Experimental Center for Medical Research, Weifang Medical University, Weifang City, People's Republic of China.
Key Laboratory of Atherosclerosis in Universities of Shandong, Institute of Atherosclerosis, Shandong First Medical University, Tai-an City, People's Republic of China.
Respir Res. 2019 Jun 26;20(1):131. doi: 10.1186/s12931-019-1099-6.
Patients with acute lung injury (ALI) have increased levels of pro-inflammatory mediators, which impair endothelial progenitor cell (EPC) function. Increasing the number of EPC and alleviating EPC dysfunction induced by pro-inflammatory mediators play important roles in suppressing ALI development. Because the high density lipoprotein reverse-D-4F (Rev-D4F) improves EPC function, we hypothesized that it might repair lipopolysaccharide (LPS)-induced lung damage by improving EPC numbers and function in an LPS-induced ALI mouse model.
LPS was used to induce ALI in mice, and then the mice received intraperitoneal injections of Rev-D4F. Immunohistochemical staining, flow cytometry, MTT, transwell, and western blotting were used to assess the effect of Rev-D4F on repairment of lung impairment, and improvement of EPC numbers and function, as well as the signaling pathways involved.
Rev-D4F inhibits LPS-induced pulmonary edema and decreases plasma levels of the pro-inflammatory mediators TNF-α and ET-1 in ALI mice. Rev-D4F inhibited infiltration of red and white blood cells into the interstitial space, reduced lung injury-induced inflammation, and restored injured pulmonary capillary endothelial cells. In addition, Rev-D4F increased numbers of circulating EPC, stimulated EPC differentiation, and improved EPC function impaired by LPS. Rev-D4F also acted via a PI3-kinase-dependent mechanism to restore levels of phospho-AKT, eNOS, and phospho-eNOS suppressed by LPS.
These findings indicate that Rev-D4F has an important vasculoprotective role in ALI by improving the EPC numbers and functions, and Rev-D4F reverses LPS-induced EPC dysfuncion partially through PI3K/AKT/eNOS signaling pathway.
急性肺损伤（ALI）患者的促炎介质水平升高，这会损害内皮祖细胞（EPC）的功能。增加 EPC 的数量并缓解促炎介质引起的 EPC 功能障碍在抑制 ALI 发展中起着重要作用。由于高密度脂蛋白反向 D-4F（Rev-D4F）可改善 EPC 功能，我们假设它可能通过改善 LPS 诱导的 ALI 小鼠模型中 EPC 的数量和功能来修复 LPS 诱导的肺损伤。
使用 LPS 诱导小鼠发生 ALI，然后给小鼠腹腔注射 Rev-D4F。免疫组织化学染色、流式细胞术、MTT、transwell 和 Western blot 用于评估 Rev-D4F 对肺损伤修复的影响，以及对 EPC 数量和功能的改善，以及涉及的信号通路。
Rev-D4F 抑制 LPS 诱导的肺水肿，并降低 ALI 小鼠中促炎介质 TNF-α和 ET-1 的血浆水平。Rev-D4F 抑制红、白细胞浸润到间质空间，减少肺损伤引起的炎症，并恢复受损的肺毛细血管内皮细胞。此外，Rev-D4F 增加循环 EPC 的数量，刺激 EPC 分化，并改善 LPS 引起的 EPC 功能障碍。Rev-D4F 还通过 PI3-激酶依赖性机制恢复 LPS 抑制的磷酸化 AKT、eNOS 和磷酸化 eNOS 的水平。
这些发现表明，Rev-D4F 通过改善 EPC 的数量和功能，在 ALI 中具有重要的血管保护作用，并且 Rev-D4F 通过 PI3K/AKT/eNOS 信号通路部分逆转 LPS 诱导的 EPC 功能障碍。
