Annals of the Russian academy of medical sciencesAnnals of the Russian academy of medical sciencesВестник Российской академии медицинских наук0869-60472414-3545"Paediatrician" Publishers LLC21510.15690/vramn.v68i2.549PHYSIOLOGY: CURRENT ISSUESАКТУАЛЬНЫЕ ВОПРОСЫ ФИЗИОЛОГИИINTRAORGANIC AND INTRATISSUE MECHANISMS OF PROTECTIVE ACTION OF ACTIVATED KUPFFER CELLS ON HEPATOCYTESВНУТРИОРГАННЫЕ И ВНУТРИТКАНЕВЫЕ МЕХАНИЗМЫ РЕГУЛЯТОРНЫХ ВОЗДЕЙСТВИЙ КЛЕТОК КУПФЕРА НА ГЕПАТОЦИТЫElbakidzeG. M.ЭлбакидзеГ. М.
Russian Federation

PhD, RANS academician, Director of Biomedical Center, Association for World Laboratory Address: 125057, Moscow, Leningradskii Prospect, 71-128; tel.: (499) 198-72-28

gmelbakidze@hotmail.comMedentsevA. G.МеденцевА. Г.
Russian Federation

PhD., Head of the Laboratory of Microorganism Adaptation, Institute of Biochemistry and Physiology of Microorganisms named after G.K. Skryabin RAS Address: 142290, Moscow region, Pushchino, Nauki Avenue, 5; tel.: (495) 956-33-70

medentsev-ag@rambler.ruAssociation for World Laboratory, Biomedical Center, Moscow, Russian FederationМедико-биологический центр Ассоциации содействия международному центру научной культуры ― «Всемирная лаборатория», Москва, Российская ФедерацияG.K. Skryabin Institute of Biochemistry and Physiology of Microorganisms, RAS, Puschino, Moscow Region, Russian FederationИнститут биохимии и физиологии микроорганизмов им. Г.К. Скрябина РАН, Московская область, Пущино, Российская Федерация22022013682Vestnik Rossiiskoi akademii medetsinskikh nauk / Annals of the Russian academy of medical sciencesВестник Российской академии медицинских наук505507082015Copyright ©; 1970, "Paediatrician" Publishers LLCCopyright ©; 1970, Издательство "Педиатръ"1970"Paediatrician" Publishers LLCИздательство "Педиатръ"https://vestnikramn.spr-journal.ru/jour/about/submissionshttps://vestnikramn.spr-journal.ru/jour/article/view/215

Endotoxine activated Kupffer cells release into the intercellular space several mediators which act directly on hepatocytes as well as via stellet cells. In both cases Kupffer cells downregulate hepatocytes as a part of paracrine system. However, downregulated part of liver parenchyma might be extended by several mechanisms. The first one is release of vasoconstrictors from activated Kupffer cells which stimulate stellet cells contraction. This effect may also be achieved by formation of hypermetabolic focuses by Kupffer cells mediators with further activation of hepatocyte–hepatocyte interactions based on the principle of cell competition for oxygen in the intercellular space. Regulatory influence of activated Kupffer cells may be spread in liver parenchyma with participation of the mechanism of intratissue hepatocyte–hepatocyte interactions which also realize tissue stress reaction.

Активированные эндотоксином клетки Купфера выделяют в межклеточное пространство медиаторы, действующие на гепатоциты как прямо, так и опосредованно, при участии звездчатых клеток. В обоих случаях клетки Купфера оказывают свое регуляторное влияние паракринно. Однако регулируемая область паренхимы печени может быть увеличенна путем реализации нескольких механизмов. Одним из них является выброс вазоконстрикторов из активированных клеток Купфера, стимулирующих сократительную способность звездчатых клеток. Этот эффект может быть достигнут также путем формирования очагов гиперметаболизма под действием медиаторов клеток Купфера с последующей активацией гепатоцит–гепатоцитарных взаимодействий, основанных на принципе конкурирования клеток за кислород в межклеточном пространстве. Регуляторное влияние активированных клеток Купфера может распространяться в паренхиме печени и с использованием механизма внутритканевых гепатоцит–гепатоцитарных взаимодействий, реализующих реакцию тканевого стресса.

endotoxineKupffer cellshepatocytestissue stresshypermetabolismэндотоксинклетки Купферагепатоцитытканевый стрессгиперметаболизм1. Decker К. Biologically active products of stimulated liver macrophages (Kupffer cells). Eur. J. Biochem. 1990; 192: 245–261.2. Mayanskii D.N. Khronicheskoe vospalenie [Chronic Inflammation]. Moscow, Meditsina, 1991. 272 p.3. Kmieć Z. Cooperation of liver cells in health and disease. Adv. Anat. Embryol. Cell Biol. 2001; 161: III–XIII.4. He Q., Kim J., Sharma R.P. Fumonisin B1 hepatotoxicity in mice is attenuated by depletion of Kupffer cells by gadolinium chloride. Toxicology. 2005; 207 (1): 137–147.5. Ketlinskii S.A, Simbirtsev A.S, Vorob'ev A.A. Endogennye immunomodulyatory [Endogenous Immunomodulators]. St. Petersburg, Meditsina, 1992. 187 p.6. Freidlin I.S. Paracrine and autocrine mechanisms of cytokine immunoregulation. Immunologiya = Immunology. 2001; (5): 4–7.7. Meltzer M.S. Macrophage activation for tumor cytotoxicity: characterization of priming and trigger signals during lymphokine activation. J. Immunol. 1981; 127 (1): 179–183.8. Wardle E.N. Kupffer cells and their functions. Liver. 1987; 7 (2): 63–75.9. Ketlinskii S.A.Simbirtsev A.S. Tsitokiny [Cytokines]. St. Petersburg, Foliant, 2008. 550 p.10. Tsukamoto H., Matsuoka M. Release of active TGFβ1 from Kupffer cells isolated from rats with alcoholic liver fibrosis: a possible paracrine mechanism of liver fibrogenesis. Cytokine. 1989; 1 (1): 134–134.11. Dieter P., Schulze-Specking A., Decker K. Release of lysosomal enzymes is not correlated with superoxide and prostaglandin production by stimulated rat Kupffer cells in primary culture. J. Hepatology. 1988; 6 (Isse 2): 167–174.12. Harbrecht B.G., Billiar T.R. The role of nitric oxide in Kupffer cell-hepatocyte interactions. Shock. 1995; 3: 79–87.13. McCallum R.E. Hepatocyte-Kupffer cell interactions in the inhibition of hepatic gluconeogenesis by bacterial endotoxin. Progr. Clin. Biol. Res.1981; 62: 99–113.14. Kuiper J., Zijlstra F.J., Kamps J.A.A.M., Van Berkel Th.J.C. Biochem. Biophys. Acta. 1988; 959: 143–152.15. Ouwendijk R.J.Th., Zijlstra F.J., Broek A.M.W.C. van den, Brower А., Wilson J.H.P., Vincent J.E.,Comparison of the production of eicosanoids by human and rat peritoneal macrophages and rat Kupffer cells. Prostaglandins. 1988; 35 (3): 437–446.16. Iwai M., Jungermann K. Leukotrienes increase glucose and lactate output and decrease flow in perfused rat liver. Biochem. Biophys. Res. Commun. 1988; 151 (1): 283–290.17. Rolfe M., James N.H., Roberts R.A. Tumour necrosis factor alpha (TNF alpha) suppresses apoptosis and induces DNA synthesis in rodent hepatocytes: a mediator of the hepatocarcinogenicity of peroxisome proliferators. Carcinogenesis. 1997; 18 (11): 2277–2280.18. Nazia S., Selzner M., Odermatt B. Tian Y., v. Rooijen N., Clavien P.–A. ICAM-1 triggers liver regeneration through leukocyte recruitment and Kupffer cell-dependent release of TNF-α/IL-6 in mice. Gastroenterology. 2003; 124 (3): 692–700.19. Holden P.R. Hasmall S.C., James N.H. , West D.R., Brindle R.D, Gonzalez F.J, Peters J.M, Roberts R.A.. Tumour necrosis factor alpha (TNFalpha): role in suppression of apoptosis by the peroxisome proliferator nafenopin. Cell. Mol. Biol. 2000; 46 (1): 29–39.20. Makogon N.V., Korneitchuk A.N., Lushnikova I.V., Alexeyeva I.N. Effects of exogenous leukotrienes B4 and C4 on the viability of cultured rat hepatocytes. Acta Physiol. Pharmacol. Bulg. 2000; 25 (3–4): 87–91.21. Maher J.J. Interactions between hepatic stellate cells and the immune system. Semin. Liver Dis. 2001; 21 (3): 417–426.22. Yokoyama Y., Nimura Y., Nagino M., Bland K.I., Chaudry I.H. Role of thromboxane in producing hepatic injury during hepatic stress. Arch. Surg. 2005; 140 (8): 801–807.23. Hoek J. B., Pastorino J. G. Ethanol, oxidative stress, and cytokine-induced liver cell injury. Alcohol. 2002; 27 (1): 63–68.24. Roberts R.A., Ganey P.E., Ju C., Kamendulis, L.M., Rusyn, I., Klaunig, J. E. Role of the Kupffer cell in mediating hepatic toxicity and carcinogenesis. Toxicol. Sci. 2007; 96 (1): 2–15.25. Winwood P.J., Arthur M.J. Kupffer cells: their activation and role in animal models of liver injury and human liver disease. Semin. Liver Dis. 1993;13 (1): 50–59.26. Kutina S.I., Zubakhin AA. Resistance of liver damage when stimulated macrophages SSI4 drugs and different classes. Byull. eksperim. biol. med. = Bulletin of experimental biology and medicine. 2001; (6): 620–622.27. Elbakidze G.M. Mechanisms of the protective effect of endotoxin-activated Kupffer cells in the hepatocytes. Vestn. RAMN = Annals of RAMS. 2012; (6): in print.28. Billiar T.R., Curran R.D., Williams D.L., Kispert P.H. Liver nonparenhimal cells are stimulated to provide interleukin-6 for production of acute phase response in endotoxemia but not in remote localized inflammation. Arch. Surg. 1992; 127: 31–37.29. Kmiec Z., Hughes R. D., Moore K.P. Sheron N., Gove D., Nouri-Aria T., Williams R. Effect of supernatants from Kupffer cells stimulated with galactosamine and endotoxin on the function of isolated rat hepatocytes. Hepatogastroenterology. 1993; 40: 259–261.30. Callery M.P., Mangino, M.J., Flye M.W. Kupffer cell prostaglandin-E2 production is amplified during hepatic regeneration. Hepatology. 1991; 14 (2): 368-372.31. Fennekohl A., Schieferdecker H.L., Jungermann K., Püschel G.P. Differential expression of prostanoid receptors in hepatocytes, Kupffer cells, sinusoidal endothelial cells and stellate cells of rat liver. J. Hepatol. 1999; 30 (1): 38–47.32. Rivera C.A., Bradford B.U., Seabra V., Thurman R.G. Role of endotoxin in the hypermetabolic state after acute ethanol exposure. Am. J. Physiol. 1998; 275 (6): 1252–1258.33. Schemmer P., Enomoto N., Bradford B.U., Bunzendahl H., Raleigh J. A., Lemasters, J. J., Thurman R. G. Activated Kupffer cells cause a hypermetabolic state after gentle in situ manipulation of liver in rats. Am. J. Physiol. Gastrointest. Liver Physiol. 2001; 280 (6): 1076–1082.34. New K.J., Eaton S., Elliott K.R.F., Spitz L., Quant P.A. Effect of lipopolysaccharide and cytokines on oxidative metabolism in neonatal rat hepatocytes. J. Pediatr. Surg. 2001; 36: 338–340.35. Dahn M.S., Lange M.P., Berberoglu E.D. Functional characteristics of the hypermetabolic isolated perfused liver. Shock. 1996; 6 (1): 52–56.36. Elbakidze G.M., Chelidze M.A., Elbakidze I.M. The tissuespecific control of calcium ion metabolism in rat liver mitocondria by liver comuton. Dokl. AN SSSR – Reports of USSR Academy of Sciences. 1990; 313 (2): 474–478.37. Elbakidze G.M., Chelidze M.A., Elbakidze I.M. The tissuespecific control of calcium ion metabolism in rat liver mitocondria by liver comuton. IEBEC Short Reports. 1994; 8: 85–85.38. Elbakidze G.M., Medentsev A.G., Elbakidze A.G., Sharyshev A.A. Intracellular regulation of mitochondrial organization processes in rat liver comuton. Dokl. AN = Reports of Academy of Sciences. 2006; 408 (5): 704–707.39. Kagramanov N.D., Katrukha G.S., Kutin A.A., Lokshin B.V., Lysyanskaya V.Ya., Marchenkov V.V, Muranova T.A., Elbakidze G.M., Fedotcheva N.I., Lazareva A.V., Medentsev A.G., Elbakidze A.G., Kolotygina I.M. Izuchenie khimicheskogo sostava komutona iz pecheni krysy. V kn.: Mitokhondrii v patologii. Mat-ly Vseross. Rab. soveshchaniya [The Chemical Composition from Rat Liver Comuton. In: Mitochondria in Pathology. Materials of Russian National Meeting]. Pushchino, 2001. p. 252–254.40. Elbakidze G.M., Medentsev A.G. A study of the conditions of accumulation in vitro thermostable rat liver comuton. Dokl. AN – Reports of Academy of Sciences. 2002; 387 (4): 553–556.41. Brovko F.A., Elbakidze G.M., Bokhua B.T. Fractionation comuton dioxygenases from rat liver. Dokl. AN = Reports of Academy of Sciences. 1994; 338 (3): 401–403.42. Morgunov I.G., Elbakidze G.M., Medentsev A.G. Isolation and purification comuton-producing enzyme from rat liver. Dokl. AN = Reports of Academy of Sciences. 2003; 289 (2): 67–70.43. Elbakidze G.M., Foigel' A.G., Maevskii E.I. , Bokhua B.T., Chelidze M.A., Elbakidze I.M., Gordeziani M.Sh. Investigation of tissue-specific Ca2 + -dependent regulation of mitochondrial thermo stable processes from rat liver comuton. Dokl. AN = Reports of Academy of Sciences. 1992; 324(1): 214–219.44. Elbakidze G.M., Elbakidze A.G., Medentsev A.G Investigation of the effect prodigiozan-dependent comuton on the slow release of calcium ions from the matrix of mitochondria of various tissue and species. Dokl. AN = Reports of Academy of Sciences. 2011; 437 (6): 842–845.45. Maggio R., Siekevitz P., Palade G.E. Studies on isolated nuclei. I. isolation and chemical characterization of a nuclear fraction from guinea pig liver. J. Cell Biol. 1963; 18: 267–291.46. Wisse E., Knook D. The investigation of sinusoidal cells: A new approach to the study of liver function. In: Progress in liver diseases. H. Popper (ed.). NY, Raven Рress. 1979. p. 151–176.47. Elbakidze G.M., Dukhin A.I., Chelidze M.A. Chelidze Interstitial control of energy metabolism in rat liver during starvation early after partial hepatectomy. Izv. AN SSSR. Ser. biol. – Proceedings of USSR Academy of Sciences. Edition biology. 1984; (4): 529–534.48. Elbakidze G.M., Elbakidze I.M. Activation of interstitial monitoring energeticheskogo metabolism in the liver by increasing the load on the special features and its damage hepatotoxin. Dokl. AN SSSR = Reports of USSR Academy of Sciences. 1986; 291 (3): 719–723.49. Balazh A., Blazhek I. Endogennye ingibitory kletochnoi proliferatsii [Endogenous Inhibitors of Cell Proliferation]. Moscow, Mir, 1982. 302 p.50. Bond M., Vadasz G., Somlyo A.V., Somlyo A.P. Subcellular calcium and magnesium mobilization in rat liver stimulated in vivo with vasopressin and glucagon. J. Biol. Chem. 1987; 262 (32): 15630-15636.51. Farber J.L. The role of calcium in lethal cell injury. Chem. Res. Toxicol. 1990; (3): 503-508.52. Orrenius S., McCabe M.J., Nicotera P. Ca2+-dependent mechanisms of cytotoxicity and programmed cell death. Toxicol. Lett. 1992; 64: 357-364.53. Poggioli J., Berthon B., Claret M. Calcium movements in in situ mitochondria following activation of alpha- adrenergic receptors in rat liver cells. FEBS Lett. 1980; 115 (2): 243-246.54. Elbakidze G.M., Elbakidze A.G. Tissue stress - the tissuespecific intratissue adaptation mechanism. VIII World Congr. of Int. Soc. for Adapt. Med., Abstract book. Moscow. 2006; 135-136.55. Elbakidze G.M., Elbakidze A.G. Principles of Tissue Growth Intratissue Regulation. Collierville: InstantPublisher. 2009. 163 p.56. Kuntz E., Kuntz H.-D. Hepatology. Principles and Practice: History, Morphology, Biochemistry, Diagnostics, Clinic, Therapy. 2th ed. Springer. 2005. 906 p.57. Steib J., Gerbes L., Bystron M., et al. Kupffer cell activation in normal and fibrotic livers increases portal pressure via thromboxane A2. J. Hepatol. 2007; 47 (2): 228-238.58. Vollmar B. Menger M. D. The Hepatic Microcirculation: Mechanistic Contributions and Therapeutic Targets in. Liver Injury and Repair. Physiol. Rev. 2009; 89(4): 1269-133959. Lemasters J. J., Ji S., Thurman R. G. Centrilobular injury following hypoxia in isolated, perfused rat liver. Science. 1981; 213 (4508): 661-663.60. Israel Y., Orrego H. Hypermetabolic state and hypoxic liver damage. Recent Dev. Alcohol. 1984; (2): 119-133.61. Luk'yanova L.D., Kirova Yu.I. Effect of hypoxic preconditioning on free radical processes in the tissues of rats with different tolerance to hypoxia. Byull. eksperim. biol. med. = Bulletin of experimental biology and medicine. 2011; 151 (3): 263-268.