School of Medicine, Sun Yat-sen University, Guangzhou, 510275, China.
School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Guangzhou, 510275, China.
Biochem Biophys Res Commun. 2022 Sep 17;621:25-31. doi: 10.1016/j.bbrc.2022.06.086. Epub 2022 Jul 2.
Acute liver injury caused by overdose usage of acetaminophen (APAP) is an intractable clinical problem. Necrotic hepatocytes release large amounts of intracellular components including damage-associated molecular patterns (DAMPs) which contribute to liver failure and may serve as therapeutic targets. However, the pathogenic mechanisms of DAMPs in APAP-induced liver injury (AILI) are remain largely uncovered. Here, we found that a recently identified DAMP, interferon-induced protein 35 (IFP35), is involved in the early phase of AILI. Our data demonstrated that although the expression level of IFP35 is not significantly increased in either patients or mice with AILI, it is released from necrotic hepatocytes. Within 24 h post APAP injection, mice lacking Ifp35 are resistant to APAP-induced toxicity, and induce less inflammatory response than that of wild-type mice, including reduced AST/ALT level, pro-inflammatory cytokines production and neutrophils infiltration. More importantly, antibody of IFP35 reduces the expression level of inflammatory factors and chemokines. This study brings new knowledge into the pathogenic mechanism of AILI.
过量使用对乙酰氨基酚（APAP）导致的急性肝损伤是一个棘手的临床问题。坏死的肝细胞会释放大量的细胞内成分，包括损伤相关分子模式（DAMPs），这些成分会导致肝衰竭，并可能成为治疗靶点。然而，DAMPs 在 APAP 诱导的肝损伤（AILI）中的致病机制在很大程度上仍未被揭示。在这里，我们发现最近发现的一种 DAMPs，干扰素诱导蛋白 35（IFP35），参与了 AILI 的早期阶段。我们的数据表明，尽管在 AILI 患者或小鼠中 IFP35 的表达水平没有显著增加，但它会从坏死的肝细胞中释放出来。在 APAP 注射后 24 小时内，缺乏 Ifp35 的小鼠对 APAP 诱导的毒性具有抗性，并且引发的炎症反应低于野生型小鼠，包括降低 AST/ALT 水平、促炎细胞因子产生和中性粒细胞浸润。更重要的是，IFP35 的抗体降低了炎症因子和趋化因子的表达水平。这项研究为 AILI 的发病机制提供了新的知识。
