Background

Liver injury is one of the most common complications during sepsis. Macrophage migration inhibitory factor (MIF) is an important proinflammatory cytokine. This study explored the role of MIF in the lipopolysaccharide (LPS)-induced liver injury through genetically manipulated mouse strains.

Methods

The model of LPS-induced liver injury was established in wild-type and Mif-knockout C57/BL6 mice. Serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin (TBil) were detected, and the expressions of MIF, tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) were measured. Liver histopathology was conducted to assess liver injury. Moreover, the inhibitions of MIF with (S,R)-3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazole acetic acid methyl ester (ISO-1) and 4-iodo-6-phenylpyrimidine (4-IPP) were used to evaluate their therapeutic potential of liver injury.

Results

Compared with wild-type mice, the liver function indices and inflammation factors presented no significant difference in the Mif^−/− mice. After 72 h of the LPS-induced liver injury, serum levels of ALT, AST, and TBil as well as TNF-α and IL-1β were significantly increased, but the knockout of Mif attenuated liver injury and inflammatory response. In liver tissue, mRNA levels of TNF-α, IL-1β and NF-κB p65 were remarkably elevated in LPS-induced liver injury, while the knockout of Mif reduced these levels. Moreover, in LPS-induced liver injury, the inhibitions of MIF with ISO-1 and 4-IPP alleviated liver injury and slightly attenuated inflammatory response. Importantly, compared to mice with LPS-induced liver injury, Mif knockout or MIF inhibitions significantly prolonged the survival of the mice.

Conclusions

In LPS-induced liver injury, the knockout of Mif or MIF inhibitions alleviated liver injury and slightly attenuated inflammatory response, thereby prolonged the survival of the mice. Targeting MIF may be an important strategy to protect the liver from injury during sepsis.

中文翻译：

---

基因敲除或抑制巨噬细胞迁移抑制因子通过抑制炎症反应减轻脂多糖诱导的肝损伤

背景

肝损伤是脓毒症最常见的并发症之一。巨噬细胞迁移抑制因子（MIF）是一种重要的促炎细胞因子。本研究通过基因操作小鼠品系探讨了 MIF 在脂多糖 (LPS) 诱导的肝损伤中的作用。

方法

在野生型和Mif敲除 C57/BL6 小鼠中建立 LPS 诱导的肝损伤模型。检测血清丙氨酸氨基转移酶（ALT）、天冬氨酸氨基转移酶（AST）、总胆红素（TBil）水平，以及MIF、肿瘤坏死因子-α（TNF- α）和白细胞介素-1β（IL-1β）的表达。被测量了。进行肝组织病理学以评估肝损伤。此外，MIF 与 (S,R)-3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazole 乙酸甲酯 (ISO-1) 和 4-iodo-6-phenylpyrimidine (4- IPP) 用于评估其对肝损伤的治疗潜力。

结果

与野生型小鼠相比，Mif ^-/-小鼠的肝功能指标和炎症因子没有显着差异。LPS 诱导的肝损伤 72 h 后，血清 ALT、AST 和 TBil 以及 TNF-α 和 IL-1β 水平显着升高，但Mif的敲除减轻了肝损伤和炎症反应。在肝组织中，LPS 诱导的肝损伤中 TNF-α、IL-1β 和 NF-κB p65 的 mRNA 水平显着升高，而Mif的敲除降低了这些水平。此外，在 LPS 诱导的肝损伤中，MIF 与 ISO-1 和 4-IPP 的抑制作用减轻了肝损伤并略微减弱了炎症反应。重要的是，与 LPS 诱导的肝损伤小鼠相比，Mif 敲除或 MIF 抑制显着延长了小鼠的存活时间。

结论

在 LPS 诱导的肝损伤中，敲除Mif或 MIF 抑制物可减轻肝损伤并略微减弱炎症反应，从而延长小鼠的存活时间。靶向 MIF 可能是在脓毒症期间保护肝脏免受损伤的重要策略。