Acute respiratory distress syndrome (ARDS) is a critical disorder characterized by immune-related damage to epithelial cells; however, its underlying mechanism remains elusive. This study investigated the effects of alterations in microRNA (miRNA) expression in mast cell-derived exosomes on human bronchial epithelial (HBE) cells and ARDS development in cellular and mouse models challenged with lipopolysaccharide. Lipopolysaccharide-treated mast cell-derived exosomes reduced glutathione peroxidase 4 (GPX4) expression and increased long-chain acyl-CoA synthetase 4 (ACSL4), 15-lipoxygenase (ALOX15), and inflammatory mediator levels in HBE cells. miRNA sequencing revealed a reduction in mast cell-derived exosomal miR-744 levels, which was associated with the regulation of ACSL4, ALOX15, and GPX4 expression. This downregulation of exosomal miR-744 expression reduced miR-744 levels and promoted ferroptosis in HBE cells, whereas the experimental upregulation of miR-744 reversed these adverse effects. Down-regulation of miR-744 induced the expression of markers for ferroptosis and inflammation in HBE cells and promoted pulmonary ferroptosis, inflammation, and injury in LPS-stimulated mice. In vivo, treatment with ACSL4, ALOX15, and GPX4 inhibitors mitigated these effects, and experimental miR-744 expression rescued the lipopolysaccharide-induced changes in HBE cells and mouse lungs. Notably, miR-744 levels were reduced in the plasma and exosomes of patients with ARDS. We concluded that decreased mast cell-derived exosomal miR-744 levels trigger epithelial cell ferroptosis, promoting lung inflammation and damage in ARDS. This study provides new mechanistic insights into the development and sustained pulmonary damage associated with ARDS and highlights potential therapeutic strategies.

中文翻译：

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肥大细胞来源的外泌体中 microRNA-744 表达降低会触发急性呼吸窘迫综合征的上皮细胞铁死亡


急性呼吸窘迫综合征 （ARDS） 是一种严重疾病，其特征是上皮细胞的免疫相关损伤;然而，其潜在机制仍然难以捉摸。本研究调查了肥大细胞来源的外泌体中 microRNA （miRNA） 表达改变对人支气管上皮 （HBE） 细胞的影响，以及脂多糖攻击的细胞和小鼠模型中 ARDS 的发展。脂多糖处理的肥大细胞衍生外泌体降低了 HBE 细胞中谷胱甘肽过氧化物酶 4 （GPX4） 的表达，并增加了长链酰基辅酶 A 合成酶 4 （ACSL4）、15-脂氧合酶 （ALOX15） 和炎症介质水平。miRNA 测序显示肥大细胞来源的外泌体 miR-744 水平降低，这与 ACSL4 、 ALOX15 和 GPX4 表达的调节有关。外泌体 miR-744 表达的这种下调降低了 HBE 细胞中的 miR-744 水平并促进了铁死亡，而 miR-744 的实验性上调逆转了这些不利影响。miR-744 的下调诱导 HBE 细胞中铁死亡和炎症标志物的表达，并促进 LPS 刺激小鼠的肺铁死亡、炎症和损伤。在体内，用 ACSL4 、 ALOX15 和 GPX4 抑制剂处理减轻了这些影响，实验性 miR-744 表达挽救了脂多糖诱导的 HBE 细胞和小鼠肺的变化。值得注意的是，ARDS 患者血浆和外泌体中的 miR-744 水平降低。我们得出结论，肥大细胞来源的外泌体 miR-744 水平降低会触发上皮细胞铁死亡，促进 ARDS 患者的肺部炎症和损伤。 这项研究为与 ARDS 相关的发展和持续肺损伤提供了新的机制见解，并强调了潜在的治疗策略。