic liver. Both protocols of intermittent vascular occlusion and ischemic preconditioning dramatically prevented injury compared to continuous occlusion for 60 minutes. This protection was associated with reduced necrosis and apoptosis, and particularly reduced activation of the apoptotic pathway through mitochondria. In conclusion, this study extends the protective effects of ischemic preconditioning and intermittent clamping to the cirrhotic liver, highlighting a diminished apoptotic pathway with dramatic improvement in the development of necrosis.