Abstract：
Accidental exposure to phosgene can cause acute lung injury (ALI), characterized by uncontrolled inflammation and impaired lung blood-gas barrier. CD34+CD45+ cells with high pituitary tumor transforming gene 1 (PTTG1) expression were identified around rat pulmonary vessels through single-cell RNA sequencing, and have been shown to attenuate P-ALI by promoting lung vascular barrier repair. As a transcription factor closely related to angiogenesis, whether PTTG1 plays a role in CD34+CD45+ cell repairing the pulmonary vascular barrier in rats with P-ALI remains unclear. This study provided compelling evidence that CD34+CD45+ cells possess endothelial differentiation potential. Rats with P-ALI were intratracheally administered with CD34+CD45+ cells transfected with or without PTTG1-overexpressing and sh-PTTG1 lentivirus. It was found that CD34+CD45+ cells reduced the pulmonary vascular permeability and mitigated the lung inflammation, which could be reversed by knocking down PTTG1. Although PTTG1 overexpression enhanced the ability of CD34+CD45+ cells to attenuate P-ALI, no significant difference was found. PTTG1 was found to regulate the endothelial differentiation of CD34+CD45+ cells. In addition, knocking down of PTTG1 significantly reduced the protein levels of VEGF and bFGF, as well as their receptors, which in turn inhibited the activation of the PI3K/AKT/eNOS signaling pathway in CD34+CD45+ cells. Moreover, LY294002 (PI3K inhibitor) treatment inhibited the endothelial differentiation of CD34+CD45+ cells, while SC79 (AKT activator) yielded the opposite effect. These findings suggest that PTTG1 can promote the endothelial differentiation of CD34+CD45+ cells by activating the VEGF-bFGF/PI3K/AKT/eNOS signaling pathway, leading to the repair of the pulmonary vascular barrier in rats with P-ALI.
摘要：
意外暴露于光气会导致急性肺损伤（ALI），以炎症失控和肺血气屏障受损为特征。通过单细胞RNA测序鉴定大鼠肺血管周围高表达垂体瘤转化基因1(PTTG1)的CD34+CD45+细胞,并已被证明通过促进肺血管屏障修复来减弱P-ALI。作为与血管生成密切相关的转录因子，PTTG1是否在P-ALI大鼠CD34+CD45+细胞修复肺血管屏障中起作用尚不清楚。这项研究提供了令人信服的证据表明CD34+CD45+细胞具有内皮分化潜能。将具有P-ALI的大鼠气管内施用转染有或没有PTTG1过表达和sh-PTTG1慢病毒的CD34+CD45+细胞。发现CD34+CD45+细胞降低肺血管通透性，减轻肺部炎症，这可以通过击倒PTTG1来逆转。尽管PTTG1过表达增强了CD34+CD45+细胞减弱P-ALI的能力，没有发现显著差异。发现PTTG1调节CD34CD45细胞的内皮分化。此外,敲低PTTG1显著降低VEGF和bFGF的蛋白水平,以及它们的受体，进而抑制CD34+CD45+细胞中PI3K/AKT/eNOS信号通路的激活。此外，LY294002(PI3K抑制剂)处理抑制CD34+CD45+细胞的内皮分化,而SC79（AKT激活剂）产生相反的效果。提示PTTG1可通过激活VEGF-bFGF/PI3K/AKT/eNOS信号通路促进CD34+CD45+细胞的内皮分化,导致P-ALI大鼠肺血管屏障的修复。
