Protective Effects Of P2x7r Antagonist In Sepsis-Induced Acute Lung Injury In Mice Via Regulation Of Circ_0001679 And Circ_0001212 And Downstream Pln, Cdh2, And Nprl3 Expression

Background Sepsis induces pulmonary P2X(7)receptor (P2X(7)R) expression and P2X(7)R-knockout reduced lung inflammation in mice. The present study investigated the expression of circular RNA (circRNA) and mRNA in sepsis-induced acute lung injury (ALI) treated with a P2X(7)R antagonist. Methods Sepsis was induced by tracheal administration of lipopolysaccharide (LPS), and the mice were then divided into two groups: without [sepsis + dimethyl sulfoxide (DMSO)] or with P2X(7)R antagonist treatment (sepsis + P2X(7)A). Sham mice were administrated sterile normal saline. Serum levels of interleukin (IL)-1 beta and tumor necrosis factor (TNF)-alpha, pathological changes, cell apoptosis and P2X(7)R expression in lung were assessed, followed by RNA sequencing (RNA-seq) and bioinformatics analyses. A quantitative reverse transcriptase-polymerase chain reaction (RT-qPCR) was used to validate circRNAs and mRNAs. Results Compared to the sham group, LPS-induced sepsis produced obvious pathological changes in lung tissue, as well as increased apoptotic lung cells, serum TNF-alpha and IL-1 beta levels, and P2X(7)R expression; P2X(7)R antagonism significantly ameliorated these changes. RNA-seq identified many dysregulated circRNAs and mRNAs during sepsis, whereas this changed with P2X(7)R antagonism. RT-qPCR confirmed thatMus musculus(mmu)_circ_0001679, mmu_circ_0001212, phospholamban (Pln), cadherin-2 (Cdh2) and nitrogen permease regulator 3-like (Nprl3) expression were significantly increased in the sepsis + DMSO group compared to that in the sham group but were decreased in the sepsis + P2X(7)A group compared to that in the sepsis + DMSO group. The circRNA-microRNA-mRNA coexpression network indicated that mmu_circ_0001679 may regulate Nprl3 and that mmu_circ_0001212 may similarly regulate Pln, Cdh2 and Nprl3 as a competing endogenous RNA. Conclusions P2X(7)R antagonism attenuates sepsis-induced ALI by inhibiting dysregulated expression of circRNA (circ_0001679, circ_0001212) and mRNA (Pln, Cdh2 and Nprl3).