Adaptive Response to Intestinal Oxidative Stress in Mammalian Hibernation

摘要

The goal of this project is demonstrate how mammalian hibernators utilize the physiologic consequences of metabolic depression, which include changes in mitochondrial function, low body temperatures (Tb) and reduced blood flow, to activate cellular signaling pathways that minimize oxidative damage to sensitive tissues during torpor-arousal cycles. Specific Aim 1 examines oxidative stress to the gut of ground squirrels during the seasonal cycle. Specific Aim 2 examines consequences of intestinal oxidative stress during hibernation including seasonal changes in NF-kB activation in intestine, seasonal changes in the intestinal mucosal immune system and the effect of hibernation on enterocyte apoptosis and cell cycle regulators. We have now developed two models of intestinal ischemia-reperfusion (I/R) in rats and ground squirrels, and preliminary studies strongly suggest that the hibernation phenotype confers protection against gut-induced trauma. Mechanisms of protection include maintenance of intestinal absorptive and barrier function and suppression of the I/R - induced inflammatory cascade (e.g., neutrophil activation, cytokine release). Importantly, these protective effects are not dependant upon hypothermia or hypometabolism, as they are present in fully aroused hibernators. Our findings provide insight into the dynamic nature of the hibernating phenotype in terms of protection against oxidative stress and suppression of pro-inflammatory processes. We anticipate that further understanding of this naturally-induced change in a mammalian model for extreme physiologic change can lead to novel approaches to protect and preconditioning humans against traumatic events.