Manganese Superoxide Dismutase Therapy in a Murine Hepatitis-Associated Injury

Abstract

We aim to test the hypothesis that Con A-induced hepatitis and cell death can be prevented by the administration of the MnSOD mimetic MnTBAP. Male C57 mice were divided into 3 groups, 1) pretreated with MnTBAP (30 mg/kg) for 2 days and then Concanavalin A (Con A) (15 mg/kg); 2) pretreated with saline for 2 days and then Con A (15 mg/kg); 3) was the control treated with saline for 3 days. Extensive hepatic necrosis, with a significant increase in apoptosis, lipid peroxidation and decreased MnSOD enzymatic activity was found in the hepatic tissue of Con A-treated mice with significantly attenuation of all factors by pretreatment with MnTBAP. MnTBAP protected hepatocytes from Con A-induced hepatic injury with less degree of liver inflammation—ConA + MnTBAP (2.1 ± 0.4) vs. Con A (2.6 ± 0.3)—and significantly less cell death (1.2 ± 0.3 vs. 2.7 ± 0.4, p = 0.03). MnSOD supplementation attenuated the oxidative-induced stress effects of Con A-induced injury and the protective effects of MnSOD supplementation against Con A-induced hepatitis could be through its anti-oxidative properties. Further evaluation of MnSOD manipulation could have the potential to prevent ongoing hepatic injury in hepatitis.

Share and Cite:

Y. Li, N. Reuter, X. Li and R. Martin, "Manganese Superoxide Dismutase Therapy in a Murine Hepatitis-Associated Injury," Journal of Cancer Therapy, Vol. 2 No. 3, 2011, pp. 431-440. doi: 10.4236/jct.2011.23058.

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1] D. Lavanchy, “Hepatitis B Virus Epidemiology, Disease Burden, Treatment, and Current and Emerging Prevention and Control Measures,” Journal of Viral Hepatitis, Vol. 11, No. 2, 2004, pp. 97-107. doi:10.1046/j.1365-2893.2003.00487.x
[2] W. M. Lee, “Hepatitis B Virus Infection,” The New England Journal of Medicine, Vol. 337, 1997, pp. 1733-1745. doi:10.1056/NEJM199712113372406
[3] A. Wasley and M. J. Alter, “Epidemiology of Hepatitis C: Geographic Differences and Temporal Trends,” Seminars in Liver Disease, Vol. 20, 2000, pp. 1-16. doi:10.1055/s-2000-9506
[4] A. K. Singal and B. S. Anand, “Mechanisms of Synergy between Alcohol and Hepatitis C Virus,” Journal of Clinical Gastroenterology, Vol. 41, No. 8, 2007, pp. 761-772. doi:10.1097/MCG.0b013e3180381584
[5] M. Levrero, “Viral Hepatitis and Liver Cancer: The Case of Hepatitis C,” Oncogene, Vol. 25, 2006, pp. 3834-3847. doi:10.1038/sj.onc.1209562
[6] S. Chitturi and G. C. Farrell, “Etiopathogenesis of Nonalcoholic Steatohepatitis,” Seminars in Liver Disease, Vol. 21, No. 1, 2001, pp. 27-41. doi:10.1055/s-2001-12927
[7] M. Vidali, S. F. Stewart and E. Albano, “Interplay between Oxidative Stress and Immunity in the Progression of Alcohol-Mediated Liver Injury,” Trends in Molecular Medicine, Vol. 14, No. 2, 2008, pp. 63-71. doi:10.1016/j.molmed.2007.12.005
[8] E. Albano, “Alcohol, Oxidative Stress and Free Radical Damage,” Proceedings of the Nutrition Society, Vol. 65, No. 3, 2006, pp. 278-290. doi:10.1079/PNS2006496
[9] J. Choi and J. H. Ou, “Mechanisms of Liver Injury. III. Oxidative Stress in the Pathogenesis of Hepatitis C Virus,” American Journal of Physiology—Gastrointestinal and Liver Physiology, Vol. 290, No. 5, 2006, pp. G847-G851. doi:10.1152/ajpgi.00522.2005
[10] D. Hutter and J. J. Greene, “Influence of the Cellular Redox State on NF-kappaB-Regulated Gene Expression,” Journal of Cellular Physiology, Vol. 183, No. 1, 2000, pp. 45-52. doi:10.1002/(SICI)1097-4652(200004)183:1<45::AID-JCP6>3.0.CO;2-P
[11] H. Bartsch and J. Nair, “Accumulation of Lipid Peroxidation-Derived DNA Lesions: Potential Lead Markers for Chemoprevention of Inflammation-Driven Malignancies,” Mutation Research, Vol. 591, No. 1-2, 2005, pp. 34-44. doi:10.1016/j.mrfmmm.2005.04.013
[12] W. E. Stehbens, “Oxidative Stress, Toxic Hepatitis, and Antioxidants with Particular Emphasis on Zinc,” Experimental and Molecular Pathology, Vol. 75, No. 3, 2003, pp. 265-276. doi:10.1016/S0014-4800(03)00097-2
[13] L. W. Oberley, “Mechanism of the Tumor Suppressive Effect of MnSOD Overexpression,” Biomedicine and Pharmacotherapy, Vol. 59, No. 4, 2005, pp. 143-148. doi:10.1016/j.biopha.2005.03.006
[14] R. C. Martin, Q. Liu, J. M. Wo, M. B. Ray and Y. Li, “Chemoprevention of Carcinogenic Progression to Esophageal Adenocarcinoma by the Manganese Superoxide Dismutase Supplementation,” Clinical Cancer Research, Vol. 13, 2007, pp. 5176-5182. doi:10.1158/1078-0432.CCR-07-1152
[15] G. Tiegs, J. Hentschel, and A. Wendel, “A T Cell-Dependent Experimental Liver Injury in Mice Inducible by Concanavalin A,” The Journal of Clinical Investigation, Vol. 90, No. 1, 1992, pp. 196-203. doi:10.1172/JCI115836
[16] H. Mizuhara, M. Uno, N. Seki, M. Yamashita, M. Yamaoka, T. Ogawa, K. Kaneda, T. Fujii, H. Senoh and H. Fujiwara, “Critical Involvement of Interferon Gamma in the Pathogenesis of T-Cell Activation-Associated Hepatitis and Regulatory Mechanisms of Interleukin-6 for the Manifestations of Hepatitis,” Hepatology, Vol. 23, 1996, pp. 1608-1615.
[17] F. Gantner, M. Leist, S. Jilg, P. G. Germann, M. A. Freudenberg and G. Tiegs, “Tumor Necrosis Factor-Induced Hepatic DNA Fragmentation as an Early Marker of T Cell-Dependent Liver Injury in Mice,” Gastroenterology, Vol. 109, 1995, pp. 166-176. doi:10.1016/0016-5085(95)90282-1
[18] F. Gantner, M. Leist, A. W. Lohse, P. G. Germann and G. Tiegs, “Concanavalin A-Induced T-Cell-Mediated Hepatic Injury in Mice: The Role of Tumor Necrosis Factor,” Hepatology, Vol. 21, 1995, pp. 190-198.
[19] R. Bruck, H. Aeed, E. Brazovsky, T. Noor and R. Hershkoviz, “Allicin, the Active Component of Garlic, Prevents Immune-Mediated, Concanavalin A-Induced Hepatic Injury in Mice,” Liver International, Vol. 25, No. 3, 2005, pp. 613-621. doi:10.1111/j.1478-3231.2005.01050.x
[20] H. Shirin, H. Aeed, A. Alin, Z. Matas, M. Kirchner, E. Brazowski, I. Goldiner and R. Bruck, “Inhibition of Immune-Mediated Concanavalin A-Induced Liver Damage by Free-Radical Scavengers,” Digestive Diseases and Sciences, Vol. 55, No. 2, 2009, pp. 268-275. doi:10.1007/s10620-009-0732-5
[21] J. K. Kolls and A. Linden, “Interleukin-17 Family Members and Inflammation,” Immunity, Vol. 21, No. 4, 2004, pp. 467-476. doi:10.1016/j.immuni.2004.08.018
[22] D. V. Jovanovic, J. A. Di Battista, J. Martel-Pelletier, F. C. Jolicoeur, Y. He, M. Zhang, F. Mineau and J. P. Pelletier, “IL-17 Stimulates the Production and Expression of Proinflammatory Cytokines, IL-Beta and TNF- Alpha, by Human Macrophages,” Journal of Immunology, Vol. 160, 1998, pp. 3513-3521.
[23] Z. Yao, W. C. Fanslow, M. F. Seldin, A. M. Rousseau, S. L. Painter, M. R. Comeau, J. I. Cohen and M. K. Spriggs, “Herpesvirus Saimiri Encodes a New Cytokine, IL-17, Which Binds to a Novel Cytokine Receptor,” Immunity, Vol. 3, No. 6, 1995, pp. 811-821. doi:10.1016/1074-7613(95)90070-5
[24] H. Park, Z. Li, X. O. Yang, S. H. Chang, R. Nurieva, Y. H. Wang, Y. Wang, L. Hood, Z. Zhu, Q. Tian and C. Dong, “A Distinct Lineage of CD4 T Cells Regulates Tissue Inflammation by Producing Interleukin 17,” Nature Immunology, Vol. 6, 2005, pp. 1133-1141. doi:10.1038/ni1261
[25] J. Schumann, D. Wolf, A. Pahl, K. Brune, T. Papadopoulos, N. van Rooijen and G. Tiegs, “Importance of Kupffer Cells for T-Cell-Dependent Liver Injury in Mice,” American Journal of Pathology, Vol. 157, No. 5, 2000, pp. 1671-1683. doi:10.1016/S0002-9440(10)64804-3
[26] C. S. Bonder, M. N. Ajuebor, L. D. Zbytnuik, P. Kubes and M. G. Swain, “Essential Role for Neutrophil Recruitment to the Liver in Concanavalin A-Induced Hepatitis,” Journal of Immunology, Vol. 172, 2004, pp. 45-53.
[27] K. Takeda, Y. Hayakawa, L. Van Kaer, H. Matsuda, H. Yagita and K. Okumura, “Critical Contribution of Liver Natural Killer T Cells to a Murine Model of Hepatitis,” Proceedings of the National Academy of Sciences of the United States of America, Vol. 97, No. 10, 2000, pp. 5498-5503. doi:10.1073/pnas.040566697
[28] G. Tiegs, “T cells, NKT Cells, and NK Cells in an Experimental Model of Autoimmune Hepatitis,” In: M. E. Gershwin, J. M. Vierling and M. P. Manns, Eds., Liver Immunology, Hanley & Belfus Inc; Philadelphia, 2003, pp. 171-183.
[29] G. Beldi, Y. Wu, Y. Banz, M. Nowak, L. Miller, K. Enjyoji, A. Haschemi, G. G. Yegutkin, D. Candinas, M. Exley and S. C. Robson, “Natural Killer T Cell Dysfunction in CD39-Null Mice Protects against Concanavalin A-Induced Hepatitis,” Hepatology, Vol. 48, No. 3, 2008, pp. 841-852. doi:10.1002/hep.22401
[30] T. Kawamura, K. Takeda, H. Kaneda, H. Matsumoto, Y. Hayakawa, D. H. Raulet, Y. Ikarashi, M. Kronenberg, H. Yagita, K. Kinoshita, T. Abo, K. Okumura and M. J. Smyth, “NKG2A Inhibits Invariant NKT Cell Activation in Hepatic Injury,” Journal of Immunology, Vol. 182, No. 1, 2009, pp. 250-258.
[31] W. Jiang, R. Sun, R. Zhou, H. Wei and Z. Tian, “TLR-9 Activation Aggravates Concanavalin A-Induced Hepatitis via Promoting Accumulation and Activation of Liver CD4+ NKT Cells,” Journal of Immunology, Vol. 182, No. 6, 2009, pp. 3768-3774. doi:10.4049/jimmunol.0800973
[32] T. Nagata, L. McKinley, J. J. Peschon, J. F. Alcorn, S. J. Aujla and J. K. Kolls, “Requirement of IL-17RA in Con A Induced Hepatitis and Negative Regulation of IL-17 Production in Mouse T Cells,” Journal of Immunology, Vol. 181, No. 11, 2008, pp. 7473-7479.
[33] H. Nakashima, M. Kinoshita, M. Nakashima, Y. Habu, S. Shono, T. Uchida, N. Shinomiya and S. Seki, “Superoxide Produced by Kupffer Cells Is an Essential Effector in Concanavalin A-Induced Hepatitis in Mice,” Hepatology, Vol. 48, No. 6, 2008, pp. 1979-1988. doi:10.1002/hep.22561
[34] H. Ohshima, M. Tatemichi and T. Sawa, “Chemical Basis of Inflammation-Induced Carcinogenesis,” Archives of Biochemistry and Biophysics, Vol. 417, No. 1, 2003, pp. 3-11. doi:10.1016/S0003-9861(03)00283-2
[35] M. Karin and F. R. Greten, “NF-kappaB: Linking Infla- mmation and Immunity to Cancer Development and Progression,” Nature Reviews Immunology, Vol. 5, 2005, pp. 749-759. doi:10.1038/nri1703
[36] H. Kamata, S. Honda, S. Maeda, L. Chang, H. Hirata and M. Karin, “Reactive Oxygen Species Promote TNFalpha-Induced Death and Sustained JNK Activation by Inhibiting MAP Kinase Phosphatases,” Cell, Vol. 120, No. 5, 2005, pp. 649-661. doi:10.1016/j.cell.2004.12.041
[37] S. Kawanishi, Y. Hiraku, S. Pinlaor and N. Ma, “Oxidative and Nitrative DNA Damage in Animals and Patients with Inflammatory Diseases in Relation to Inflammation-Related Carcinogenesis,” The Journal of Biological Chemistry, Vol. 387, No. 4, 2006, pp. 365-372. doi:10.1515/BC.2006.049
[38] K. Koike, “Molecular Basis of Hepatitis C Virus-Associated Hepatocarcinogenesis: Lessons from Animal Model Studies,” Clinical Gastroenterology and Hepatology, Vol. 3, No. 2, 2005, pp. S132-S135. doi:10.1016/S1542-3565(05)00700-7
[39] X. W. Wang, S. P. Hussain, T. I. Huo, C. G. Wu, M. Forgues, L. J. Hofseth, C. Brechot and C. C. Harris, “Molecular Pathogenesis of Human Hepatocellular Carcinoma,” Toxicology, Vols. 181-182, 2002, pp. 43-47. doi:10.1016/S0300-483X(02)00253-6
[40] R. C. Martin, Q. Liu, J. M. Wo, M. B. Ray and Y. Li, “Chemoprevention of Carcinogenic Progression to Esophageal Adenocarcinoma by the Manganese Superoxide Dismutase Supplementation,” Clinical Cancer Research, Vol. 13, 2007, pp. 5176-5182. doi:10.1158/1078-0432.CCR-07-1152
[41] M. Patel and B. J. Day, “Metalloporphyrin Class of Therapeutic Catalytic Antioxidants,” Trends in Pharmacological Sciences, Vol. 20, No. 9, 1999, pp. 359-364. doi:10.1016/S0165-6147(99)01336-X
[42] S. Cuzzocrea, B. Zingarelli, G. Costantino and A. P. Caputi, “Beneficial Effects of Mn(III)Tetrakis (4-benzoic acid) Porphyrin (MnTBAP), a Superoxide Dismutase Mimetic, in Carrageenan-Induced Pleurisy,” Free Radical Biology & Medicine, Vol. 26, No. 1-2, 1999, pp. 25-33. doi:10.1016/S0891-5849(98)00142-7
[43] A. G. Estevez, N. Spear, S. M. Manuel, R. Radi, C. E. Henderson, L. Barbeito and J. S. Beckman, “Nitric Oxide and Superoxide Contribute to Motor Neuron Apoptosis Induced by Trophic Factor Deprivation,” The Journal of Neuroscience, Vol. 18, No. 3, 1998, pp. 923-931.
[44] B. J. Day, I. Fridovich and J. D. Crapo, “Manganic Porphyrins Possess Catalase Activity and Protect Endothelial Cells against Hydrogen Peroxide-Mediated Injury,” Archives of Biochemistry and Biophysics, Vol. 347, No. 2, 1997, pp. 256-262. doi:10.1006/abbi.1997.0341

Copyright © 2024 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.