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Article

Role of the heme oxygenase/carbon monoxide pathway in the pathogenesis and prevention of hepatic encephalopathy

  • Authors:
    • Qiu-Ming Wang
    • Xue-Ying Yin
    • Zhi-Jun Duan
    • Shi-Bin Guo
    • Xiao-Yu Sun
  • View Affiliations / Copyright

    Affiliations: Department of Gastroenterology, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116011, P.R. China
  • Pages: 67-74
    |
    Published online on: May 13, 2013
       https://doi.org/10.3892/mmr.2013.1472
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Abstract

Hepatic encephalopathy (HE) is a severe complication of liver cirrhosis and its pathogenesis has yet to be fully elucidated. Previous studies have demonstrated that heme oxygenase-1 (HO-1) is important in the induction of liver cirrhosis. The present study aimed to investigate the role of HO-1 in the pathogenesis of HE. Rats were divided into 5 treatment groups; sham, bile duct ligation (BDL), HE, zinc protoporphyrin (ZnPP) and cobalt protoporphyrin (CoPP). The levels of HO-1 were examined by western blotting and quantitative real-time PCR (qRT-PCR). Serum levels of carboxyhemoglobin (COHb), ammonia levels in the plasma and brain, brain water content and portal vein pressure (PVP) were also quantified. Aquaporin-4 expression levels were measured by immunohistochemistry and qRT-PCR. The results demonstrated that the levels of HO-1 in the brain and the serum levels of COHb were significantly increased in the HE group compared with the BDL group. Brain water content, PVP and ammonia levels in the plasma and brain were increased in the HE and CoPP groups; however, these were reduced following the treatment with ZnPP. The levels of AQP-4 expression and oxidative stress in the brain were reduced following treatment with ZnPP and increased following treatment with CoPP. In conclusion, following the inhibition of HO-1 expression, treatment with ZnPP improved HE due to reducing the expression levels of AQP-4 and oxidative stress. Therefore, ZnPP treatment may represent a novel therapeutic approach for HE.
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1 

Ferenci P, Lockwood A, Mullen K, Tarter R, Weissenborn K and Blei AT: Hepatic encephalopathy - definition, nomenclature, diagnosis, and quantification: final report of the working party at the 11th World Congresses of Gastroenterology, Vienna, 1998. Hepatology. 35:716–721. 2002. View Article : Google Scholar

2 

Atluri DK, Prakash R and Mullen KD: Pathogenesis, diagnosis, and treatment of hepatic encephalopathy. J Clin Exp Hepatol. 2:77–86. 2011. View Article : Google Scholar

3 

Sass G, Barikbin R and Tiegs G: The multiple functions of heme oxygenase-1 in the liver. Z Gastroenterol. 50:34–40. 2012. View Article : Google Scholar : PubMed/NCBI

4 

Barañano DE and Snyder SH: Neural roles for heme oxygenase: contrasts to nitric oxide synthase. Proc Natl Acad Sci USA. 98:10996–11002. 2001.PubMed/NCBI

5 

Turner CP, Bergeron M, Matz P, et al: Heme oxygenase-1 is induced in glia throughout brain by subarachnoid hemoglobin. J Cereb Blood Flow Metab. 18:257–273. 1998. View Article : Google Scholar : PubMed/NCBI

6 

Matz PG, Weinstein PR and Sharp FR: Heme oxygenase-1 and heat shock protein 70 induction in glia and neurons throughout rat brain after experimental intracerebral hemorrhage. Neurosurgery. 40:152–160. 1997.PubMed/NCBI

7 

Chao XD, Ma YH, Luo P, et al: Up-regulation of heme oxygenase-1 attenuates brain damage after cerebral ischemia via simultaneous inhibition of superoxide production and preservation of NO bioavailability. Exp Neurol. 239:163–169. 2013. View Article : Google Scholar : PubMed/NCBI

8 

Cuadrado A and Rojo AI: Heme oxygenase-1 as a therapeutic target in neurodegenerative diseases and brain infections. Curr Pharm Des. 14:429–442. 2008. View Article : Google Scholar : PubMed/NCBI

9 

Guo SB, Duan ZJ, Li Q and Sun XY: Effect of heme oxygenase-1 on renal function in rats with liver cirrhosis. Shi Jie Wei Chang Bing Xue Za Zhi Bian Ji Bu. 17:322–328. 2011.(In Chinese).

10 

Guo SB, Duan ZJ, Li Q and Sun XY: Effects of heme oxygenase-1 on pulmonary function and structure in rats with liver cirrhosis. Zhong Hua Yi Xue Za Zhi Bian Ji Bu. 124:918–922. 2011.(In Chinese).

11 

Sun XY, Duan ZJ, Li YL and Chang QS: Detection of carboxyhemoglobin in patients with hepatic encephalopathy due to hepatitis B virus-related cirrhosis. Zhong Hua Yi Xue Za Zhi Bian Ji Bu. 125:3991–3996. 2012.(In Chinese).

12 

Jover R, Rodrigo R, Felipo V, et al: Brain edema and inflammatory activation in bile duct ligated rats with diet-induced hyperammonemia: A model of hepatic encephalopathy in cirrhosis. Hepatology. 43:1257–1266. 2006. View Article : Google Scholar : PubMed/NCBI

13 

Amersi F, Buelow R, Kato H, Ke B, Coito AJ, Shen XD, Zhao D, Zaky J, Melinek J, Lassman CR, Kolls JK, Alam J, Ritter T, Volk HD, Farmer DG, Ghobrial RM, Busuttil RW and Kupiec-Weglinski JW: Upregulation of heme oxygenase-1 protects genetically fat Zucker rat livers from ischemia/reperfusion injury. J Clin Invest. 104:1631–1639. 1999. View Article : Google Scholar : PubMed/NCBI

14 

Jiang W, Desjardins P and Butterworth RF: Hypothermia attenuates oxidative/nitrosative stress, encephalopathy and brain edema in acute (ischemic) liver failure. Neurochem Int. 55:124–128. 2009. View Article : Google Scholar

15 

Butterworth RF, Lalonde R, Power C, Baker GB, Gamrani H and Ahboucha S: Dehydroepiandrosterone sulphate improves cholestasis-associated fatigue in bile duct ligated rats. Neurogastroenterol Motil. 21:1319–1325. 2009. View Article : Google Scholar : PubMed/NCBI

16 

Shackelford C, Long G, Wolf J, Okerberg C and Herbert R: Qualitative and quantitative analysis of nonneoplastic lesions in toxicology studies. Toxicol Pathol. 30:93–96. 2002. View Article : Google Scholar : PubMed/NCBI

17 

Remmele W and Stegner HE: Recommendation for uniform definition of an immunoreactive score (IRS) for immunohistochemical estrogen receptor detection (ER-ICA) in breast cancer tissue. Pathologe. 8:138–140. 1987.(In German).

18 

Kakinuma S, Tanaka Y, Chinzei R, et al: Human umbilical cord blood as a source of transplantable hepatic progenitor cells. Stem Cells. 21:217–227. 2003.PubMed/NCBI

19 

Van Landeghem L, Laleman W, Vander Elst I, et al: Carbon monoxide produced by intrasinusoidally located haem-oxygenase-1 regulates the vascular tone in cirrhotic rat liver. Liver Int. 29:650–660. 2009.PubMed/NCBI

20 

Chopra VS, Chalifour LE and Schipper HM: Differential effects of cysteamine on heat shock protein induction and cytoplasmic granulation in astrocytes and glioma cells. Brain Res Mol Brain Res. 31:173–184. 1995. View Article : Google Scholar : PubMed/NCBI

21 

Jiang W, Desjardins P and Butterworth RF: Minocycline attenuates oxidative/nitrosative stress and cerebral complications of acute liver failure in rats. Neurochem Int. 55:601–605. 2009. View Article : Google Scholar : PubMed/NCBI

22 

Chastre A, Jiang W, Desjardins P and Butterworth RF: Ammonia and proinflammatory cytokines modify expression of genes coding for astrocytic proteins implicated in brain edema in acute liver failure. Metab Brain Dis. 25:17–21. 2010. View Article : Google Scholar : PubMed/NCBI

23 

Chen K, Gunter K and Maines MD: Neurons overexpressing heme oxygenase-1 resist oxidative stress-mediated cell death. J Neurochem. 75:304–313. 2000. View Article : Google Scholar : PubMed/NCBI

24 

Wang J and Doré S: Heme oxygenase-1 exacerbates early brain injury after intracerebral haemorrhage. Brain. 130:1643–1652. 2007. View Article : Google Scholar : PubMed/NCBI

25 

Koeppen AH, Dickson AC and Smith J: Heme oxygenase in experimental intracerebral hemorrhage: the benefit of tin-mesoporphyrin. J Neuropathol Exp Neurol. 63:587–597. 2004.PubMed/NCBI

26 

Malaguarnera L, Madeddu R, Palio E, Arena N and Malaguarnera M: Heme oxygenase-1 levels and oxidative stress-related parameters in non-alcoholic fatty liver disease patients. J Hepatol. 42:585–591. 2005. View Article : Google Scholar : PubMed/NCBI

27 

Froh M, Conzelmann L, Walbrun P, et al: Heme oxygenase-1 overexpression increases liver injury after bile duct ligation in rats. Shi Jie Wei Chang Bing Xue Za Zhi Bian Ji Bu. 13:3478–3486. 2007.(In Chinese).

28 

Warskulat U, Görg B, Bidmon HJ, Müller HW, Schliess F and Häussinger D: Ammonia-induced heme oxygenase-1 expression in cultured rat astrocytes and rat brain in vivo. Glia. 40:324–336. 2002. View Article : Google Scholar : PubMed/NCBI

29 

Xia ZW, Li CE, Jin YX, et al: Reduction of bilirubin by targeting human heme oxygenase-1 through siRNA. Exp Biol Med (Maywood). 232:495–502. 2007.PubMed/NCBI

30 

De las Heras D, Fernändez J, Ginès P, et al: Increased carbon monoxide production in patients with cirrhosis with and without spontaneous bacterial peritonitis. Hepatology. 38:452–459. 2003.PubMed/NCBI

31 

Tran TT, Martin P, Ly H, Balfe D and Mosenifar Z: Carboxyhemoglobin and its correlation to disease severity in cirrhotics. J Clin Gastroenterol. 41:211–215. 2007. View Article : Google Scholar : PubMed/NCBI

32 

Carter EP, Hartsfield CL, Miyazono M, Jakkula M, Morris KG Jr and McMurtry IF: Regulation of heme oxygenase-1 by nitric oxide during hepatopulmonary syndrome. Am J Physiol Lung Cell Mol Physiol. 283:L346–L353. 2002. View Article : Google Scholar : PubMed/NCBI

33 

Liu J, Duan J, Zhu L, Yang D, Wang L and Shao H: The preliminary study of the relationship between oxygenase-carbon monoxide system and plasma endothelin in hepatic cirrhotic patients with portal hypertension. Zheng Zhou Da Xue. 9:745–748. 2008.(In Chinese).

34 

Tarquini R, Masini E, La Villa G, et al: Increased plasma carbon monoxide in patients with viral cirrhosis and hyperdynamic circulation. Am J Gastroenterol. 104:891–897. 2009. View Article : Google Scholar : PubMed/NCBI

35 

Chen YC, Ginès P, Yang J, et al: Increased vascular heme oxygenase-1 expression contributes to arterial vasodilation in experimental cirrhosis in rats. Hepatology. 39:1075–1087. 2004. View Article : Google Scholar : PubMed/NCBI

36 

Fernandez M, Lambrecht RW and Bonkovsky HL: Increased heme oxygenase activity in splanchnic organs from portal hypertensive rats: role in modulating mesenteric vascular reactivity. J Hepatol. 34:812–817. 2001. View Article : Google Scholar : PubMed/NCBI

37 

Angermayr B, Mejias M, Gracia-Sancho J, Garcia-Pagan JC, Bosch J and Fernandez M: Heme oxygenase attenuates oxidative stress and inflammation, and increases VEGF expression in portal hypertensive rats. J Hepatol. 44:1033–1039. 2006. View Article : Google Scholar : PubMed/NCBI

38 

Pietrangelo A: Metals, oxidative stress, and hepatic fibrogenesis. Semin Liver Dis. 16:13–30. 1996. View Article : Google Scholar

39 

Rama Rao KV and Norenberg MD: Aquaporin-4 in hepatic encephalopathy. Metab Brain Dis. 22:265–275. 2007.PubMed/NCBI

40 

Papadopoulos MC and Verkman AS: Aquaporin-4 and brain edema. Pediatr Nephrol. 22:778–784. 2007. View Article : Google Scholar : PubMed/NCBI

41 

Badaut J, Ashwal S, Adami A, et al: Brain water mobility decreases after astrocytic aquaporin-4 inhibition using RNA interference. J Cereb Blood Flow Metab. 31:819–831. 2011. View Article : Google Scholar

42 

Kleindienst A, Dunbar JG, Glisson R and Marmarou A: The role of vasopressin V1A receptors in cytotoxic brain edema formation following brain injury. Acta Neurochir (Wien). 155:151–164. 2012. View Article : Google Scholar : PubMed/NCBI

43 

Bemeur C, Desjardins P and Butterworth RF: Evidence for oxidative/nitrosative stress in the pathogenesis of hepatic encephalopathy. Metab Brain Dis. 25:3–9. 2010. View Article : Google Scholar : PubMed/NCBI

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Copy and paste a formatted citation
Spandidos Publications style
Wang Q, Yin X, Duan Z, Guo S and Sun X: Role of the heme oxygenase/carbon monoxide pathway in the pathogenesis and prevention of hepatic encephalopathy. Mol Med Rep 8: 67-74, 2013.
APA
Wang, Q., Yin, X., Duan, Z., Guo, S., & Sun, X. (2013). Role of the heme oxygenase/carbon monoxide pathway in the pathogenesis and prevention of hepatic encephalopathy. Molecular Medicine Reports, 8, 67-74. https://doi.org/10.3892/mmr.2013.1472
MLA
Wang, Q., Yin, X., Duan, Z., Guo, S., Sun, X."Role of the heme oxygenase/carbon monoxide pathway in the pathogenesis and prevention of hepatic encephalopathy". Molecular Medicine Reports 8.1 (2013): 67-74.
Chicago
Wang, Q., Yin, X., Duan, Z., Guo, S., Sun, X."Role of the heme oxygenase/carbon monoxide pathway in the pathogenesis and prevention of hepatic encephalopathy". Molecular Medicine Reports 8, no. 1 (2013): 67-74. https://doi.org/10.3892/mmr.2013.1472
Copy and paste a formatted citation
x
Spandidos Publications style
Wang Q, Yin X, Duan Z, Guo S and Sun X: Role of the heme oxygenase/carbon monoxide pathway in the pathogenesis and prevention of hepatic encephalopathy. Mol Med Rep 8: 67-74, 2013.
APA
Wang, Q., Yin, X., Duan, Z., Guo, S., & Sun, X. (2013). Role of the heme oxygenase/carbon monoxide pathway in the pathogenesis and prevention of hepatic encephalopathy. Molecular Medicine Reports, 8, 67-74. https://doi.org/10.3892/mmr.2013.1472
MLA
Wang, Q., Yin, X., Duan, Z., Guo, S., Sun, X."Role of the heme oxygenase/carbon monoxide pathway in the pathogenesis and prevention of hepatic encephalopathy". Molecular Medicine Reports 8.1 (2013): 67-74.
Chicago
Wang, Q., Yin, X., Duan, Z., Guo, S., Sun, X."Role of the heme oxygenase/carbon monoxide pathway in the pathogenesis and prevention of hepatic encephalopathy". Molecular Medicine Reports 8, no. 1 (2013): 67-74. https://doi.org/10.3892/mmr.2013.1472
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