Infection and Drug Resistance (Jun 2022)
CCL25 Inhibition Alleviates Sepsis-Induced Acute Lung Injury and Inflammation
Abstract
Demeng Xia,1,* Sheng Wang,2,* Anwei Liu,1,3,* Lei Li,2 Panyu Zhou,2 Shuogui Xu2 1Luodian Clinical Drug Research Center, Shanghai Baoshan Luodian Hospital, Shanghai University, Shanghai, People’s Republic of China; 2Department of Emergency, Changhai Hospital, The Naval Medical University, Shanghai, People’s Republic of China; 3Department of Critical Care Medicine, Hospital of Southern Theatre Command of PLA, Guangzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Shuogui Xu; Panyu Zhou, Department of Emergency, Changhai Hospital, Naval Medical University, Xiangyin Road, Shanghai, 200433, People’s Republic of China, Tel +8613176535161 ; +8619821317892, Email [email protected]; [email protected]: Acute lung injury (ALI) is a common clinical syndrome with high mortality. The chemokine ligand 25 (CCL25) is involved in inflammation, leukocyte trafficking and immunoregulation. However, the role and mechanism of CCL25 in ALI are not fully understood yet. The aim of this study was to explore the relationship between acute lung injury and CCL25.Patients and Methods: In this study, we first examined chemokine expression in sepsis patients and found that serum CCL25 expression levels were relatively high in sepsis patients compared to healthy individuals. Based on this, we designed in vitro and in vivo experiments to verify the validity of the theory. In vitro, we used lipopolysaccharide-stimulated human pulmonary microvascular endothelial cells (HPMECs). In vivo, we established male C57BL/6 mice cecal ligation puncture (CLP) model of sepsis.Results: In vitro, we used lipopolysaccharide-stimulated human pulmonary microvascular endothelial cells (HPMECs) and found significantly higher expression of CCL25 by enzyme-linked immunosorbent assay. Inhibition of CCL25 resulted in a significant decrease in the expression of inflammatory cytokines in HPMECs. In addition, we found that CCL25 promoted increased endothelial permeability by reducing the expression of tight junction proteins and was associated with activation of the P38 MAPK pathway by measuring the transepithelial electrical resistance and fluorescence intensity of fluorescein isothiocyanate. Results from luciferase assays and chromatin immunoprecipitation assays showed that inhibition of NF-κB activity in HPMECs decreased CCL25 expression, but addition of recombinant CCL25 increased cell permeability and inflammatory cytokine expression. In vivo, we established male C57BL/6 mice cecal ligation puncture (CLP) model of sepsis. We found that inhibition of CCL25 significantly reduced inflammatory cytokine expression in a CLP-induced sepsis model, thereby alleviating lung tissue damage in mice.Conclusion: Our study suggests that CCL25 contributed to the development of ALI by modulating the functions of microvascular endothelial cells.Keywords: CCL25/CCR11, inflammatory cytokines, cell permeability, acute lung injury, P38, NF-κB
