Mechanisms of hypothermic protection against ischemic liver injury in mice

Abstract

Mechanisms of hypothermic protection against ischemic liver injury in mice. Am J Physiol Gastrointest Liver Physiol 282: G608-G616, 2002. 10.1152/ajpgi.00454.2001.-Hepatic hypothermia can safely prolong the duration of hepatic inflow occlusion during complex liver resectional surgeries. The mechanism(s) by which hypothermia protects against this form of liver ischemia-reperfusion injury are not completely understood. In this study, we sought to determine whether hypothermia protects against ischemia-reperfusion injury by altering the hepatic inflammatory response. Mice undergoing 90 min of partial hepatic ischemia followed by up to 8 h of reperfusion had their body temperatures regulated at 35-37°C (normothermic) or unregulated, in which rectal temperature dropped as low as 25°C by the end of ischemia (hypothermic). Hypothermic mice had less liver injury vs. normothermic mice, as assessed histologically, by serum transaminase levels (89% decrease), and by liver wet-to-dry weight ratios (91% decrease). Neutrophil accumulation was absent in hypothermic mice (99% reduction vs. normothermic mice). Production of the proinflammatory cytokines tumor necrosis factor-␣, interleukin-1␤, and macrophage inflammatory protein-2 were reduced by up to 92%. Activation of the transcription factor nuclear factor-B was not reduced in hypothermic mice, but activation of c-Jun NH 2-terminal kinase (JNK) and the transcription factor activator protein (AP)-1 were greatly diminished. These data suggest that hypothermia suppresses the hepatic inflammatory response through selective inhibition of JNK and AP-1.

Protective Mechanisms of Hypothermia in Liver Surgery and Transplantation

“…In a mouse model of 90 min of partial hepatic ischemia performed at either 37°C or ±25°C, neutrophil influx at 8 h of reperfusion was reduced by 99% in the hypothermic group. A similar extent of immunosuppression was observed in both hypothermic groups of a rat study comparing 45 min of partial hepatic ischemia at 37°C, 34°C and 31°C, thereby confirming that per-ischemic hypothermia can suppress the I/R immune response (26,42).…”

“…To explain this phenomenon, mRNA and serum levels of the neutrophil chemoattractants tumor necrosis factor ( TNF)-α and chemokine (C-X-C motif) ligand 2 (CXCL2) were measured in the aforementioned mouse model, which were all reduced in mice subjected to I/R under hypothermic conditions (40,42). It was additionally shown that mice exposed to hypothermic I/R had reduced activation of the protein kinase c-jun N-terminal kinase (JNK) and the transcription factor activator protein 1 (AP-1), the latter of which is known to encode a host of I/R-pertinent cytokines (18,42).…”

“…It was additionally shown that mice exposed to hypothermic I/R had reduced activation of the protein kinase c-jun N-terminal kinase (JNK) and the transcription factor activator protein 1 (AP-1), the latter of which is known to encode a host of I/R-pertinent cytokines (18,42). oncotic necrosis, thereby releasing DAMPs into the circulation (35).…”

“…Several reports have shown that hypothermia curtails the signaling cascades that derail glucose metabolism during and after surgery. First, the activation of JNK is reduced after 90-min partial hepatic ischemia in mice under hypothermic conditions, thereby neutralizing the most important trigger for insulin receptor inactivation (see Hypothermia and Immunomodulation) (42). Second, hypothermia has immunomodulatory effects, which could improve insulin sensitivity by lowering TNF-α and IL-6 levels (see Hypothermia and Immunomodulation).…”

Keeping cool in acute liver failure: Rationale for the use of mild hypothermia

“…Studies suggest that hypothermia reduces liver injury [164], [165] and [166], but it may impair liver regeneration [167]. Further research will be needed to clarify these issues.…”