Gadolinium Chloride Induced Blockade of Kupffer Cells (KC) Ameliorates Ischemia/Reperfusion (I/R) Injury in the Steatotic Liver.:

280 Background: Due to the increase in liver transplant recipients, more poorly functioning steatotic donor organs are being used.Purpose: To determine the benefits of KC blockade by gadolinium chloride (GdCl), a known inhibitor of KC activation and phagocytosis, in steatotic hepatic I/R injury. Methods: Cohorts of male genetically fatty Zucker rats (350-400 gms) were pretreated for 2 days with GdCl (15 mg/kg/day) IV. The steatotic Zucker livers were procured and stored at 4°C for 6 hrs in UW solution. Following storage, livers were reperfused for 2 hrs via an isolated perfused rat liver (IPRL) apparatus. The following parameters were evaluated at 30 min intervals: portal vein blood flow/pressure; bile output; and hepatic vein effluent transaminase release. Additionally, hepatocyte injury was analyzed histologically and graded according to Suzuki's classification. Results: In anex-vivo cold ischemia steatotic rat liver model, GdCl provided protection to I/R injury as measured by transaminase release, portal blood flow, bile production, and hepatocyte damage. As shown inFigure 1, SGOT release was markedly reduced in the GdCl pretreatment group (p<0.05). Moreover, treatment with GdCl resulted in improved portal blood flow (Fig. 2).Fig. 1: SGOT releaseFig. 2: Portal Blood FlowPretreatment with GdCl also improved bile production, 0.66±0.26 ml/hr vs. 0.11±0.08 ml/hr (p=0.02). In addition, GdCl significantly decreased the degree of histologic hepatocyte injury (Suzuki's severity score 1.42±0.51 vs. 1.84±0.50 (p=0.014). Conclusions: Kupffer cells play a significant role in I/R injury of the steatotic rat liver. Early downregulation of KCs decreases hepatocyte injury and improves liver function. These findings demonstrating a non-MHC dependent injury may have clinical applicability in our attempt to expand the transplant donor pool.