Critical roles of PAI-1 in lipopolysaccharide-induced acute lung injury

Abstract

PurposePlasminogen 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). Material and methodsALI 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. ResultsCompared 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. ConclusionsPAI-1 KO could aggravate ALI induced by LPS at 48 ​h. PAI-1 may be an important target to improve the prognosis of ALI.