BRD3308 suppresses macrophage oxidative stress and pyroptosis via upregulating acetylation of H3K27 in sepsis-induced acute lung injury.

IF 6.3 1区 医学 Q1 DERMATOLOGY
Burns & Trauma Pub Date : 2024-09-02 eCollection Date: 2024-01-01 DOI:10.1093/burnst/tkae033
Bohao Liu, Ning Li, Yi Liu, Yan Zhang, Limei Qu, Hongfei Cai, Yang Li, Xiaojing Wu, Qing Geng
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Abstract

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.

在脓毒症诱发的急性肺损伤中,BRD3308通过上调H3K27的乙酰化抑制巨噬细胞氧化应激和脓毒症。
背景:败血症诱发的急性肺损伤(ALI)会导致严重的低氧血症和呼吸衰竭,导致败血症患者预后不良。内毒素扩散引发氧化应激和巨噬细胞释放炎性细胞因子,导致肺泡弥漫性损伤。人们越来越认识到表观遗传组蛋白修饰在器官损伤中的作用。本研究旨在探讨使用组蛋白修饰抑制剂缓解脓毒症诱发的 ALI,为改善脓毒症患者存活率揭示一种新策略: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,还通过脂多糖刺激 Tamm-Horsfall 蛋白-1(THP-1)细胞模拟体外发病过程。利用血红素和伊红染色、血气分析和肺功能测试来评估肺组织损伤的程度。Western 印迹分析、实时聚合酶链反应、酶联免疫吸附试验和免疫荧光被用来测量细胞和组织中所述指标的水平和分布。使用特定探针检测了活性氧和自噬通量的变化:结果:BRD3308 是组蛋白去乙酰化酶 3 的抑制剂,它通过抑制巨噬细胞中 Nod 样受体蛋白 3 介导的热凋亡,改善了 ALI 中的肺组织损伤、炎症浸润和水肿。通过上调自噬,BRD3308 改善了巨噬细胞中氧化还原平衡的破坏,减少了活性氧的积累。从机理上讲,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。组蛋白去乙酰化酶 3 受抑制后,H3K27 的乙酰化显著增加。此外,H3K27Ac的增加导致自噬相关基因5(自噬体的关键成分)的上调,从而激活了自噬:BRD3308通过调节组蛋白乙酰化抑制巨噬细胞中的氧化应激和脓毒症,从而预防脓毒症诱发的ALI。本研究为脓毒症诱发的 ALI 的临床治疗提供了潜在的策略和理论依据。
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来源期刊
Burns & Trauma
Burns & Trauma 医学-皮肤病学
CiteScore
8.40
自引率
9.40%
发文量
186
审稿时长
6 weeks
期刊介绍: The first open access journal in the field of burns and trauma injury in the Asia-Pacific region, Burns & Trauma publishes the latest developments in basic, clinical and translational research in the field. With a special focus on prevention, clinical treatment and basic research, the journal welcomes submissions in various aspects of biomaterials, tissue engineering, stem cells, critical care, immunobiology, skin transplantation, and the prevention and regeneration of burns and trauma injuries. With an expert Editorial Board and a team of dedicated scientific editors, the journal enjoys a large readership and is supported by Southwest Hospital, which covers authors'' article processing charges.
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