Shao Min, Tang Song-Tao, Liu Bao, Zhu Hua-Qing
Department of Critical Care Medicine, Affiliated Provincial Hospital of Anhui Medical University, Hefei, Anhui 230001, P.R. China.
Laboratory of Molecular Biology and Department of Biochemistry, Anhui Medical University, Hefei, Anhui 230032, P.R. China.
Mol Med Rep. 2016 Jan;13(1):529-35. doi: 10.3892/mmr.2015.4521. Epub 2015 Nov 6.
The pathology of acute respiratory distress syndrome (ARDS) is closely associated with the failure of alveolar‑capillary barrier integrity and alveolar filling by high protein pulmonary edema, resulting from hyperpermeability. High mobility group box 1 (HMGB1) is a novel late mediator of sepsis, which is specifically involved in endotoxin‑induced acute lung injury and sepsis‑associated lethality. Although the role of HMGB1 in endothelial cell cytoskeletal rearrangement and vascular permeability have been investigated preliminarily, the molecular mechanisms remain to be fully elucidated. As the ras‑related C3 botulinum toxin substrate 1 (Rac1) gene is important role in regulating microvascular barrier maintenance, the present study was designed to determine whether Rac1 is involved in HMGB1‑induced hyperpermeability in pulmonary microvascular endothelial cells (PMVECs). The results of the present study demonstrated that HMGB1 induced dose and time‑dependent decreases in transendothelial electrical resistance (TER). Notably, HMGB1 induced a dose‑dependent increase in the activity and expression levels of Rac1. Using small interfering RNA and an agonist of Rac1, the present study demonstrated that Rac1 was a novel factor mediating the HMGB1‑induced decrease in TER via extracellular signal‑regulated kinase and p38 mitogen‑activated protein kinase (MAPK) activation. These data suggested that Rac1 is involved in HMGB1‑induced hyperpermeability in PMVECs via MAPK signal transduction.
急性呼吸窘迫综合征（ARDS）的病理与肺泡-毛细血管屏障完整性的破坏以及高通透性导致的高蛋白性肺水肿引起的肺泡充盈密切相关。高迁移率族蛋白B1（HMGB1）是脓毒症的一种新型晚期介质，它特别参与内毒素诱导的急性肺损伤和脓毒症相关的致死率。尽管已经初步研究了HMGB1在内皮细胞细胞骨架重排和血管通透性中的作用，但其分子机制仍有待充分阐明。由于ras相关的C3肉毒杆菌毒素底物1（Rac1）基因在调节微血管屏障维持中起重要作用，本研究旨在确定Rac1是否参与HMGB1诱导的肺微血管内皮细胞（PMVECs）通透性增加。本研究结果表明，HMGB1诱导跨内皮电阻（TER）呈剂量和时间依赖性降低。值得注意的是，HMGB1诱导Rac1的活性和表达水平呈剂量依赖性增加。使用小干扰RNA和Rac1激动剂，本研究表明Rac1是通过细胞外信号调节激酶和p38丝裂原活化蛋白激酶（MAPK）激活介导HMGB1诱导的TER降低的新因子。这些数据表明，Rac1通过MAPK信号转导参与HMGB1诱导的PMVECs通透性增加。
