Attenuation of Lipopolysaccharide-Induced Acute Lung Injury by Cyclosporine-A via Suppression of Mitochondrial DNA

Abstract

BackgroundLipopolysaccharide (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/MethodsTwenty-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.ResultsCsA 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-α (TNF-α, 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).ConclusionsThe 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.

Cyclosporine A prevents cardiac arrest-induced acute respiratory failure: a post-hoc analysis of the CYRUS trial

“…We report here the first clinical data suggesting that CsA might limit the severity of ARF at 24 h following OHCA. Even though this post-hoc analysis of the CYRUS trial does not provide mechanistic insight, our findings are in line with both experimental and clinical studies reporting potent protective effects of CsA against ischemia/reperfusion (I/R) injury [1,2,3,5]. CsA may indeed limit I/R-induced cellular damages by inhibiting the cyclophilin D-dependent opening of the mitochondrial permeability transition pore and by preserving oxidative phosphorylation [5].…”

“…This finding opens new therapeutic perspectives, targeting lung injury, to improve the prognosis of OHCA patients. Experimentally, Cyclosporine A (CsA) has been shown to prevent systemic inflammation-induced ARF [2,3]. To investigate the effect of CsA on ARF in the clinical setting, we conducted a post-hoc analysis of the prospective, multicenter, randomized CsA in OHCA resuscitation (CYRUS) trial (ClinicalTrials.gov identifier: NCT01595958).…”

“…CsA may indeed limit I/R-induced cellular damages by inhibiting the cyclophilin D-dependent opening of the mitochondrial permeability transition pore and by preserving oxidative phosphorylation [5]. In acute lung injury models, cytoprotection was also attributed to a decrease in circulating mitochondrial pro-inflammatory and pro-apoptotic factors [2,3]. Studies are now needed to examine the longer-term effects of CsA on lung injury, which could not be done here due to high early mortality rate.…”

Mitochondrial Dysfunction, Oxidative Stress, and Neuroinflammation: Intertwined Roads to Neurodegeneration

“…However, mitochondrial ROS also participate in other cellular processes including the activation of mitochondrial permeability transition pore (mPTP), dysregulation of mitophagy, imbalances in mitochondrial dynamics, and programmed cell death [48]. These processes represent potential routes for mtDNA displacement following ROS burst as evidenced by the finding of oxidized mtDNA fragments outside of mitochondria in the setting of several metabolic diseases [43,[49][50][51][52][53] (Figure 1). Under several stressors (e.g., mitochondrial dysfunction and consequent reactive oxygen species (ROS) production, viral and bacterial infections), several types of damage are inflicted to mitochondrial DNA (mtDNA) and a set of signaling pathways are activated to promote mitochondrial recovery or demise depending on the damage severity.…”

“…However, mitochondrial ROS also participate in other cellular processes including the activation of mitochondrial permeability transition pore (mPTP), dysregulation of mitophagy, imbalances in mitochondrial dynamics, and programmed cell death [ 48 ]. These processes represent potential routes for mtDNA displacement following ROS burst as evidenced by the finding of oxidized mtDNA fragments outside of mitochondria in the setting of several metabolic diseases [ 43 , 49 , 50 , 51 , 52 , 53 ] ( Figure 1 ).…”