Deletion of the Ron receptor tyrosine kinase domain in mice provides protection from endotoxin-induced acute liver failure
Deletion of the Ron receptor tyrosine kinase domain in mice provides protection from endotoxin-induced acute liver failure
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DOI：
10.1053/jhep.2002.36822
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发表时间：
2002-11-01
期刊：
影响因子：
13.5
通讯作者：
Waltz, SE
中科院分区：
文献类型：
--
作者：
Leonis, NA;Toney-Earley, K;Waltz, SE
小鼠Ron受体酪氨酸激酶（TK）细胞质结构域的靶向缺失导致几种小鼠炎症模型中对损伤的反应夸大，以及内毒素（脂多糖[LPS]）反应的致死率增加。利用半乳糖胺（GalN）致敏小鼠lps诱导的急性肝衰竭（ALF）模型，我们发现与对照组Ron TK+/+小鼠相比，Ron TK-/-小鼠表现出明显的保护作用。与对照小鼠血清转氨酶水平（肝细胞损伤的标志）和肝脏出血性坏死显著升高相反，Ron TK-/-小鼠的转氨酶水平轻度升高，肝脏组织学相对正常。这些发现与Ron TK-/-小鼠中发生凋亡的肝细胞数量减少有关。矛盾的是，用LPS/GalN治疗Ron TK-/-小鼠会导致血清肿瘤坏死因子(TNF) α水平显著升高（3.5倍），TNF- α是肝损伤模型中的关键炎症介质，同时白细胞介素（IL） 10 （TNF - α产生的抑制因子）和干扰素(IFN)- γ （TNF - α致敏剂）的含量降低。这些结果表明，即使在血清tnf - α水平过高的情况下，在LPS/GalN治疗下，Ron受体TK活性的消融也可以防止肝细胞凋亡的发生。总之，我们的研究表明，Ron受体TK在调节肝脏对内毒素的反应中起着关键作用。
The targeted deletion of the cytoplasmic domain of the Ron receptor tyrosine kinase (TK) in mice leads to exaggerated responses to injury in several murine models of inflammation as well as increased lethality in response to endotoxin (lipopolysaccharide [LPS]). Using a well-characterized model of LPS-induced acute liver failure (ALF) in galactosamine (GalN)-sensitized mice, we show that Ron TK-/- mice display marked protection compared with control Ron TK+/+ mice. Whereas control mice have profound elevation of serum aminotransferase levels (a marker of hepatocyte injury) and hemorrhagic necrosis of the liver, in dramatic contrast, Ron TK-/- mice have mild elevation of aminotransferase levels and relatively normal liver histology. These findings are associated with a reduction in the number of liver cells undergoing apoptosis in Ron TK-/- mice. Paradoxically, treatment of Ron TK-/- mice with LPS/GalN leads to markedly elevated (3.5-fold) serum levels of tumor necrosis factor (TNF) alpha, a key inflammatory mediator in this liver injury model, as well as reduced amounts of interleukin (IL) 10 (a suppressor of TNF-alpha production) and interferon (IFN)-gamma (a TNF-alpha sensitizer). These results show that ablation of the TK activity of the Ron receptor leads to protection from the development of hepatocellular apoptosis in response to treatment with LPS/GalN, even in the presence of excessive levels of serum TNF-alpha. In conclusion, our studies show that the Ron receptor TK plays a critical role in modulating the response of the liver to endotoxin.