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首页> 外文期刊>Hepatology: Official Journal of the American Association for the Study of Liver Diseases >Pentamidine Blocks Hepatotoxic Injury in Mice
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Pentamidine Blocks Hepatotoxic Injury in Mice

机译：芬太丁阻断小鼠肝毒性损伤

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Toxin-induced liver diseases lack effective therapies despite increased understanding of the role factors such as an overactive innate immune response play in the pathogenesis of this form of hepatic injury. Pentamidine is an effective antimicrobial agent against several human pathogens, but studies have also suggested that this drug inhibits inflammation. This potential anti-inflammatory mechanism of action, together with the development of a new oral form of pentamidine isethionate VLX103, led to investigations of the effectiveness of this drug in the prevention and treatment of hepatotoxic liver injury. Pretreatment with a single injection of VLX103 in the D-galactosamine (GalN) and lipopolysaccharide (LPS) model of acute, fulminant liver injury dramatically decreased serum alanine aminotransferase levels, histological injury, the number of terminal deoxynucleotide transferase-mediated deoxyuridine triphosphate nick end-labeling (TUNEL)-positive cells and mortality compared with vehicle-injected controls. VLX103 decreased GalN/LPS induction of tumor necrosis factor (TNF) but had no effect on other proinflammatory cytokines. VLX103 prevented the proinflammatory activation of cultured hepatic macrophages and partially blocked liver injury from GalN/TNF. In GalN/LPS-treated mice, VLX103 decreased activation of both the mitochondrial death pathway and downstream effector caspases 3 and 7, which resulted from reduced c-Jun N-terminal kinase activation and initiator caspase 8 cleavage. Delaying VLX103 treatment for up to 3 hours after GalN/LPS administration was still remarkably effective in blocking liver injury in this model. Oral administration of VLX103 also decreased hepatotoxic injury in a second more chronic model of alcohol-induced liver injury, as demonstrated by decreased serum alanine and aspartate aminotransferase levels and numbers of TUNEL-positive cells. Conclusion: VLX103 effectively decreases toxin-induced liver injury in mice and may be an effective therapy for this and other forms of human liver disease.
机译：尽管对这种形式的肝损伤的发病机制中的发病机制增加了诸如过度活跃的先天免疫反应起作用，但毒素诱导的肝病缺乏有效的疗法。芬太丁是一种有效的抗微生物剂，针对几种人类病原体，但研究还表明这种药物抑制炎症。这种潜在的抗炎作用机制，以及开发新的口腔吲哚啶异乙醇酯VLX103，导致该药在预防和治疗肝毒性肝损伤中的有效性的研究。在D-半乳糖胺（GALN）和脂多糖（LPS）模型中对VLX103的单一注射的预处理，急性肝损伤的模型显着降低了血清丙氨酸氨基转移酶水平，组织学损伤，末端脱氧核苷酸转移酶介导的脱氧尿嘧啶三磷酸碎片 - 与载体注射的对照相比，标记（TUNEL） - 阳性细胞和死亡率。 VLX103减少了肿瘤坏死因子（TNF）的Galn / LPS诱导，但对其他促炎细胞因子没有影响。 VLX103防止了培养的肝巨噬细胞的促炎症激活，并从Galn / TNF部分阻断肝损伤。在GALN / LPS处理的小鼠中，VLX103降低了线粒体死亡途径和下游效应子酶3和7的活化，这是由C-JUM N-末端激酶活化和引发剂胱天蛋酶8切割产生的。延迟VLX103在Galn / LPS施用后长达3小时的治疗在该模型中阻断肝损伤仍然有效。 VLX103的口服给药也降低了肝毒性损伤的第二次慢性模型，如血清丙氨酸和天冬氨酸氨基转移酶水平和TUNEL阳性细胞的数量所示。结论：VLX103有效地降低了小鼠的毒素诱导的肝损伤，可能是这种和其他形式的人肝病的有效治疗。

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