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

Abstract

The present study examined the role of hepatocyte NF-kappaB activation during ischemia-reperfusion injury. Second, we evaluated the effects of ischemic hypothermia on NF-kappaB 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 degrees C, 33 and 35 degrees C, 29 and 33 degrees C or unregulated, where temperature fell to <29 degrees 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 degrees C) being highly protected and the normothermic group (35-37 degrees C) displaying the greatest injury. Inflammation, as measured by production of TNF-alpha and liver recruitment of neutrophils, was greatest in the normothermic groups and lowest in the ischemic hypothermia groups. Interestingly, hepatocyte NF-kappaB activation was highest in the hypothermic group and least in the normothermic group. Paradoxically, degradation of IkappaB proteins, IkappaB-alpha and IkappaB-beta, was greatest in the normothermic group, suggesting an alternate NF-kappaB regulatory mechanism during ischemia-reperfusion injury. Subsequently, we found that NF-kappaB 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-kappaB activation in hepatocytes is a protective response during ischemia-reperfusion and can be augmented by ischemic hypothermia. Furthermore, it appears that Pin1 promotes NF-kappaB p65 protein stability such that decreased expression of Pin1 during ischemia-reperfusion results in p65 degradation, reduced nuclear translocation of NF-kappaB, and enhanced hepatocellular injury.

• Authors: Satoshi Kuboki, Tomohisa Okaya, Rebecca Schuster, John Blanchard, Alvin Denenberg, Hector R Wong, Alex B Lentsch
• Journal: American journal of physiology. Gastrointestinal and liver physiology (Am J Physiol Gastrointest Liver Physiol) Vol. 292 Issue 1 Pg. G201-7 (Jan 2007) ISSN: 0193-1857 [Print] United States
• PMID: 16950761 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• NF-kappa B
• Aspartate Aminotransferases
• Alanine Transaminase

Topics

• Alanine Transaminase (blood)
• Animals
• Aspartate Aminotransferases (blood)
• Cell Nucleus (physiology)
• Hepatocytes (physiology)
• Hypothermia (physiopathology)
• Ischemia (physiopathology)
• Liver (physiopathology)
• Liver Circulation
• Male
• Mice
• Mice, Inbred C57BL
• NF-kappa B (metabolism)
• Neutrophils (physiology)
• Reperfusion Injury (prevention & control)