A long graft survival of the steatotic liver after the inhibition of chemokine production and the remodeling of the altered extracellular matrix

本研究旨在探讨肝缺血再灌注（IR）损伤的有效治疗策略。IR损伤在脂肪变性肝移植术后原发性无功能中起着至关重要的作用。我们的研究小组先前发现，在酒精性脂肪肝中，中性粒细胞趋化因子有助于肝细胞坏死，这与IR后的细胞凋亡有关（《肝脏学》32:278,2000）。此外，在该模型体内，抑制肝巨噬细胞活性完全抑制趋化因子的产生，保护肝脏免受IR后广泛坏死的影响。当我们评估上述结果时，我们幸运地发现趋化因子与细胞外基质的牢固附着是肝脏中性粒细胞浸润和炎症性坏死的先决条件。在一项使用原代肝细胞的体内研究中，我们有证据表明线粒体功能改变对脂肪肝肝细胞凋亡的贡献。因此，我们提出了以下三种可能的脂肪肝移植存活策略：1. 抑制趋化因子的产生；2. 受损肝脏细胞外基质的重塑；3. 肝细胞线粒体功能的改善。

The aim of this research project is to approach an effective strategy against the hepatic ischemia-reperfusion (IR) injury. The IR injury plays a crucial role in the primary non-function after hepatic transplantation using a steatotic graft.Our group has previously found that in the alcoholic fatty liver a neutrophil-chemokine contributes to hepatocyte necrosis which is associated with apoptosis after IR (Hepatology 32:278, 2000). Additionally, in this model in vivo, the suppression of hepatic macrophage activity completely inhibits the production of the chemokine and protects the liver from the extensive necrosis after IR.When we evaluated the above results, we fortunately found that a firm attachment of the chemokine with extracellular matrices was prerequisite for the neutrophil infiltration and inflammatory necrosis in the liver. In an in vivo study using primary hepatocytes, we had an evidence for a contribution of the altered mitochondrial function to hepatic apoptosis in fatty liver.Thus, we raise three possible strategies for graft survival of the fatty livers as follows; 1. An inhibition of the chemokine production; 2. A remodeling of the extracellular matrix in the damaged liver; 3. An improvement of the mitochondrial function of the liver cells.