Hepatic Expression of Nitric Oxide Isoforms and Serum Nitrites/Nitrates in Chronic Hepatitis C With or Without Schistosomiasis
Keywords:
Inducible nitric oxide synthase, Endothelial nitric oxide synthase, Chronic hepatitis C, Schistosomiasis, Immunohistochemistry.
Abstract
Background: Role of nitric oxide (NO) in pathogenesis of chronic viral hepatitis is not fully understood but it seemsthat its overproduction is responsible for the pathological changes under inflammatory conditions.Methods: This study was undertaken to evaluate hepatic expression of inducible NO synthase (iNOS) and endothelial NO synthase (eNOS) as well as assessment ofserum nitrates/nitrites representative to NO releasein Egyptian chronic hepatitis C (CHC) with or without schistosomiasis and their relation to histopathologyin 72 core liver biopsies from CHC patients. Hepatic sections were immunohistochemically stained by antibodies of iNOS and eNOS.Results: In control livers, iNOS was detected in hepatocytes and localized mainly inperiportal zone of liver acinus, while eNOS was uniformly distributed in hepatocytes as well as in sinusoidaland vascular endothelium. In diseased livers, both isoformsoverexpressed in a diffuse distribution pattern, eNOS translocated to hepatocytic nuclei, and iNOS consistently labeled portal tract inflammatory cells. Over expression of iNOS and serum level of NO correlated with hepatitis activity and fibrosis, while that of eNOS correlated with Schistosomal coinfection.Conclusions: Chronic hepatitis C is accompanied by significant iNOS up-regulated expression and increased serum level of NO that reflect disease severity. Schistosomal coinfection can be considered as a risk factor for haemodynamic disturbance. Further studies are required to determine whether iNOS inhibitors could be useful in reducing liver disease severity and improve the benefits of antiviral therapies.References
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29- Iwakiri Y, Kim MY. Nitric oxide in liver diseases.Trends in Pharmacological sciences 2015;36(8):524-536.
30- Sanz-Cameno P, Medina J, Garcia-Buey L, Garcia-Sanchez A, Borque MJ, Martin-Vilchez S, et al. Enhanced intrahepatic inducible nitric oxide synthase expression and nitrotyrosine accumulation in primary biliary cirrhosis and autoimmune hepatitis. J Hepatol 2002; 37: 723-9.
31- Machida k, Cheng k, Sung V, Lee kj, Levine A, Lai M. Hepatitis C virus infection activates the immunologic (Type II) isoform of nitric oxide synthase and thereby enhances DNA damage and mutations of cellular genes. J Virol 2004; 78: 8835–8843.
32- Parvu AE, Negrean V, Manea LP, Cosma A, Draghici A, Uifalean A, et al.Nitric oxide in patients with chronic liver diseases. Romannian J Gastroenterol 2005;14(3):225-230.
33- Arkenau HT, Stichtenoth DO, Frolich JC, Manns MP, Boker KH. Elevated nitric oxide levels in patients with chronic liverdisease and cirrhosis correlate with disease stage and parameters of hyperdynamic circulation.Z Gastroenterol.2002; 40(11):907-920.
34- El-Sherif AM, Abou-Shady MA, Al-Bahrawy AM, Bakr RM, Hosny AM.Nitric oxide levels in chronic liver disease patients with and withoutoesophagealvarices.HepatolInt 2008;2:341-345.
35- Deshmukh A, More UK, Tilak MA, Sontakke AN, Deshmukh UD. Role of Nitric Oxide in liver cirrhosis. Indian J of basic and applied medical res 2013; 2(6):546-550.
36- McNaughton L, Puttagunta L, Martinez-Cuesta M, Kneteman N, Mayers I, Moqbel R, et al. Distribution of nitric oxide synthase in normal and cirrhotic human liver. ProcNatlAcadSci2002; 99:17161-6.
37- Feng Y, Venema VJ, Venema RC, Tsai N, Caldwell RB.VEGF induces nuclear translocation of Flk-1/KDR, endothelial nitric oxide synthase, and caveolin-1 in vascular endothelial cells. BiochemBiophys Res Commun 1999; 256: 192-197.
38- Harada K, Shiota G, Kawasaki H. Transforming growth factor-alpha and epidermal growth factor receptor in chronic liver disease and hepatocellular carcinoma. Liver 1999;19: 318-325.
39- Oliveira SDS, Silva RC, Silva CLM. Endothelial P2X7 receptors’ expression is reduced by schistosomiasis. Purinergic Signaling.2013; 9:81-89.
2- Mohamoud YA, Mumtaz GR, Rimo S, Miller D, Abu Raddad LJ. The epidemiology of hepatitis C in Egypt: a systemic review and data synthesis. Infect Dis 2013; 24(13):288-309.
3- Ibrahim M, Gomaa W, Ibrahim Y, El Hadad H, Shatat M, Abdel Aleem A, et al. Nitric oxide levels and sustained virological response to pegylated-interferon alpha2a plus ribavirin in chronic HCV genotype 4 hepatitis: a prospective study. J Gastrointesin LiverDis 2010; 19(4):387-392.
4- Barakat SMR. Epidemiology of Schistosomiasis in Egypt: Travel through time:review. J Advanced Research 2013; 4(5):425-432.
5- World Health Organization (WHO). Schistosomiasis. http://www.who.int/schistosomiasis/en/.Accessed2011; 23 Feb 2012.
6- Strickland GT. Liver disease in Egypt: hepatitis C superseded schistosomiasis as a result of iatrogenic and biological factors. Hepatol. 2006; 34(5):915-937.
7- Diesen DL, Kuo PC.Nitric oxide and redox regulation in the liver: Part I. General considerations and redox biology in hepatitis. J SurgRes 2010;162(1): 95-109
8- Tache DE, Stanciulescu CE, Banit IM, Purcaru SO, Andrei AM, Comanescu V,et al. Inducible nitric oxide synthase expression (iNOS) in chronic viral hepatitis and its correlation with liver fibrosis. Rom J MorpholEmbryol 2014; 55(2):539-543.
9- Antonescu A, Muresan M, Micle O, Dobjanschi L,Vicas L, Dorofteiu M. Serum oxidative stress parameters and homocysteine levels in patients with renal transplant.Farmacia.LVI 2008; (3):352-358.
10- Vince AR, Hayes MA, Jefferson BJ, Stalker MJ. Hepatic injury correlates with apoptosis, regeneration, and nitric oxide synthase expression in canine chronic liver disease. Veterinary Pathology 2013; 51(5):932-945.
11- Mohammed NA, Abd El-Aleem S, Appleton I, Maklouf MM, Said M, McMahon RF. Expression of nitric oxide synthase isoforms in human liver cirrhosis. J Pathol 2003; 200 (5): 647-655.
12- Kim HS, Jung YY, Do SI. Hepatic inducible nitric oxide synthase expression increases upon exposure to hypergravity. Braz J Med Biol Res 2014; 47(11):940-946
13- Parola M, Robino G. Oxidative stress –related molecules and liver fibrosis. J Hepatol 2001; 35(2):297-306.
14- Ahn B, Han BS, Kim DJ, Ohshima H. Immunohistochemical localization of inducible nitric oxide synthase and 3-nitrotyrosine in rat liver tumors induced by N-nitrosodiethylamine. Carcinogenesis 1999; 20:1337-1344.
15- Atik E, Onlen Y, Savas L, Doran F. Inducible nitric oxide synthase and histopathological correlation in chronic viral hepatitis. Int J Infect Dis 2008; 12(1):12-15.
16- Kim PK, Zamora R, Petrosko P, Billiar TR. The regulatory role of nitric oxide in apoptosis. IntImmunopharmacol 2001; 1(8): 1421-1441.
17- Hon WM, Lee KH, Khoo HE. Nitric oxide in liver diseases: friend, foe, or just passerby? Ann NY AcadSci 2002; 962: 275-95.
18- Wu J, Wang K, Han LY, Fan YC. Increased expression of inducible nitric oxide synthase in chronic hepatitis B patients is correlated with histopathological grading and staging. Zhonghua Shi Yan He Lin Chuang Bing Du XueZaZhi2008;22(1):57-59.
19- Leung TM, Fung ML, Liong EC, Lau TYH,Nanji AA, Tipoe GL. Role of nitric oxide in the regulation of fibrogenic factors in experimental fibrosis in mice. HistolHistopathol 2011;26:201-211.
20- Hu LS, George J, WangJH. Current concepts on the role of nitric oxide in portal hypertension. World J Gastroenterol2013;19(11):1707-1717.
21- Maruyama H, Yokosuka O. Pathophysiology of portal hypertension and esophageal varices. International J Hepatol2012;Article ID 895787,7 pages.
22- Chang CC, Huang HC, Wang SS, Lee FY, Chang FY, Lin HC, et al. Involvement of constitutive nitric oxide synthase in the portal-systemic collaterals of portal hypertensive rats.J Chinese Medical Association 2005;68(6):245-249.
23- Hassan MI, Kassim SK, Ali HS, Sayed El-DA, Khalifa A. Evaluation of nitric oxide (NO) levels in hepatitis C virus (HCV) infection: relationship to schistosomiasis and liver cirrhosis among Egyptian patients. Dis Markers 2002; 18(3): 137-42.
24- Reitaman, S. and Frankel, S. A colourimetric method for the determination of serum glutamic oxaloacetic and glutamic pyruvic transaminases. Am J ClinPathol1957; 28: 56-63.
25- Demerdash ZA, Mohamed SH, Shaker ZA, Hassan SI, El Attar GM, Saad-El Din A, et al. Detection of circulating schistosoma antigens in serum and urine of Schistosomiasis patients and assessment of cure by a monoclonal antibody. J Egypt SocParasitol 1995; 25:471-484.
26- Engvall E, Perlman P. Enzyme linked immunosorbent assay (ELISA). Quantitative assay of immunoglobulin G. J Immunochem 1971;8: 871-874.
27- Saber MA, Omar M, Badawi H. Comparative studies in serological diagnosis of hepatitis C virus(HCV) infection. J HepGastInf Dis1995; 3: 47-51.
28- Brunt EM. Grading and staging the histopathological lesions of chronic hepatitis: The knodell histologic activity index and beyond. Hepatology 2000; 13(1): 241-246.
29- Iwakiri Y, Kim MY. Nitric oxide in liver diseases.Trends in Pharmacological sciences 2015;36(8):524-536.
30- Sanz-Cameno P, Medina J, Garcia-Buey L, Garcia-Sanchez A, Borque MJ, Martin-Vilchez S, et al. Enhanced intrahepatic inducible nitric oxide synthase expression and nitrotyrosine accumulation in primary biliary cirrhosis and autoimmune hepatitis. J Hepatol 2002; 37: 723-9.
31- Machida k, Cheng k, Sung V, Lee kj, Levine A, Lai M. Hepatitis C virus infection activates the immunologic (Type II) isoform of nitric oxide synthase and thereby enhances DNA damage and mutations of cellular genes. J Virol 2004; 78: 8835–8843.
32- Parvu AE, Negrean V, Manea LP, Cosma A, Draghici A, Uifalean A, et al.Nitric oxide in patients with chronic liver diseases. Romannian J Gastroenterol 2005;14(3):225-230.
33- Arkenau HT, Stichtenoth DO, Frolich JC, Manns MP, Boker KH. Elevated nitric oxide levels in patients with chronic liverdisease and cirrhosis correlate with disease stage and parameters of hyperdynamic circulation.Z Gastroenterol.2002; 40(11):907-920.
34- El-Sherif AM, Abou-Shady MA, Al-Bahrawy AM, Bakr RM, Hosny AM.Nitric oxide levels in chronic liver disease patients with and withoutoesophagealvarices.HepatolInt 2008;2:341-345.
35- Deshmukh A, More UK, Tilak MA, Sontakke AN, Deshmukh UD. Role of Nitric Oxide in liver cirrhosis. Indian J of basic and applied medical res 2013; 2(6):546-550.
36- McNaughton L, Puttagunta L, Martinez-Cuesta M, Kneteman N, Mayers I, Moqbel R, et al. Distribution of nitric oxide synthase in normal and cirrhotic human liver. ProcNatlAcadSci2002; 99:17161-6.
37- Feng Y, Venema VJ, Venema RC, Tsai N, Caldwell RB.VEGF induces nuclear translocation of Flk-1/KDR, endothelial nitric oxide synthase, and caveolin-1 in vascular endothelial cells. BiochemBiophys Res Commun 1999; 256: 192-197.
38- Harada K, Shiota G, Kawasaki H. Transforming growth factor-alpha and epidermal growth factor receptor in chronic liver disease and hepatocellular carcinoma. Liver 1999;19: 318-325.
39- Oliveira SDS, Silva RC, Silva CLM. Endothelial P2X7 receptors’ expression is reduced by schistosomiasis. Purinergic Signaling.2013; 9:81-89.
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2016-10-11
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