Department of Critical Care Medicine, the Affiliated Hospital of Guizhou Medical University, Guiyang, China.
Department of Hepatobiliary Surgery, Guizhou Provincial People's Hospital, Guiyang, China.
Int Immunopharmacol. 2023 Jul;120:110318. doi: 10.1016/j.intimp.2023.110318. Epub 2023 May 16.
Acute respiratory distress syndrome (ARDS) is a clinical and pathophysiological complex syndrome with high mortality. Alveolar hypercoagulation and fibrinolytic inhibition constitute the core part of the pathophysiology of ARDS. miR-9 (microRNA-9a-5p) plays an important role in the pathogenesis of ARDS, but whether it regulates alveolar pro-coagulation and fibrinolysis inhibition in ARDS remains to be elucidated. We aimed to determine the contributing role of miR-9 on alveolar hypercoagulation and fibrinolysis inhibition in ARDS.
In the ARDS animal model, we first observed the miR-9 and runt-related transcription factor 1 (RUNX1) expression in lung tissue, the effects of miR-9 on alveolar hypercoagulation and fibrinolytic inhibition in ARDS rats, and the efficacy of miR-9 on acute lung injury. In the cell, alveolar epithelial cells type II (AECII) were treated with LPS, and the levels of miR-9 and RUNX1 were detected. Then we observed the effects of miR-9 on procoagulant and fibrinolysis inhibitor factors in cells. Finally, we explored whether the efficacies of miR-9 were associated with RUNX1; we also preliminarily examined the miR-9 and RUNX1 levels in plasma in patients with ARDS.
In ARDS rats, miR-9 expression decreased, but RUNX1 expression increased in the pulmonary tissue of ARDS rats. miR-9 displayed to attenuate lung injury and pulmonary wet/dry ratio. Study results in vivo demonstrated that miR-9 ameliorated alveolar hypercoagulation and fibrinolysis inhibition and attenuated the collagen III expressions in tissue. miR-9 also inhibited NF-κB signaling pathway activation in ARDS. In LPS-induced AECII, the expression changes of both miR-9 and RUNX1 were similar to those in pulmonary tissue in the animal ARDS model. miR-9 effectively inhabited tissue factor (TF), plasma activator inhibitor (PAI-1) expressions, and NF-κB activation in LPS-treated ACEII cells. Besides, miR-9 directly targeted RUNX1, inhibiting TF and PAI-1 expression and attenuating NF-κB activation in LPS-treated AECII cells. Clinically, we preliminarily found that the expression of miR-9 was significantly reduced in ARDS patients compared to non-ARDS patients.
Our experimental data indicate that by directly targeting RUNX1, miR-9 improves alveolar hypercoagulation and fibrinolysis inhibition via suppressing NF-κB pathway activation in LPS-induced rat ARDS, implying that miR-9/RUNX1 is expected to be a new therapeutic target for ARDS treatment.
急性呼吸窘迫综合征（ARDS）是一种具有高死亡率的临床和病理生理复杂综合征。肺泡过度凝血和纤维蛋白溶解抑制构成了 ARDS 病理生理学的核心部分。miR-9（miRNA-9a-5p）在 ARDS 的发病机制中发挥着重要作用，但它是否调节 ARDS 中的肺泡促凝血和纤维蛋白溶解抑制仍有待阐明。我们旨在确定 miR-9 在 ARDS 中的肺泡过度凝血和纤维蛋白溶解抑制中的作用。
在 ARDS 动物模型中，我们首先观察了肺组织中 miR-9 和 runt 相关转录因子 1（RUNX1）的表达，miR-9 对 ARDS 大鼠肺泡过度凝血和纤维蛋白溶解抑制的影响，以及 miR-9 对急性肺损伤的疗效。在细胞中，用 LPS 处理肺泡上皮细胞 II 型（AECII），并检测 miR-9 和 RUNX1 的水平。然后，我们观察了 miR-9 对促凝血和纤维蛋白溶解抑制剂因子的影响。最后，我们探讨了 miR-9 的疗效是否与 RUNX1 相关；我们还初步检测了 ARDS 患者血浆中的 miR-9 和 RUNX1 水平。
在 ARDS 大鼠中，miR-9 的表达减少，而 RUNX1 的表达在 ARDS 大鼠的肺组织中增加。miR-9 表现出减轻肺损伤和肺湿/干比的作用。体内研究结果表明，miR-9 改善了肺泡过度凝血和纤维蛋白溶解抑制，并减轻了组织中的胶原 III 表达。miR-9 还抑制了 NF-κB 信号通路的激活。在 LPS 诱导的 AECII 中，miR-9 和 RUNX1 的表达变化与动物 ARDS 模型中的肺组织相似。miR-9 有效地抑制了组织因子（TF）、血浆激活物抑制剂（PAI-1）的表达和 LPS 处理 ACEII 细胞中的 NF-κB 激活。此外，miR-9 直接靶向 RUNX1，抑制 LPS 处理的 AECII 细胞中的 TF 和 PAI-1 表达，并减轻 NF-κB 的激活。临床上，我们初步发现，与非 ARDS 患者相比，ARDS 患者的 miR-9 表达明显降低。
我们的实验数据表明，通过直接靶向 RUNX1，miR-9 通过抑制 LPS 诱导的大鼠 ARDS 中 NF-κB 通路的激活，改善肺泡过度凝血和纤维蛋白溶解抑制，这意味着 miR-9/RUNX1 有望成为 ARDS 治疗的新靶点。
