Cheng-Hsin Veterinary Pathology Center, Taichung, Taiwan.
Immunopharmacol Immunotoxicol. 2013 Apr;35(2):296-303. doi: 10.3109/08923973.2013.764503. Epub 2013 Feb 6.
Liver injury can be induced by various hepatotoxicants, including Pseudomonas aeruginosa exotoxin A (PEA). Our previous study indicated that PEA-induced rat hepatotoxicity was T cells and Kupffer cells dependent. Several reports have demonstrated that non-toxic doses of bacterial lipopolysaccharide (LPS) can protect liver against the chemicals-induced toxicity such as acetaminophen and concanavalin-A.
This study aimed to investigate the protecting mechanisms of LPS on PEA-induced hepatotoxicity.
Rats pretreated with LPS (40 μg/kg, 12 h before PEA admission) significantly decreased animal mortality, serum enzyme (ALT, AST and T-bil) activities, histopathological changes and hepatocytes apoptosis following challenge with PEA. The concentrations of tumor necrosis factor-alpha (TNF-α), interferon-gamma (IFN-γ) and interleukin-2 (IL-2) were reduced, but IL-6 and IL-10 were increased in the serum. In addition, prior treatment of these LPS-pretreated rats with gadolinium chloride (GdCl3), a selective Kupffer cell depletion agent, markedly enhanced liver injury after PEA administration. In contrast, the pretreatment of LPS to T-cell deficient athymic nude rats still display significant attenuation of PEA-induced liver injury. This observation further confirmed our hypothesis that LPS ameliorate PEA-hepatotoxicity was through Kupffer cells but not T cells. Moreover, LPS-induced hepatoprotection ability was neutralized by co-treatment with anti-TNF-α antibodies, but not with anti-IFN-γ antibodies. Finally, replacement of LPS with RS-LPS (Rhodobacter sphaeroides LPS), a Toll like receptor-4 (TLR-4) antagonist, resulted in severe hepatotoxicity.
These results suggested that Kupffer cells, TNF-α and TLR-4 play central mediator roles during the hepatoprotection against PEA-induced hepatotoxicity conferred by LPS.
肝损伤可由多种肝毒性物质引起，包括铜绿假单胞菌外毒素 A（PEA）。我们之前的研究表明，PEA 诱导的大鼠肝毒性依赖于 T 细胞和枯否细胞。有几项报道表明，细菌脂多糖（LPS）的无毒剂量可以保护肝脏免受化学物质引起的毒性，如对乙酰氨基酚和伴刀豆球蛋白 A。
本研究旨在探讨 LPS 对 PEA 诱导的肝毒性的保护机制。
PEA 攻击前用 LPS（40μg/kg，12 小时）预处理的大鼠，动物死亡率、血清酶（ALT、AST 和 T-bil）活性、组织病理学变化和肝细胞凋亡明显降低。血清中肿瘤坏死因子-α（TNF-α）、干扰素-γ（IFN-γ）和白细胞介素-2（IL-2）的浓度降低，而白细胞介素-6（IL-6）和白细胞介素-10（IL-10）的浓度升高。此外，用钆氯化物（GdCl3）预处理这些 LPS 预处理的大鼠，这是一种选择性枯否细胞耗竭剂，在给予 PEA 后明显加重肝损伤。相反，LPS 预处理 T 细胞缺陷的无胸腺裸鼠仍显示出对 PEA 诱导的肝损伤有显著的抑制作用。这一观察结果进一步证实了我们的假设，即 LPS 通过枯否细胞而不是 T 细胞改善 PEA 肝毒性。此外，LPS 诱导的肝保护能力被抗 TNF-α 抗体中和，但不受抗 IFN-γ 抗体的影响。最后，用 Rhodobacter sphaeroides LPS（TLR-4 拮抗剂）替代 LPS，导致严重的肝毒性。
这些结果表明，枯否细胞、TNF-α 和 TLR-4 在 LPS 对抗 PEA 诱导的肝毒性的肝保护作用中发挥中心介质作用。
