Li Miao, Song Juan, Tang Xinjun, Bi Jing, Li Yufan, Chen Cuicui, Feng Nana, Song Yuanlin, Wang Linlin
Shanghai Key Laboratory of Lung Inflammation and Injury, Department of Pulmonary and Critical Care Medicine, Zhongshan Hospital, Fudan University, Shanghai, China.
Shanghai Key Laboratory of Lung Inflammation and Injury, Department of Pulmonary and Critical Care Medicine, Zhongshan Hospital, Fudan University, Shanghai, China; Shanghai Institute of Infectious Diseases and Biosafety, Shanghai, China.
Adv Med Sci. 2024 Mar;69(1):90-102. doi: 10.1016/j.advms.2024.01.004. Epub 2024 Feb 21.
Plasminogen activator inhibitor-1 (PAI-1) is the main inhibitor of fibrinolytic systems. The effect of PAI-1 on inflammatory response is still inconsistent. Our study was conducted to investigate its effects on inflammation to clarify the role of PAI-1 in acute lung injury (ALI) induced by lipopolysaccharide (LPS).
ALI models were established in wild-type (WT) and PAI-1 knockout (KO) mice by LPS intervention for 48 h. Lung histopathology, wet-dry ratio, total cell count and TNF-α concentration in bronchoalveolar lavage fluid (BALF), and inflammation related proteins were detected. Flow cytometry was used to sort neutrophils, macrophages, regulatory T cells (Treg) and T helper cell 17 (Th17). RNA sequencing was performed to find differentially expressed genes. Masson staining and immunohistochemistry were used to analyze pulmonary fiber deposition and proliferation.
Compared with ALI (WT) group, the wet-dry ratio, the total number of BALF cells, the concentration of TNF-α in BALF, and the expression of pp65 in the lung tissue was increased in ALI (PAI-1 KO) group, with increased proportion of neutrophils, decreased proportion of macrophages and decreased proportion of Treg/Th17 in the lung tissue. Collagen fiber deposition and PCNA expression were lighter in ALI (PAI-1 KO) group than ALI (WT) group. PPI analysis showed that PAI-1 was closely related to TNF, IL-6, IL-1β, Smad2/3 and mainly concentrated in the complement and coagulation system, TNF-α and IL-17 signaling pathways.
PAI-1 KO could aggravate ALI induced by LPS at 48 h. PAI-1 may be an important target to improve the prognosis of ALI.
纤溶酶原激活物抑制剂-1（PAI-1）是纤维蛋白溶解系统的主要抑制剂。PAI-1对炎症反应的影响仍不一致。本研究旨在探讨其对炎症的影响，以阐明PAI-1在脂多糖（LPS）诱导的急性肺损伤（ALI）中的作用。
通过LPS干预48小时，在野生型（WT）和PAI-1基因敲除（KO）小鼠中建立ALI模型。检测肺组织病理学、湿干比、支气管肺泡灌洗液（BALF）中的总细胞计数和TNF-α浓度以及炎症相关蛋白。采用流式细胞术分选中性粒细胞、巨噬细胞、调节性T细胞（Treg）和辅助性T细胞17（Th17）。进行RNA测序以发现差异表达基因。采用Masson染色和免疫组织化学分析肺纤维沉积和增殖情况。
与ALI（WT）组相比，ALI（PAI-1 KO）组的湿干比、BALF细胞总数、BALF中TNF-α浓度以及肺组织中pp65的表达增加，肺组织中中性粒细胞比例增加，巨噬细胞比例降低，Treg/Th17比例降低。ALI（PAI-1 KO）组的胶原纤维沉积和PCNA表达比ALI（WT）组轻。蛋白质-蛋白质相互作用分析表明，PAI-1与TNF、IL-6、IL-1β、Smad2/3密切相关，主要集中在补体和凝血系统、TNF-α和IL-17信号通路。
PAI-1基因敲除可加重LPS诱导的48小时ALI。PAI-1可能是改善ALI预后的重要靶点。
