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Requirement for interleukin‐12 in the pathogenesis of warm hepatic ischemia/reperfusion injury in mice
Author(s) -
Lentsch Alex B.,
Yoshidome Hiroyuki,
Kato Atsushi,
Warner Roscoe L.,
Cheadle William G.,
Ward Peter A.,
Edwards Michael J.
Publication year - 1999
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.510300615
Subject(s) - medicine , reperfusion injury , ischemia , myeloperoxidase , liver injury , tumor necrosis factor alpha , immunology , inflammation , pharmacology , endocrinology
Hepatic ischemia and reperfusion causes neutrophil‐dependent liver injury. Although the mechanisms of ischemia/reperfusion‐induced liver neutrophil recruitment are somewhat understood, less is known regarding the early events that initiate the inflammatory injury. Using a murine model of partial hepatic ischemia and reperfusion, we evaluated the role of endogenous interleukin (IL)‐12 in this inflammatory response. Hepatic ischemia for 90 minutes and reperfusion for up to 4 hours resulted in hepatocyte expression of IL‐12. By 8 hours of reperfusion there were large increases in serum levels of interferon‐γ (IFNγ) and tumor necrosis factor‐α (TNFα). In addition, hepatic ischemia/reperfusion caused significant increases in liver neutrophil recruitment, hepatocellular injury, and liver edema, as defined by liver myeloperoxidase content, serum alanine aminotransferase, and liver wet to dry weight ratios, respectively. In mice treated with neutralizing antibody to IL‐12 and in mice deficient in the IL‐12 p40 gene, ischemia/reperfusion‐induced increases in IFNγ and TNFα were greatly diminished. These conditions also caused significant reductions in liver myeloperoxidase content and attenuated the parameters of liver injury. The data suggest that IL‐12 is required for the full induction of injury after hepatic ischemia and reperfusion.