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. (Hepatology 2017;66:922–935).

中文翻译：

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喷他脒阻断小鼠肝毒性损伤

尽管人们对过度活跃的先天免疫反应等因素在这种形式的肝损伤的发病机制中的作用有了更多的了解，但毒素诱导的肝病仍缺乏有效的治疗方法。喷他脒是一种有效的抗微生物剂，可以对抗多种人类病原体，但研究也表明这种药物可以抑制炎症。这种潜在的抗炎作用机制，连同新的口服形式的喷他脒羟乙基磺酸盐 VLX103 的开发，导致了对该药物在预防和治疗肝毒性肝损伤中的有效性的研究。在急性暴发性肝损伤的 d-半乳糖胺 (GalN) 和脂多糖 (LPS) 模型中单次注射 VLX103 进行预处理可显着降低血清丙氨酸转氨酶水平、组织学损伤、与注射载体的对照相比，末端脱氧核苷酸转移酶介导的脱氧尿苷三磷酸切口末端标记（TUNEL）阳性细胞的数量和死亡率。VLX103 降低了肿瘤坏死因子 (TNF) 的 GalN/LPS 诱导，但对其他促炎细胞因子没有影响。VLX103 阻止培养的肝巨噬细胞的促炎激活并部分阻止 GalN/TNF 引起的肝损伤。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 caspase 3 和 7 的激活，这是由于 c-Jun N 端激酶激活和起始 caspase 8 裂解减少所致。在该模型中，在给予 GalN/LPS 后延迟 VLX103 治疗长达 3 小时仍能显着有效地阻止肝损伤。VLX103 的口服给药还减少了酒精性肝损伤的第二种更慢性模型中的肝毒性损伤，如血清丙氨酸和天冬氨酸转氨酶水平降低以及 TUNEL 阳性细胞数量减少所证明的那样。结论：VLX103 可有效减少小鼠毒素诱导的肝损伤，可能是治疗这种和其他形式的人类肝病的有效疗法。（肝病学 2017；66：922-935）。