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LIVER AND BILIARY TRACT

Hepatocyte NF-B activation is hepatoprotective during ischemia-reperfusion injury and is augmented by ischemic hypothermia

¹The Laboratory of Trauma, Sepsis and Inflammation Research, Department of Surgery, University of Cincinnati College of Medicine; and ²Division of Critical Care Medicine, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio

The present study examined the role of hepatocyte NF-B activation during ischemia-reperfusion injury. Second, we evaluated the effects of ischemic hypothermia on NF-B activation and liver injury. C57BL/6 mice underwent 90 min of partial hepatic ischemia and up to 8 h of reperfusion. Body temperature was regulated during the ischemic period between 35 and 37°C, 33 and 35°C, 29 and 33°C or unregulated, where temperature fell to <29°C. Liver injury, as measured by serum alanine aminotransferase as well as liver histopathology, was inversely proportional to regulated body temperature, with the unregulated group (<29°C) being highly protected and the normothermic group (35–37°C) displaying the greatest injury. Inflammation, as measured by production of TNF- and liver recruitment of neutrophils, was greatest in the normothermic groups and lowest in the ischemic hypothermia groups. Interestingly, hepatocyte NF-B activation was highest in the hypothermic group and least in the normothermic group. Paradoxically, degradation of IB proteins, IB- and IB-, was greatest in the normothermic group, suggesting an alternate NF-B regulatory mechanism during ischemia-reperfusion injury. Subsequently, we found that NF-B p65 protein was increasingly degraded in normothermic versus hypothermic groups, and this degradation was specific for hepatocytes and was associated with decreased expression of the peptidyl-prolyl isomerase Pin1. The data suggest that NF-B activation in hepatocytes is a protective response during ischemia-reperfusion and can be augmented by ischemic hypothermia. Furthermore, it appears that Pin1 promotes NF-B p65 protein stability such that decreased expression of Pin1 during ischemia-reperfusion results in p65 degradation, reduced nuclear translocation of NF-B, and enhanced hepatocellular injury.

liver inflammation; nuclear factor-B p65; Pin1

This article has been cited by other articles:

				S. Kuboki, R. Schuster, J. Blanchard, T. A. Pritts, H. R. Wong, and A. B. Lentsch Role of heat shock protein 70 in hepatic ischemia-reperfusion injury in mice Am J Physiol Gastrointest Liver Physiol, April 1, 2007; 292(4): G1141 - G1149. [Abstract] [Full Text] [PDF]