Attenuation of Lipopolysaccharide-Induced Acute Lung Injury by Cyclosporine-A via Suppression of Mitochondrial DNA
Zhenghua Xiao, Bangsheng Jia, Xueshan Zhao, Siwei Bi, Wei Meng
Department of Cardiovascular Surgery, West China Hospital/West China School of Medicine, Sichuan University, Chengdu, Sichuan, China (mainland)
Med Sci Monit 2018; 24:7682-7688
Lipopolysaccharide (LPS) is generally associated with sepsis, which causes multiple system injuries and systemic inflammatory response. Mitochondrial DNA (mtDNA) is of great importance in mediation of inflammation. The aim of this study was to investigate the protective profiles of Cyclosporine-A (CsA) in LPS-induced acute lung injury (ALI) and systemic inflammation by the inhibition of mtDNA and Toll-like receptor.
MATERIAL AND METHODS: Twenty-four C57BL/6 mice were randomly assigned to 4 groups: a sham group (n=6); an experiment group (ALI induced through intraperitoneal injection of 10 mg/ml LPS, n=6); a low-CsA group (injection of 2.5 mg/kg of CsA 15 min after injection of LPS, n=6); and a high-CsA group (injection of 25 mg/kg of CsA 15 min after injection of LPS, n=6). Lung tissue, bronchoalveolar lavage fluid (BALF), and blood samples were collected at 6 h for further analyses.
RESULTS: CsA treatment significantly attenuated LPS-induced lung histopathological changes (P<.05), myeloperoxidase (MPO) activity (P<.05) and lung wet-to-dry weight ratio (P<.05). In addition, injection of CsA decreased total cells (P<.05), neutrophils (P<.05), and total protein (P<.05) in BALF and inflammatory mediators, including tumor necrosis factor-a (TNF-a, P<.05) and interleukin-6 (IL-6, P<.05) in a dose-dependent manner. A significant decrease in mtDNA was observed in the CsA group when compared with controls (P<.05). Furthermore, we demonstrated that there was a significant difference between the high-CsA group and low-CsA group in lung injury score (P<.05), mtDNA (P<.05), and MPO (P<.05).
CONCLUSIONS: The evidence from this study suggests that CsA attenuated lung inflammation after LPS injection, and the protective mechanism may at least in part involve decreasing the release of inflammatory cytokines and mtDNA.
Keywords: acute lung injury, Cyclosporine, DNA, Mitochondrial, Lipopolysaccharides