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Regulation of hepatic NF‐κB activation during reperfusion after normothermic and hypothermic ischemia
Author(s) -
Kuboki Satoshi,
Blanchard John,
Schuster Rebecca,
Wong Hector,
Lentsch Alex B.
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.5.a1082-b
Subject(s) - hypothermia , ischemia , medicine , liver transplantation , reperfusion injury , proinflammatory cytokine , anesthesia , chemokine , transplantation , endocrinology , inflammation
Hepatic ischemia/reperfusion (I/R) injury may occur as a result of liver resectional surgery or transplantation. Throughout the history of liver surgery, hypothermic techniques have shown some benefit in the prevention of ischemic injury. We have previously shown that hypothermia attenuates the inflammatory response induced by ischemia/reperfusion. Because the transcription factor, NF‐κB, is known to be a primary regulator of inflammatory gene expression, we sought to determine if hypothermia affected the activation of this transcription factor. Male C57BL/6 mice were subjected to 90 minutes of partial hepatic ischemia followed by up to 8 hours of reperfusion. One group of mice had their body temperature maintained at 36.5 ± 0.2 °C (normothermic) throughout the surgical procedure and recovery period. In the other group of mice (hypothermic), body temperature was uncontrolled during the period of liver ischemia and was quickly returned to normal upon reperfusion. In this latter group, mean rectal temperature fell to 23.1 ± 0.5 °C by the end of the ischemic period. Hypothermic mice were significantly protected from hepatic I/R injury, as determined by serum ALT. Hypothermia resulted in reduced serum levels of the proinflammatory chemokine, TNFα. However, there was increased NF‐κB activation in hypothermic mice compared to normothermic mice. IKK kinase activity was also increased in livers of hypothermic mice compared to normothermic mice. Immunofluorescence staining of NF‐κB p65 in liver sections indicated that the increased activation in hypothermic mice occurred widely in hepatocytes. We conclude that NF‐κB activation in hepatocytes in hypothermic mice is hepatoprotective and that in normothermic mice, NF‐κB activity likely occurs in Kupffer cells leading to the elaboration of proinflammatory cytokines.