Liu Bohao, Li Ning, Liu Yi, Zhang Yan, Qu Limei, Cai Hongfei, Li Yang, Wu Xiaojing, Geng Qing
Department of Thoracic Surgery, The First Hospital of Jilin University, 71 Xinmin Street, Chaoyang District, Changchun, Jilin, 130021, China.
Department of Thoracic Surgery, Renmin Hospital of Wuhan University, 238 Jiefang Road, Wuchang District, Wuhan, Hubei, 430060, China.
Burns Trauma. 2024 Sep 2;12:tkae033. doi: 10.1093/burnst/tkae033. eCollection 2024.
Sepsis-induced acute lung injury (ALI) leads to severe hypoxemia and respiratory failure, contributing to poor prognosis in septic patients. Endotoxin dissemination triggers oxidative stress and the release of inflammatory cytokines in macrophages, initiating diffuse alveolar damage. The role of epigenetic histone modifications in organ injury is increasingly recognized. The present study aimed to investigate the use of a histone modification inhibitor to alleviate sepsis-induced ALI, revealing a new strategy for improving sepsis patient survival.
models of ALI were established through the intraperitoneal injection of lipopolysaccharide and cecal ligation and puncture surgery. Furthermore, the disease process was simulated by stimulating Tamm-Horsfall protein-1 (THP-1) cells with lipopolysaccharide. Hematoxylin and eosin staining, blood gas analysis and pulmonary function tests were utilized to assess the extent of lung tissue damage. Western blot analysis, real-time polymerase chain reaction, enzyme-linked immunosorbent assay and immunofluorescence were used to measure the levels and distribution of the indicated indicators within cells and tissues. Reactive oxygen species and autophagic flux alterations were detected using specific probes.
BRD3308, which is a inhibitor of histone deacetylase 3, improved lung tissue damage, inflammatory infiltration and edema in ALI by inhibiting Nod-like receptor protein3-mediated pyroptosis in macrophages. By upregulating autophagy, BRD3308 improved the disruption of redox balance in macrophages and reduced the accumulation of reactive oxygen species. Mechanistically, BRD3308 inhibited histone deacetylase 3 activity by binding to it and altering its conformation. Following histone deacetylase 3 inhibition, acetylation of H3K27 was significantly increased. Moreover, the increase in H3K27Ac led to the upregulation of autophagy-related gene 5, a key component of autophagosomes, thereby activating autophagy.
BRD3308 inhibits oxidative stress and pyroptosis in macrophages by modulating histone acetylation, thereby preventing sepsis-induced ALI. The present study provides a potential strategy and theoretical basis for the clinical treatment of sepsis-induced ALI.
脓毒症诱导的急性肺损伤（ALI）会导致严重的低氧血症和呼吸衰竭，致使脓毒症患者预后不良。内毒素播散会引发氧化应激以及巨噬细胞中炎性细胞因子的释放，进而引发弥漫性肺泡损伤。表观遗传组蛋白修饰在器官损伤中的作用日益受到认可。本研究旨在探究使用组蛋白修饰抑制剂来减轻脓毒症诱导的ALI，从而揭示一种改善脓毒症患者生存率的新策略。
通过腹腔注射脂多糖和盲肠结扎穿刺手术建立ALI模型。此外，用脂多糖刺激人肾小管髓袢升支粗段上皮细胞（THP-1）细胞来模拟疾病进程。利用苏木精-伊红染色、血气分析和肺功能测试来评估肺组织损伤程度。采用蛋白质免疫印迹分析、实时聚合酶链反应、酶联免疫吸附测定和免疫荧光法来检测细胞和组织内指定指标的水平及分布。使用特异性探针检测活性氧和自噬通量变化。
组蛋白去乙酰化酶3抑制剂BRD3308通过抑制巨噬细胞中NOD样受体蛋白3介导的细胞焦亡，改善了ALI中的肺组织损伤、炎性浸润和水肿。通过上调自噬，BRD3308改善了巨噬细胞中氧化还原平衡的破坏，并减少了活性氧的积累。从机制上讲，BRD3308通过与组蛋白去乙酰化酶3结合并改变其构象来抑制其活性。在组蛋白去乙酰化酶3受到抑制后，组蛋白H3赖氨酸27（H3K27）的乙酰化显著增加。此外，H3K27乙酰化的增加导致自噬相关基因5（自噬体的关键组成部分）上调，从而激活自噬。
BRD3308通过调节组蛋白乙酰化来抑制巨噬细胞中的氧化应激和细胞焦亡，从而预防脓毒症诱导的ALI。本研究为脓毒症诱导的ALI的临床治疗提供了一种潜在策略和理论依据。
