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| Effects of metformin on mitochondrial oxidative stress in lung tissue of rats with acute lung injury induced by sepsis |
| Zhang Meng-li, Li Wen-qiang |
| Department of Emergency, Renmin Hospital of Wuhan University, Wuhan 430060, China |
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Abstract Objective: To observe the effect of metformin on mitochondrial oxidative stress in lung tissue of rats with acute lung injury induced by sepsis. Methods: The rat model of sepsis was established by cecal ligation and perforation (CLP). Forty male Wistar rats were randomly divided into four groups: normal control group (Sham group), control group (Sham/M group), sepsis group (CLP group), sepsis treatment group (CLP/M group). Each group was divided into 6 h, 12 h, 24 h subgroups according to observation time points. Sham/M group was injected with metformin (100 mg/kg) and the same group as Sham group 1.5 h before operation. The sham rats underwent surgery, but without ligation and puncture. CLP/M group was injected with metformin (100 mg /kg) by intragastric administration 1.5 h before operation. The levels of TNF-α and IL-1β in lung tissue were detected by enzyme-linked immunosorbent assay (ELISA). The activity of mitochondrial superoxide dismutase (SOD) was measured by xanthine oxidase method. The expression of AMPK protein was detected by protein immunoblotting test (Western blotting). The pathological changes of lung tissue were observed by HE staining. Results: ①There were no significant differences in TNF-α and IL-1β levels between the Sham group and the Sham/M group at 12 h and 24 h (P＞0.05). At 12 h and 24 h, the CLP group and the CLP/M group were significantly (P＜0.01). The levels of TNF-α and IL-1β in lung tissue of CLP/M group were significantly lower than those in CLP group (P＜0.01), and the level of TNF-α and IL-1β in lung tissue of CLP (P＜0.05). ②The levels of SOD in the mitochondria of Sham group and Sham/M group were significantly lower than those in Sham group (P＜0.01), CLP/M (P＜0.05). ③The expression of AMPK protein in Sham group and Sham/M group was not significantly different (P＞0.05), CLP/M and CLP group were higher than Sham group (P＜0.05); CLP/M group was significantly higher than CLP group (P＜0.05). ④The pathological morphology and ultrastructural injury of CLP group were heavier under light microscope. After treatment with metformin, the pathological morphology and ultrasonography microstructure damage has been reduced. Conclusion: Metformin may protect the acute lung injury induced by sepsis, which may be related to the decrease of TNF-α and IL-1β inflammatory mediators, the increase of SOD level and the activation of AMPK protein.
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Received: 16 May 2017
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Corresponding Authors:
Li Wen-qiang, E-mail: 13971583642@139.com
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| ［1］Khan MM, Yang WL, Wang P. Endoplasmic reticulum stress in sepsis［J］. Shock， 2015， 44（4）:294-304.
［2］Mikkelsen ME,Shah CV,Meyer NJ,et al.The epidemiology of acute respiratory distress syndrome in patients presenting to the emergency department with severe sepsis［J］.Shock, 2013, 40(5):375-381.
［3］Barreto-Torres G, Parodi-Rullán R, Javadov S. The role of PPARα in metformin-induced attenuation of mitochondrial dysfunction in acute cardiac ischemia/reperfusion in rats［J］. Int J Mol Sci, 2012, 13(6):7694-7709．
［4］Hardie DG, Ross FA, Hawley SA. AMP-activated protein kinase: a target for drugs both ancient and modern［J］. Chem Biol, 2012, 19(10):1222-1236.
［5］Parker SJ, Watkins PE. Experimental models of gram-negative sepsis［J］.Br J Surg, 2001, 88(1):22-30.
［6］Janz DR, Bastarache JA, Rice TW, et al. Randomized, placebo-controlled trial of acetaminophen for the reduction of oxidative injury in severe sepsis: the across trial［J］. Crit Care Med, 2015, 43(3):534-541.
［7］Singer M. Mitochondrial function in sepsis: acute phase versus multiple organ failure［J］. Crit Care Med， 2007， 35(9 Suppl):S441-448.
［8］Liu Z, Bone N, Jiang S, et al. AMP-activated protein kinase and Glycogen Synthase Kinase 3β modulate the severity of sepsis-induced lung injury［J］. Mol Med, 2015, Epub ahead of print.
［9］Piwkowska A, Rogacka D, Jankowski M, et al. Metformin induces suppression of NAD(P)H oxidase activity in podocytes［J］. Biochem Biophys Res Commun, 2010, 393(2):268-273.
［10］Hou X, Song J, Li XN, et al. Metformin reduces intracellular reactive oxygen species levels by upregulating expression of the antioxidant thioredoxin via the AMPK-FOXO3 pathway ［J］. Biochem Biophys Res Commun, 2010, 396(2):199-205.
［11］Jian MY, Alexeyev MF, Wolkowicz PE, et al. Metformin-stimulated AMPK-1β promotes microvascular repair in acute lung injury［J］. Am J Physiol Lung Cell Mol Physiol, 2013, 305(11):L844-855. |
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