Dun Yu, Hu Hanbing, Liu Fuli, Shao Yiru, He Daikun, Zhang Lin, Shen Jie
Center of Emergency and Critical Medicine, Jinshan Hospital of Fudan University, China; Research Center for Chemical Injury, Emergency and Critical Medicine of Fudan University, China; Key Laboratory of Chemical Injury, Emergency and Critical Medicine of Shanghai Municipal Health Commission, China.
Center of Emergency and Critical Medicine, Jinshan Hospital of Fudan University, China; Research Center for Chemical Injury, Emergency and Critical Medicine of Fudan University, China; Key Laboratory of Chemical Injury, Emergency and Critical Medicine of Shanghai Municipal Health Commission, China.
Biomed Pharmacother. 2023 Jun;162:114654. doi: 10.1016/j.biopha.2023.114654. Epub 2023 Apr 3.
Accidental exposure to phosgene can cause acute lung injury (ALI), characterized by uncontrolled inflammation and impaired lung blood-gas barrier. CD34CD45 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 CD34CD45 cell repairing the pulmonary vascular barrier in rats with P-ALI remains unclear. This study provided compelling evidence that CD34CD45 cells possess endothelial differentiation potential. Rats with P-ALI were intratracheally administered with CD34CD45 cells transfected with or without PTTG1-overexpressing and sh-PTTG1 lentivirus. It was found that CD34CD45 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 CD34CD45 cells to attenuate P-ALI, no significant difference was found. PTTG1 was found to regulate the endothelial differentiation of CD34CD45 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 CD34CD45 cells. Moreover, LY294002 (PI3K inhibitor) treatment inhibited the endothelial differentiation of CD34CD45 cells, while SC79 (AKT activator) yielded the opposite effect. These findings suggest that PTTG1 can promote the endothelial differentiation of CD34CD45 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.
意外接触光气可导致急性肺损伤（ALI），其特征为不受控制的炎症反应和肺气血屏障受损。通过单细胞RNA测序在大鼠肺血管周围鉴定出高表达垂体肿瘤转化基因1（PTTG1）的CD34CD45细胞，并且已证明这些细胞可通过促进肺血管屏障修复来减轻P-ALI。作为与血管生成密切相关的转录因子，PTTG1在P-ALI大鼠中是否在CD34CD45细胞修复肺血管屏障中发挥作用仍不清楚。本研究提供了令人信服的证据，表明CD34CD45细胞具有内皮分化潜能。对P-ALI大鼠经气管内给予转染有或未转染过表达PTTG1和sh-PTTG1慢病毒的CD34CD45细胞。结果发现，CD34CD45细胞降低了肺血管通透性并减轻了肺部炎症，敲低PTTG1可使其逆转。尽管过表达PTTG1增强了CD34CD45细胞减轻P-ALI的能力，但未发现显著差异。发现PTTG1可调节CD34CD45细胞的内皮分化。此外，敲低PTTG1可显著降低VEGF和bFGF及其受体的蛋白水平，进而抑制CD34CD45细胞中PI3K/AKT/eNOS信号通路的激活。此外，LY294002（PI3K抑制剂）处理可抑制CD34CD45细胞的内皮分化，而SC79（AKT激活剂）则产生相反的效果。这些发现表明，PTTG1可通过激活VEGF-bFGF/PI3K/AKT/eNOS信号通路促进CD34CD45细胞的内皮分化，从而导致P-ALI大鼠肺血管屏障的修复。
