Ischemia at 4°C: a novel mouse model to investigate the effect of hypothermia on postischemic hepatic microcirculatory injury

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Abstract
Hypothermia of the ischemic organ at 4°C protects hepatic microcirculation from ischemia-reperfusion (IR) injury. The effect of hypothermia during ischemia was investigated in animal models using liver transplantation and storage of the harvested organ in cold preservation solutions. No investigation of the isolated influence of hypothermia at 4°C of the ischemic organ on hepatic IR injury exists, due to the lack of an appropriate animal model. Therefore, the aim of our present study was to develop such a model using intravital video fluorescence microscopy (IVM). In C57BL/6 mice, a reversible isolated ischemia of the left liver lobe was induced for 90 min, followed by 240 min of reperfusion. The temperature of the ischemic organ was adjusted to either 4°C or 37°C by superfusion with 0.9% NaCl. Sham-operated animals without IR served as controls. The hepatic microcirculation was analyzed using IVM at 30 min and 240 min after reperfusion by quantifying sinusoidal perfusion and leukocyte-endothelial cell interaction in postsinusoidal venules. At the end of the experiment, blood and tissue samples were taken for measurement of liver enzyme activities and light and electron microscopy. Mean arterial pressure and body temperature were kept constant throughout the experiment, while the temperature of the ischemic liver lobe was adjusted to predefined levels. After normothermic ischemia, hepatic microvascular perfusion was significantly impaired compared with sham-operated animals. Perfusion failure was significantly reduced in hypothermic livers and did not differ from livers of the sham-group. Liver enzyme activities in the normothermic group were significantly higher than in the sham and hypothermic groups. Light and electron microscopy revealed severe histological alterations at 37°C ischemia, whereas at 4°C ischemia only minimal lesions were encountered. Our novel model allows for isolated adjustment of ischemic liver lobe temperature without changing body temperature and systemic macrohemodynamic parameters. Hypothermia at 4°C largely attenuates postischemic microvascular perfusion injury of the liver.