Iten Manuela, Gschwend Camille, Ostini Alessandro, Cameron David Robert, Goepfert Christine, Berger David, Haenggi Matthias
Department of Intensive Care Medicine, Inselspital, University Hospital Bern, Freiburgstrasse 16, 3010, Bern, Switzerland.
Department of Intensive Care Medicine, Cantonal Hospital Aarau, Tellstrasse 25, 5001, Aarau, Switzerland.
Intensive Care Med Exp. 2024 Feb 26;12(1):19. doi: 10.1186/s40635-024-00604-z.
Acute respiratory distress syndrome (ARDS) is a form of respiratory failure stemming from various underlying conditions that ultimately lead to inflammation and lung fibrosis. Bromodomain and Extra-Terminal motif (BET) inhibitors are a class of medications that selectively bind to the bromodomains of BET motif proteins, effectively reducing inflammation. However, the use of BET inhibitors in ARDS treatment has not been previously investigated. In our study, we induced ARDS in rats using endotoxin and administered a BET inhibitor. We evaluated the outcomes by examining inflammation markers and lung histopathology.
Nine animals received treatment, while 12 served as controls. In the lung tissue of treated animals, we observed a significant reduction in TNFα levels (549 [149-977] pg/mg vs. 3010 [396-5529] pg/mg; p = 0.009) and IL-1β levels (447 [369-580] pg/mg vs. 662 [523-924] pg/mg; p = 0.012), although IL-6 and IL-10 levels showed no significant differences. In the blood, treated animals exhibited a reduced TNFα level (25 [25-424] pg/ml vs. 900 [285-1744] pg/ml, p = 0.016), but IL-1β levels were significantly higher (1254 [435-2474] pg/ml vs. 384 [213-907] pg/ml, p = 0.049). No differences were observed in IL-6 and IL-10 levels. There were no significant variations in lung tissue levels of TGF-β, SP-D, or RAGE. Histopathological analysis revealed substantial damage, with notably less perivascular edema (3 vs 2; p = 0.0046) and visually more inflammatory cells. However, two semi-quantitative histopathologic scoring systems did not indicate significant differences.
These preliminary findings suggest a potential beneficial effect of BET inhibitors in the treatment of acute lung injury and ARDS. Further validation and replication of these results with a larger cohort of animals, in diverse models, and using different BET inhibitors are needed to explore their clinical implications.
急性呼吸窘迫综合征（ARDS）是一种由多种潜在疾病引发的呼吸衰竭形式，最终会导致炎症和肺纤维化。溴结构域和额外末端基序（BET）抑制剂是一类能选择性结合BET基序蛋白溴结构域的药物，可有效减轻炎症。然而，此前尚未研究过BET抑制剂在ARDS治疗中的应用。在我们的研究中，我们使用内毒素诱导大鼠发生ARDS，并给予一种BET抑制剂。我们通过检测炎症标志物和肺组织病理学来评估结果。
9只动物接受了治疗，12只作为对照。在接受治疗的动物肺组织中，我们观察到肿瘤坏死因子α（TNFα）水平显著降低（549[149 - 977]皮克/毫克 vs. 3010[396 - 5529]皮克/毫克；p = 0.009）和白细胞介素 - 1β（IL - 1β）水平显著降低（447[369 - 580]皮克/毫克 vs. 6(62[523 - 924]皮克/毫克；p = 0.012），尽管IL - 6和IL - 10水平没有显著差异。在血液中，接受治疗的动物TNFα水平降低（25[25 - 424]皮克/毫升 vs. 900[285 - 1744]皮克/毫升，p = 0.016），但IL - 1β水平显著更高（1254[435 - 2474]皮克/毫升 vs. 384[213 - 907]皮克/毫升，p = 0.049）。IL - 6和IL - 10水平没有差异。转化生长因子 - β（TGF - β）、表面活性蛋白 - D（SP - D）或晚期糖基化终末产物受体（RAGE）的肺组织水平没有显著变化。组织病理学分析显示有严重损伤，血管周围水肿明显减轻（3比2；p = 0.0046），且可见更多炎症细胞。然而，两个半定量组织病理学评分系统并未显示出显著差异。
这些初步发现表明BET抑制剂在治疗急性肺损伤和ARDS方面可能具有有益作用。需要在更多动物群体、不同模型以及使用不同BET抑制剂的情况下进一步验证和重复这些结果，以探索其临床意义。
