A role of cell apoptosis in lipopolysaccharide (LPS)-induced nonlethal liver injury in D-galactosamine (D-GalN)-sensitized rats
A role of cell apoptosis in lipopolysaccharide (LPS)-induced nonlethal liver injury in D-galactosamine (D-GalN)-sensitized rats
复制标题
细胞凋亡在脂多糖（LPS）诱导的 D-半乳糖胺（D-GalN）致敏大鼠非致死性肝损伤中的作用
DOI：
10.1007/s10620-007-9994-y
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发表时间：
2008-05-01
影响因子：
3.1
通讯作者：
Sun, Sui-Lin
中科院分区：
文献类型：
--
作者：
Liu, Liang-Ming;Zhang, Ji-Xiang;Sun, Sui-Lin
脂多糖（LPS）与急性肝损伤的病理学有关，当与D-氨基半乳糖（D-GalN）同时给药时，可诱导致死性肝衰竭。目前，低剂量LPS/D-GalN激发后的非致死性肝衰竭（临床意义的肝损伤）尚未完全了解。我们在这里报告我们的调查后，非致死剂量的LPS/D-GalN肝损伤的影响和细胞凋亡在这种疾病中的作用。血清谷丙转氨酶（ALT）、谷草转氨酶（AST）和总胆红素（TBIL）在注射LPS/D-GalN后6 h即开始升高，24 h达高峰，48 h持续高水平。在注射后24和48 h发现肝脏外观异常。6 h开始出现肝细胞死亡、炎性细胞浸润和出血等肝损伤的组织学改变，24 h和48 h明显加重。非致死剂量的LPS/D-GalN攻击可显著诱导细胞凋亡，末端转移酶dUTP缺口末端标记（TUNEL）检测显示，24 h和48 h处理组大鼠的凋亡指数（AI）约为70%。炎性细胞因子IL-1 β的mRNA水平在6小时显著升高，并在24和48小时维持高水平;然而，TNF-α水平在6、24和48小时处理的大鼠的肝组织中是正常的。损伤基因一氧化氮合酶（NOS）mRNA表达在LPS/D-GalN刺激早期即被诱导，6 h达高峰，随后呈阶梯状逐渐下降;相反地，肝细胞凋亡诱导基因p53 mRNA在注射后早期（6 h）没有高表达，但在肝细胞凋亡高峰期（24 h）出现高表达并维持该水平直至晚期（48 h）。LPS/D-GalN刺激24 h后，caspase-3、-8、-9和-12被激活。这些结果表明，低剂量LPS与D-GalN联合攻击可诱导非致死性但显著的肝衰竭，其主要形态学特征是肝细胞凋亡，这可能与诱导型NOS（注射后早期）和p53基因（在中期和晚期）的高表达有关，并且至少有三种凋亡途径参与发病机制。
Lipopolysaccharide (LPS) is implicated in the pathology of acute liver injury and can induce lethal liver failure when simultaneously administered with D-galactosamine (D-GalN). At the present time, nonlethal liver failure, the liver injury of clinical implication, is incompletely understood following challenge by low-dose LPS/D-GalN. We report here our investigation of the effects of liver injury following a nonlethal dose LPS/D-GalN and the role of apoptosis in this disorder. Blood biochemistry indexes, including those of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and total bilirubin (TBIL), had risen by 6 h post-LPS/D-GalN injection, reached a peak at 24 h and sustained high levels at 48 h. An abnormal liver appearance was found at 24 and 48 h post-injection. Histopathological changes of hepatic injuries accompanied by hepatocellular death, inflammatory infiltration and hemorrhage began to appear at 6 h and were markedly aggravated at 24 and 48 h. Cell apoptosis was significantly induced by the nonlethal dose LPS/D-GalN challenge, and the apoptotic indexes (AIs) in 24 h-and 48 h- treated rats were approximately 70%, as estimated by the terminal transferase dUTP nick end labeling (TUNEL) assay. The mRNA levels of the inflammatory cytokine IL-1 beta rose markedly at 6 h and maintained high levels at 24 and 48 h; however, TNF-alpha a levels were normal in the liver tissues of 6-, 24- and 48- h-treated rats. mRNA expression of the damage gene nitric oxide synthase (NOS) was also induced early by the LPS/D-GalN challenge, reaching a peak at 6 h, then gradually decreasing in a stepwise manner; conversely, high expression levels of the apoptosis-inducing gene p53 mRNA were not found in the early post-injection period ( 6 h) but emerged in the crest-time of liver apoptosis (24 h) and were maintained at this level until the late stage (48 h). We also observed that in 24 h-treated rats, caspase-3,-8, -9 and -12 were markedly activated by LPS/D-GalN challenge. These results suggest that a challenge with low-dose LPS in conjunction with D-GalN can induce nonlethal but marked liver failure, the main morphological feature of which is hepatic apoptosis, which may be associated with a high expression of inducible (i) NOS (early post-injection period) and p53 genes (in the mid and late stages) and at least three apoptosis pathways participate in the pathogenesis.