Background 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. Methods In vivo models of ALI were established through the intraperitoneal injection of lipopolysaccharide and cecal ligation and puncture surgery. Furthermore, the disease process was simulated in vitro 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. Results 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. Conclusions 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.

中文翻译：

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BRD3308 通过上调脓毒症引起的急性肺损伤中 H3K27 的乙酰化来抑制巨噬细胞氧化应激和细胞焦亡。


背景脓毒症引起的急性肺损伤（ALI）导致严重低氧血症和呼吸衰竭，导致脓毒症患者预后不良。内毒素传播引发氧化应激和巨噬细胞中炎症细胞因子的释放，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得到认识。本研究旨在探讨使用组蛋白修饰抑制剂来缓解脓毒症引起的 ALI，揭示提高脓毒症患者生存率的新策略。方法通过腹腔注射脂多糖和盲肠结扎穿刺手术建立ALI体内模型。此外，通过用脂多糖刺激 Tamm-Horsfall 蛋白 1 (THP-1) 细胞，在体外模拟了疾病过程。利用苏木精和伊红染色、血气分析和肺功能测试来评估肺组织损伤的程度。采用蛋白质印迹分析、实时聚合酶链反应、酶联免疫吸附测定和免疫荧光来测量细胞和组织内指定指标的水平和分布。使用特定探针检测活性氧和自噬通量的变化。结果 BRD3308 是一种组蛋白脱乙酰酶 3 抑制剂，通过抑制 Nod 样受体蛋白 3 介导的巨噬细胞焦亡，改善 ALI 中的肺组织损伤、炎症浸润和水肿。通过上调自噬，BRD3308 改善了巨噬细胞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 通过与组蛋白脱乙酰酶 3 结合并改变其构象来抑制其活性。 组蛋白脱乙酰酶 3 抑制后，H3K27 的乙酰化显着增加。此外，H3K27Ac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。结论 BRD3308 通过调节组蛋白乙酰化抑制巨噬细胞氧化应激和焦亡，从而预防脓毒症引起的 ALI。本研究为脓毒症所致ALI的临床治疗提供了潜在的策略和理论基础。