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Low‐dose TNF‐α protects against hepatic ischemia‐reperfusion injury in mice: Implications for preconditioning
Author(s) -
Teoh Narci,
Leclercq Isabelle,
Pena Aileen Dela,
Farrell Geoffrey
Publication year - 2003
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1053/jhep.2003.50009
Subject(s) - ischemic preconditioning , ischemia , tumor necrosis factor alpha , reperfusion injury , medicine , hepatocyte , necrosis , liver injury , endocrinology , cell cycle , pharmacology , chemistry , biochemistry , cancer , in vitro
Tumor necrosis factor α (TNF‐α) is implicated in the pathogenesis of hepatic ischemia reperfusion injury but can also prime hepatocytes to enter the cell cycle. Ischemic preconditioning protects against ischemia‐reperfusion (IR) liver injury and is associated with activation of nuclear factor κB (NF‐κB) and cell cycle entry. We examined the pattern of TNF‐α release during hepatic IR in the presence or absence of ischemic preconditioning, and we tested whether a single low‐dose injection of TNF could mimic the biologic effects of ischemic preconditioning. In naïve mice, hepatic and plasma levels of TNF‐α rose during hepatic ischemia, reaching high levels after 90 minutes; values remained elevated during reperfusion until 44 hours. Following the ischemic preconditioning stimulus, there was an early rise in hepatic and serum TNF‐α levels, but, during a second prolonged ischemic interval peak, TNF‐α values were lower than in naïve mice and declined to negligible levels by 2 hours reperfusion. An injection with 1 μg or 5 μg/kg body weight TNF‐α 30 minutes prior to hepatic IR substantially reduced liver injury determined by liver histology and serum alanine aminotransferase (ALT) levels. As in ischemic preconditioning, TNF‐α pretreatment activated NF‐κB DNA binding, STAT3, cyclin D1, cyclin‐dependent kinase 4 (cdk4) expression, and cell cycle entry, determined by proliferating cell nuclear antigen (PCNA) staining of hepatocyte nuclei. In conclusion, the hepatoprotective effects of “preconditioning” can be simulated by TNF‐α injection, which has identical downstream effects on cell cycle entry. We propose that transient increases in TNF‐α levels may substitute for, as well as, mediate the hepatoprotective effects of ischemic preconditioning against hepatic IR injury.