Tumor necrosis factor-α-null mice are not resistant to cadmium chloride-induced hepatotoxicity
Tumor necrosis factor-α-null mice are not resistant to cadmium chloride-induced hepatotoxicity
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DOI：
10.1006/taap.2001.9362
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发表时间：
2002-03-15
影响因子：
3.8
通讯作者：
Klaassen, CD
中科院分区：
文献类型：
--
作者：
Harstad, EB;Klaassen, CD
急性服用镉会导致肝脏毒性。最近的研究表明，Kupffer细胞是肝脏的驻留巨噬细胞，参与了化学性肝毒性的表现。肿瘤坏死因子-α(TNT-α)是一种促炎症细胞因子，是枯否细胞的主要产物，介导内毒素(LPS)的肝毒性作用。据推测，镉还可能通过库普弗细胞产生肿瘤坏死因子-α而发挥其肝毒性作用。因此，这项研究是为了确定缺乏肿瘤坏死因子-α的小鼠是否对镉诱导的肝毒性具有抵抗力。用生理盐水、内毒素(0.1 mg/kg)/谷氨酰胺(D-氨基半乳糖，700 mg/kg)或氯化镉(2.2、2.8、3.4、3.9mgCd/kg)灌胃肿瘤坏死因子α缺失(TNF-KO)小鼠和野生型(WT)小鼠。测定血清丙氨酸氨基转移酶(ALT)和山梨醇脱氢酶(SDH)活性以评估肝损伤程度。半胱氨酸天冬氨酸氨基转移酶-3活性定量检测肝细胞凋亡。LPS/Gln治疗使WT小鼠的ALT(17倍)和SDH(21倍)增加。相反，内毒素/谷氨酰胺处理并未显著升高肿瘤坏死因子-KO小鼠的ALT和SDH。LPS/Gln治疗可使WT小鼠caspase-3活性增加7.8倍，但对肿瘤坏死因子-KO小鼠caspase-3活性无明显影响。镉对WT和TNF-KO小鼠的肝损伤均呈剂量依赖性增加。但在任何剂量下，Cd对肿瘤坏死因子-KO小鼠的肝损伤与WT组无明显差异。在任何镉处理的小鼠中都没有检测到caspase-3活性的显著增加。这些数据表明，与脂多糖/谷氨酰胺诱导的肝毒性相反，TNT-a似乎不介导镉诱导的肝毒性。(C)2002年埃尔塞维尔科学公司(美国)。
Acute administration of cadmium results in hepatotoxicity. Recent reports indicate that Kupffer cells, the resident macrophages of the liver, participate in the manifestation of chemical-induced hepatotoxicity. Tumor necrosis factor-alpha (TNT-alpha) is a proinflammatory cytokine that is a major product of Kupffer cells and mediates the hepatotoxic effects of lipopolysaccharide (LPS). It has been speculated that cadmium also may exert its hepatotoxicity via the production of TNF-alpha by the Kupffer cells. Therefore, this study was undertaken to determine whether mice deficient in TNF-alpha are resistant to Cd-induced hepatotoxicity. TNF-alpha-null (TNF-KO) and wild-type (WT) mice were dosed ip with saline, LPS (0.1 mg/kg)/Gln (D-galactosamine, 700 mg/kg), or CdCl2 (2.2, 2.8, 3.4, and 3.9 mg Cd/kg). Serum alanine aminotransferase (ALT) and sorbitol dehydrogenase (SDH) activities were quantified to assess liver injury. Caspase-3 activity was quantified to assess hepatocellular apoptosis. LPS/Gln treatment increased ALT (17-fold) and SDH (21-fold) in WT mice. In contrast, LPS/Gln-treatment did not significantly increase ALT or SDH in TNF-KO mice. LPS/Gln-treatment caused a 7.8-fold increase in caspase-3 activity in WT mice but did not increase caspase-3 in TNF-KO mice. Cadmium caused a dose-dependent increase in liver injury in both WT and TNF-KO mice. However, the liver injury produced by Cd in the TNF-KO mice was not different from that in WT at any dose. No significant increase in caspase-3 activity was detected in any of the Cd-treated mice. These data indicate that, in contrast to LPS/Gln-induced hepatotoxicity, TNT-a does not appear to mediate Cd-induced hepatotoxicity. (C) 2002 Elsevier Science (USA).