Fibronectin prevents D-galactosamine/lipopolysaccharide-induced lethal hepatic failure in mice
Fibronectin prevents D-galactosamine/lipopolysaccharide-induced lethal hepatic failure in mice
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DOI：
10.1097/01.shk.0000185797.04589.5c
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发表时间：
2006-01-01
期刊：
影响因子：
3.1
通讯作者：
Hirao, Y
中科院分区：
文献类型：
--
作者：
Qiu, ZY;Kwon, AH;Hirao, Y
血浆纤连蛋白（FN）具有广泛的生物学功能，涉及细胞粘附、运动、分化、凋亡、止血、伤口愈合、网状内皮系统功能和缺血性损伤。在这项研究中，我们研究了 FN 对 D-半乳糖胺 (GalN)/脂多糖 (LPS) 诱导的小鼠暴发性肝衰竭的影响。雌性Balb/c小鼠同时腹腔注射50μg/kg LPS和400mg/kg GAIN。给予GalIN/LPS前30分钟，静脉给予人血浆FN（FN组）或相同剂量的人血清白蛋白（对照组）。 GaIN/LPS 导致血浆 FN 显着降低，FN 预处理可逆转这一现象。与对照组（存活率0%）相比，FN组的存活率显着提高，呈剂量依赖性。 FN 可防止与肝损伤相关的血清酶和总胆红素浓度升高。与对照组相比，FN预处理显着抑制肿瘤坏死因子（TNF）-α、干扰素（IFN）-γ和白细胞介素（IL）-6水平，并增强血清和肝组织中IL-10水平。此外，与对照组相比，FN 治疗组大鼠的 TUNEL 染色、半胱天冬酶 3 和 8 活性以及残余肝脏坏死显着减少。此外，FN预处理抑制了核因子（NF）-κB的激活并增加了肝组织中Bcl-xL蛋白的表达。这些结果表明，FN 通过抑制 NF-κ B 激活的机制来防止 GaIN/LPS 诱导的肝衰竭，NF-κ B 激活导致 TNF-α 下调并涉及 IL-10 上调，而 Bcl-xL 的升高则诱导细胞凋亡信号阻断，从而抑制由 GaIN/LPS 引起的肝细胞凋亡。
Plasma fibronectin (FN) has a broad range of biological functions involved in cellular adhesion, motility, differentiation, apoptosis, hemostasis, wound healing, reticuloendothelial system function, and ischemic injury. In this study, we examined the effects of FN on D-galactosamine (GalN)/lipopolysaccharide (LPS)-induced fulminant liver failure in mice. Female Balb/c mice received intraperitoneal injection of 50 mu g/kg of LPS and 400 mg/kg of GAIN simultaneously. Thirty minutes before GaIN/LPS administration, human plasma FN (FN group) or the same dose of human serum albumin (control group) was given intravenously. GaIN/LPS induced a marked decrease in plasma FN, which was reversed by FN pretreatment. The survival rate of the FN group was markedly improved in a dose-dependent manner compared with that of the control group (survival rate 0%). FN prevented increases in the concentrations of serum enzymes and total bilirubin related to liver injury. FN pretreatment significantly suppressed tumor necrosis factor (TNF)-alpha, interferon (IFN)-gamma, and interleukin (IL)-6 levels, and enhanced IL-10 levels in serum and liver tissue compared with the control group. Moreover, TUNEL staining, caspase 3 and 8 activities, and necrosis in the remnant liver were significantly decreased in the FN-treated rats compared with the controls. Furthermore, FN pretreatment inhibited the activation of nuclear factor (NF)-kappa B and increased the expression of Bcl-xL protein in liver tissue. These results suggest that FN protected against GaIN/LPS-induced liver failure by a mechanism involving inhibition of NF-kappa B activation, which caused down-regulation of TNF-alpha and involved up-regulation of IL-10, and elevation of Bcl-xL induced a blockage of apoptotic signals, by which apoptosis of hepatocytes caused by GaIN/LPS was suppressed.