Hydrogen-rich saline protects against mitochondrial dysfunction and apoptosis in mice with obstructive jaundice

Liu,Qu; Li,Bao‑Shan; Song,Yu‑Jiao; Hu,Ming‑Gen; Lu,Jian‑Yue; Gao,Ang; Sun,Xue‑Jun; Guo,Xi‑Ming; Liu,Rong

doi:10.3892/mmr.2016.4954

Hydrogen-rich saline protects against mitochondrial dysfunction and apoptosis in mice with obstructive jaundice

Authors:
- Qu Liu
- Bao‑Shan Li
- Yu‑Jiao Song
- Ming‑Gen Hu
- Jian‑Yue Lu
- Ang Gao
- Xue‑Jun Sun
- Xi‑Ming Guo
- Rong Liu
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Affiliations: Department of Surgical Oncology, The General Hospital of Chinese People's Liberation Army, Beijing 100853, P.R. China, Department of General Surgery, People's Liberation Army No. 254 Hospital, Nankai University, Tianjin 300141, P.R. China, Department of Cell Biology, Beijing Institute of Basic Medical Sciences, Academy of Military Medicine, Beijing 100850, P.R. China, Department of Diving Medicine, Faculty of Naval Medicine, Second Military Medical University, Shanghai 200433, P.R. China
Published online on: March 1, 2016 https://doi.org/10.3892/mmr.2016.4954
Pages: 3588-3596

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Abstract

Previous studies have demonstrated that hydrogen-rich saline (HS) protects against bile duct ligation (BDL)-induced liver injury by suppressing oxidative stress and inflammation. Mitochondria, which are targets of excessive reactive oxygen species and central mediators of apoptosis, have a pivotal role in hepatic injury during obstructive jaundice (OJ); however, the implications of HS in the hepatic mitochondria of BDL mice remain unknown. The present study investigated the hypothesis that HS could reduce OJ‑induced liver injury through the protection of mitochondrial structure and function, as well as inhibition of the mitochondrial apoptotic pathway. Male C57BL/6 mice were randomly divided into three experimental groups: Sham operation group, BDL injury with normal saline (NS) treatment group, and BDL‑injury with HS treatment group. Mitochondrial damage and apoptotic parameters were determined 3 days post‑BDL injury and treatment. The results demonstrated that mitochondria isolated from the livers of NS-treated BDL mice exhibited increased mitochondrial swelling, cytochrome c release, and oxidative damage. In addition, liver samples from NS‑treated BDL mice exhibited significant increases in B‑cell lymphoma 2 (Bcl‑2)‑associated X protein expression, caspase activities, and hepatocyte apoptosis compared with livers from sham‑operated controls. Notably, treatment with HS reduced the levels of these markers and alleviated morphological defects in the mitochondria following injury. In addition, HS markedly increased the antioxidant potential of mitochondria, as evidenced by elevated adenosine triphosphate levels, mitochondrial respiratory function, and increased levels of active Bcl‑2. In conclusion, HS attenuates mitochondrial oxidative stress and dysfunction, and inhibits mitochondrial-mediated apoptosis in the livers of BDL mice.

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1	Poupon R, Chazouillères O and Poupon RE: Chronic cholestatic diseases. J Hepatol. 32(Suppl 1): 129–140. 2000. View Article : Google Scholar : PubMed/NCBI
2	Greig JD, Krukowski ZH and Matheson NA: Surgical morbidity and mortality in one hundred and twenty-nine patients with obstructive jaundice. Br J Surg. 75:216–219. 1988. View Article : Google Scholar : PubMed/NCBI
3	Vendemiale G, Grattagliano I, Lupo L, Memeo V and Altomare E: Hepatic oxidative alterations in patients with extra-hepatic cholestasis. Effect of surgical drainage J Hepatol. 37:601–605. 2002.
4	Assimakopoulos SF, Vagianos CE, Zervoudakis G, Filos KS, Georgiou C, Nikolopoulou V and Scopa CD: Gut regulatory peptides bombesin and neurotensin reduce hepatic oxidative stress and histological alterations in bile duct ligated rats. Regul Pept. 120:185–193. 2004. View Article : Google Scholar : PubMed/NCBI
5	Liu TZ, Lee KT, Chern CL, Cheng JT, Stern A and Tsai LY: Free radical-triggered hepatic injury of experimental obstructive jaundice of rats involves overproduction of proinflammatory cytokines and enhanced activation of nuclear factor kappaB. Ann Clin Lab Sci. 31:383–390. 2001.PubMed/NCBI
6	Kantrow SP, Tatro LG and Piantadosi CA: Oxidative stress and adenine nucleotide control of mitochondrial permeability transition. Free Radic Biol Med. 28:251–260. 2000. View Article : Google Scholar
7	Kim JS, He L, Qian T and Lemasters JJ: Role of the mitochondrial permeability transition in apoptotic and necrotic death after ischemia/reperfusion injury to hepatocytes. Curr Mol Med. 3:527–535. 2003. View Article : Google Scholar : PubMed/NCBI
8	Miyoshi H, Rust C, Roberts PJ, Burgart LJ and Gores GJ: Hepatocyte apoptosis after bile duct ligation in the mouse involves Fas. Gastroenterology. 117:669–677. 1999. View Article : Google Scholar : PubMed/NCBI
9	Canbay A, Feldstein A, Baskin-Bey E, Bronk SF and Gores GJ: The caspase inhibitor IDN-6556 attenuates hepatic injury and fibrosis in the bile duct ligated mouse. J Pharmacol Exp Ther. 308:1191–1196. 2004. View Article : Google Scholar
10	Wang L, Hartmann P, Haimerl M, Bathena SP, Sjöwall C, Almer S, Alnouti Y, Hofmann AF and Schnabl B: Nod2 deficiency protects mice from cholestatic liver disease by increasing renal excretion of bile acids. J Hepatol. 60:1259–1267. 2014. View Article : Google Scholar : PubMed/NCBI
11	Ohsawa I, Ishikawa M, Takahashi K, Watanabe M, Nishimaki K, Yamagata K, Katsura K, Katayama Y, Asoh S and Ohta S: Hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals. Nat Med. 13:688–694. 2007. View Article : Google Scholar : PubMed/NCBI
12	Zheng X, Mao Y, Cai J, Li Y, Liu W, Sun P, Zhang JH, Sun X and Yuan H: Hydrogen-rich saline protects against intestinal ischemia/reperfusion injury in rats. Free Radic Res. 43:478–484. 2009. View Article : Google Scholar : PubMed/NCBI
13	Kajiya M, Silva MJ, Sato K, Ouhara K and Kawai T: Hydrogen mediates suppression of colon inflammation induced by dextran sodium sulfate. Biochem Biophys Res Commun. 386:11–15. 2009. View Article : Google Scholar : PubMed/NCBI
14	Liu Q, Shen WF, Sun HY, Fan DF, Nakao A, Cai JM, Yan G, Zhou WP, Shen RX, Yang JM and Sun XJ: Hydrogen-rich saline protects against liver injury in rats with obstructive jaundice. Liver Int. 30:958–968. 2010. View Article : Google Scholar : PubMed/NCBI
15	Cai J, Kang Z, Liu K, Liu W, Li R, Zhang JH, Luo X and Sun X: Neuroprotective effects of hydrogen saline in neonatal hypoxia-ischemia rat model. Brain Res. 1256:129–137. 2009. View Article : Google Scholar
16	Zhuge J and Cederbaum AI: Serum deprivation-induced HepG2 cell death is potentiated by CYP2E1. Free Radic Biol Med. 40:63–74. 2006. View Article : Google Scholar
17	Zhuge J and Cederbaum AI: Increased toxicity by transforming growth factor-beta 1 in liver cells overexpressing CYP2E1. Free Radic Biol Med. 41:1100–1112. 2006. View Article : Google Scholar : PubMed/NCBI
18	Sherwood SW and Schimke RT: Cell cycle analysis of apoptosis using flow cytometry. Methods Cell Biol. 46:77–97. 1995. View Article : Google Scholar : PubMed/NCBI
19	Wu D and Cederbaum A: Cytochrome P4502E1 sensitizes to tumor necrosis factor alpha-induced liver injury through activation of mitogen-activated protein kinases in mice. Hepatology. 47:1005–1017. 2008. View Article : Google Scholar
20	Rickmann M, Vaquero EC, Malagelada JR and Molero X: Tocotrienols induce apoptosis and autophagy in rat pancreatic stellate cells through the mitochondrial death pathway. Gastroenterology. 132:2518–2532. 2007. View Article : Google Scholar : PubMed/NCBI
21	Yang L and Yu T: Prolonged donor heart preservation with pinacidil: The role of mitochondria and the mitochondrial adenosine triphosphate-sensitive potassium channel. J Thorac Cardiovasc Surg. 139:1057–1063. 2010. View Article : Google Scholar : PubMed/NCBI
22	Gogvadze V, Orrenius S and Zhivotovsky B: Analysis of mitochondrial dysfunction during cell death. Curr Protoc Cell Biol Chapter. 18:Unit 18.5. 2003. View Article : Google Scholar
23	Youle RJ and Strasser A: The BCL-2 protein family: Opposing activities that mediate cell death. Nat Rev Mol Cell Biol. 9:47–59. 2008. View Article : Google Scholar
24	Palmeira CM and Rolo AP: Mitochondrially-mediated toxicity of bile acids. Toxicology. 203:1–15. 2004. View Article : Google Scholar : PubMed/NCBI
25	Sun Q, Kang Z, Cai J, Liu W, Liu Y, Zhang JH, Denoble PJ, Tao H and Sun X: Hydrogen-rich saline protects myocardium against ischemia/reperfusion injury in rats. Exp Biol Med (Maywood). 234:1212–1219. 2009. View Article : Google Scholar
26	Mantena SK, King AL, Andringa KK, Eccleston HB and Bailey SM: Mitochondrial dysfunction and oxidative stress in the pathogenesis of alcohol- and obesity-induced fatty liver diseases. Free Radic Biol Med. 44:1259–1272. 2008. View Article : Google Scholar : PubMed/NCBI
27	Cederbaum AI, Lu Y and Wu D: Role of oxidative stress in alcohol-induced liver injury. Arch Toxicol. 83:519–548. 2009. View Article : Google Scholar : PubMed/NCBI
28	Zorov DB, Juhaszova M and Sollott SJ: Mitochondrial ROS-induced ROS release: An update and review. Biochim Biophys Acta. 1757:509–517. 2006. View Article : Google Scholar : PubMed/NCBI
29	Zorov DB, Filburn CR, Klotz LO, Zweier JL and Sollott SJ: Reactive oxygen species (ROS)-induced ROS release: A new phenomenon accompanying induction of the mitochondrial permeability transition in cardiac myocytes. J Exp Med. 192:1001–1014. 2000. View Article : Google Scholar : PubMed/NCBI
30	Petronilli V, Costantini P, Scorrano L, Colonna R, Passamonti S and Bernardi P: The voltage sensor of the mitochondrial permeability transition pore is tuned by the oxidation-reduction state of vicinal thiols. Increase of the gating potential by oxidants and its reversal by reducing agents. J Biol Chem. 269:16638–16642. 1994.PubMed/NCBI
31	Kim JS, He L and Lemasters JJ: Mitochondrial permeability transition: A common pathway to necrosis and apoptosis. Biochem Biophys Res Commun. 304:463–470. 2003. View Article : Google Scholar : PubMed/NCBI
32	Adams JM and Cory S: The Bcl-2 protein family: Arbiters of cell survival. Science. 281:1322–1326. 1998. View Article : Google Scholar : PubMed/NCBI
33	Malhi H, Gores GJ and Lemasters JJ: Apoptosis and necrosis in the liver: A tale of two deaths? Hepatology. 43(2 Suppl 1): S31–S44. 2006. View Article : Google Scholar : PubMed/NCBI
34	Wei MC, Zong WX, Cheng EH, Lindsten T, Panoutsakopoulou V, Ross AJ, Roth KA, MacGregor GR, Thompson CB and Korsmeyer SJ: Proapoptotic BAX and BAK: A requisite gateway to mitochondrial dysfunction and death. Science. 292:727–730. 2001. View Article : Google Scholar : PubMed/NCBI
35	Chaudhary K, Liedtke C, Wertenbruch S, Trautwein C and Streetz KL: Caspase 8 differentially controls hepatocytes and non-parenchymal liver cells during chronic cholestatic liver injury in mice. J Hepatol. 59:1292–1298. 2013. View Article : Google Scholar : PubMed/NCBI
36	Tiao MM, Lin TK, Liou CW, Wang PW, Chen JB, Kuo FY, Huang CC, Chou YM and Chuang JH: Early transcriptional deregulation of hepatic mitochondrial biogenesis and its consequent effects on murine cholestatic liver injury. Apoptosis. 14:890–899. 2009. View Article : Google Scholar : PubMed/NCBI
37	Kahraman A, Barreyro FJ, Bronk SF, Werneburg NW, Mott JL, Akazawa Y, Masuoka HC, Howe CL and Gores GJ: TRAIL mediates liver injury by the innate immune system in the bile duct-ligated mouse. Hepatology. 47:1317–1330. 2008. View Article : Google Scholar : PubMed/NCBI
38	Green DR and Reed JC: Mitochondria and apoptosis. Science. 281:1309–1312. 1998. View Article : Google Scholar : PubMed/NCBI
39	Yoon JH and Gores GJ: Death receptor-mediated apoptosis and the liver. J Hepatol. 37:400–410. 2002. View Article : Google Scholar : PubMed/NCBI
40	Marin JJ, Hernandez A, Revuelta IE, Gonzalez-Sanchez E, Gonzalez-Buitrago JM and Perez MJ: Mitochondrial genome depletion in human liver cells abolishes bile acid-induced apoptosis: Role of the Akt/mTOR survival pathway and Bcl-2 family proteins. Free Radic Biol Med. 61:218–228. 2013. View Article : Google Scholar : PubMed/NCBI