PROTECTIVE EFFECTS OF ISCHEMIC PRECONDITIONING ON THE COLD-PRESERVED LIVER ARE TYROSINE KINASE DEPENDENT

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Abstract
Little data exist regarding the use of ischemic preconditioning before sustained hepatic cold storage. We hypothesized that ischemic preconditioning protects hepatic grafts via a tyrosine kinase–dependent pathway. Six porcine livers underwent routine harvest (control). Five other livers underwent 15 min of in situ ischemia followed by 15 min of reflow before harvest (ischemic preconditioning). Another five livers were pretreated with a tyrosine kinase inhibitor (genistein) before preconditioning. Upon reperfusion and after 2 hours of cold storage, graft function, graft circulatory impairment, and markers of cellular damage were analyzed. Tissue cytoplasmic extracts were analyzed for tyrosine phosphorylation with Western blot. Significance was determined with t tests. Ischemic-preconditioned grafts demonstrated enhanced bile production, augmented responses to a bile acid challenge, and elevated O2 consumption (P <0.05) compared to controls. Also, preconditioned grafts demonstrated improved hepatic tissue blood flow and decreased hepatic vascular resistance (P <0.005) compared to controls. Endothelial cell preservation (factor VIII immunostain) was improved in preconditioned graft biopsies compared to controls. With genistein pretreatment, all observed improvements returned to control levels. Analysis of cytoplasmic extracts demonstrated an increase in tyrosine phosphorylation before cold ischemia in preconditioned grafts only, but not in control or genistein-pretreated grafts. The data indicate that ischemic preconditioning protects the liver from sustained cold ischemia and that tyrosine kinases are involved in preconditioning responses.