The importance of liver detoxication function and the severity of endotoxinemia in the formation and implementation of central dysregulatory effects on body temperature

At the present stage of the development of medical science, no one doubts that dysregulation underlies many pathological processes. Endotoxinemia serves as a key factor in the pathogenesis of these processes, and its severity is largely determined by the state of detoxication function of the liver. The aim of this study was to clarify the importance of liver detoxication function and the severity of endotoxinemia in the formation and manifestation of central dysregulatory effects on body temperature. Experiments conducted on rats and rabbits revealed that the direction of changes in body temperature, as well as the nature of changes in catabolic and anabolic processes of the body under the action of E. сoli endotoxin, depend on the state of the liver detoxication function, the severity of endotoxemia, and the accompanying neurotransmitter, hormonal, and humoral imbalances, ensuring the interaction of various organs and systems. It has been shown that, depending on the state of liver detoxification capacity, the same dose of endotoxin can lead to an increase in body temperature, have no effect on it, or cause hypothermia. Additionally, under conditions of bacterial endotoxinemia, accompanied by elevated body temperature and increased liver arginase activity, the level of the amino acid arginine in blood plasma decreases. Furthermore, the liver arginase deficiency in conditions of endotoxin fever prevents the activation of liver detoxication function and the increase in body temperature. It was established that the ambiguous direction and nature of the revealed changes in the processes are largely due to changes in the properties of cerebral neurons, particularly within the cholinergic and adrenoreactive systems of the hypothalamic region of the brain. These changes are caused by the intake of arginine from blood plasma and cerebrospinal fluid into the structures of the hypothalamus. The findings indicate that insufficient liver detoxication function and the severity of endotoxinemia are significant factors in the formation and implementation of central dysregulatory effects on body temperature. 

1. Yakovlev M. Yu. Systemic endotoxinemia. Homeostasis and general pathology. Moscow, Nauka Publ., 2021. 184 p. (in Russian).

2. Vismont F. I. Endotoxinemia role in dysregulation pathologies. Zdravookhranenie [Healthcare], 2012, no. 1, pp. 17–21 (in Russian).

3. Vismont F. I. Endotoxinemia, dysregulation and the pre-illness formation. Vestsi Natsyyanal’nai akademii navuk Belarusi. Serуya medуtsynskikh navuk = Proceedings of the National Academy of Sciences of Belarus. Medical series, 2018, vol. 15, no. 1, pp. 7–16 (in Russian).

4. Vismont F. I. The importance of the liver detoxication function and endotoxinemia in the occurrence of dysregulation and the formation of pre-disease. Klinicheskaya patofiziologiya = Clinical pathophysiology, 2024, vol. 30 (suppl.), no. S2, p. 29 (in Russian).

5. Kryzhanovskii G. N. Dysregulation pathology. Dysregulation pathology. Moscow, 2002, pp. 18–78 (in Russian).

6. Akmaev I. G. Physiology of regulatory systems and dysregulatory pathology. Dysregulation pathology. Moscow, 2002, pp. 79–96 (in Russian).

7. Mayanskii D. N. Kupffer cells and liver pathology. Patologicheskaya fiziologiya i eksperimental’naya terapiya [Pathological physiology and experimental medicine], 1985, vol. 29, no. 4, pp. 80–86 (in Russian).

8. On the norms of feeding laboratory animals and producers: order of the USSR Ministry of Health on March 10, 1966, No. 163. Library of legal acts of the Union of Soviet Socialist Republics. Avialable at: https://www.libussr.ru/doc_ussr/usr_6382.htm (accessed 20.01.2025) (in Russian).

9. Sehice E., Hunter W. S., Ungar A. L., Blatteis C. M. Blockade of Kupffer cells prevents the febrile and preoptic prostaglandin E2 responses to intravenous lipopolysaccharide in guinea pigs. Annals of the New York Academy of Sciences, 1997, vol. 813, no. 1, pp. 448–452. https://doi.org/10.1111/j.1749-6632.1997.tb51732.x

10. Elizarova O. N. Determination of threshold doses of industrial poisons upon oral administration. Moscow, Medgiz Publ., 1962. 174 p. (in Russian).

11. Moin V. M., Nikolaichik V. V., Kirkovskii V. V., Lobacheva G. A., Mazur L. I. Method of determining substances belonging to the group of mean molecules in biological liquids. Patent USSR No. SU 1520445 A1, 1989. 2 p. (in Russian).

12. Rad’kova O. A., Boyarinov G. A., Balishina I. N., Krylov K. V. Biological liquid toxicity determination method. Patent USSR No. SU 1146570 A1, 1985. 2 p. (in Russian).

13. Park D. V. Biochemistry of foreign compounds. Moscow, Medicine Publ., 1973. 287 p.

14. Sawyer C. H., Everett J. W., Green J. D. The rabbit diencephalon in stereotaxic coordinates. Journal of Comparative Neurology, 1954, vol. 101, no. 3, pp. 801–824. https://doi.org/10.1002/cne.901010307

15. Geyer J. W., Dabich D. Rapid method for determination of arginase activity in tissue homogenates. Analytical Biochemistry, 1971, vol. 39, no. 2, pp. 412–417. https://doi.org/10.1016/0003-2697(71)90431-3

16. Moshage H. Cytokines and the hepatic acute phase response. Pathology, 1997, vol. 181, no. 3, pp. 257–266. https://doi.org/10.1002/(sici)1096-9896(199703)181:3<257::aid-path756>3.0.co;2-u

17. Iversen L. L., Glowinski J. Regional studies of catecholamines in the rat brain. II. Rate of turnover catecholamines in varius brain regions. Journal of Neurochemistry, 1966, vol. 13, no. 8, pp. 661–669. https://doi.org/10.1111/j.1471-4159.1966.tb09874.x

18. Putilina F. Ye., Eshchenko N. D. Activity of some dehydrogenases of the Krebs cycle in the brain, liver and kidneys. Vestnik Leningradskogo universiteta. Seriya Biologiya [Bulletin of Leningrad University. Series Biology], 1969, vol. 4, no. 21, pp. 74–78 (in Russian).

19. Malyuk V. I. Determination of cytochrome-c-oxidase in mitochondria of animal tissues. Voprosy meditsinskoi khimii [Issues of medical chemistry], 1965, vol. 11, no. 4, pp. 88–91 (in Russian).

20. Laverty R., Taylor K. The fluorometric assay of catecholamines and related compounds. Journal of Analytical Biochemistry, 1968, vol. 22, no. 2, pp. 269–279. https://doi.org/10.1016/0003-2697(68)90316-3

21. Vismont F. I. The role of endotoxinemia in the formation of the thyroid status of the body and thermoregulation. Zdravookhranenie [Healthcare], 2011, no. 9, pp. 26–29 (in Russian).

22. Shust O. G., Vismont F. I. On the role of functional liver failure in the pathogenesis of endotoxin fever. Zdravookhranenie [Healthcare], 2000, no. 8, pp. 23–25 (in Russian).

23. Vismont F. I., Shust O. G. The role of the liver detoxification function and blood α1-antitrypsin in the mechanisms of endotoxin fever development. Vestsi Natsyyanal’nai akademii navuk Belarusi. Seryya medyka-biyalagichnykh navuk [Proceedings of the National Academy of Sciences of Belarus. Medical and biological sciences series], 2001, no. 1, pp. 41–48 (in Russian).

24. Vismont F. I., Gurin V. N. Hyperthermic effect of trypsin inhibitor in rats and rabbits. Byulleten’ eksperimental’noi biologii i meditsiny [Bulletin of experimental biology and medicine], 1985, vol. 100, no. 11, pp. 543–544 (in Russian).

25. Vismont F. I., Glebov M. A. The role of Kupffer cells and plasma α1-antitrypsin in the regulation of the liver detoxification function, the formation of thyroid status and thermoregulation in bacterial endotoxinemia. Meditsinskii zhurnal [Medical journal], 2013, no. 4, pp. 54–57 (in Russian).

26. Vismont F. I., Grishchenko K. N. Participation of Kupffer cells and hepatocytes in the formation of thermoregulatory reactions of the body to the action of endotoxin. Zdravookhranenie [Healthcare], 2001, no. 8, pp. 29–30 (in Russian).

27. Vismont F. I., Glebov M. A. Role of the liver detoxification function in thyroid status formation and thermoregulation. Mediko-biologicheskie problemy zhiznedeyatel’nosti [Medical and biological problems of life activity], 2013, no. 10, pp. 61–65 (in Russian).

28. Turakulov Ya. Kh., Tashkodzhayeva T. P., Artykbayeva G. M. Activity of thyroxine conversion to triiodothyronine in the liver and kidneys of rats. Problemy endokrinologii [Problems of endocrinology], 1991, vol. 37, no. 4, pp. 44–46 (in Russian).

29. Greg Kelly N. D. Peripheral metabolism of thyroid hormones. Alternative Medicine Review, 2000, vol. 5, no. 4, pp. 306–333.

30. Gurin A. V. Proteinase inhibitors and blood cytokines in the mechanisms of hyperthermia under stress. Minsk, Tekhnoprint Publ., 2003. 124 р. (in Russian).

31. Vismont F. I. The role of central adrenoreactive systems in the regulation of lipid metabolism in animals under conditions of overheating and prostaglandin fever. Zdravookhranenie Belorussii [Healthcare in Belarus], 1981, no. 9, pp. 61–62 (in Russian).

32. Vismont F. I., Tret’yakovich E. A. On the role of central adrenoreactive systems in the mechanisms of antipyretic action of acupuncture in endotoxin fever in rabbits. Meditsinskii zhurnal [Medical journal], 2007, no. 3, pp. 45–47 (in Russian).

33. Vismont F. I. Angiotensin II as a factor of endogenous antipyresis in rats and rabbits. Thermoregulation and temperature adaptation. Minsk, 1995, pp. 73–78.

34. Vismont F. I. On the participation of angiotensin II in the mechanis ms regulating the functional activity of α-adrenoreactive systems of the hypothalamic region of the brain and body temperature in rats and rabbits. Fiziologiya i biokhimiya mediatornykh protsessov: tezisy dokladov V vsesoyuznoi konferentsii, posvyashchennoi 90-letiyu so dnya rozhdeniya akademika AN Armyanskoi SSR, chlena-korrespondenta AN SSSR Kh. S. Koshtoyantsa, Moskva, oktyabr’ 1990 goda [Physiology and biochemistry of mediator processes: abstracts of reports of the All-Union conference dedicated to the 90th anniversary of the birth of Academician of the Academy of Sciences of the Armenian SSR, Corresponding Member of the USSR Academy of Sciences Kh. S. Koshtoyants, Moscow, October 1990]. Moscow, 1990, р. 57 (in Russian).

35. Vismont F. I. On the role of the renin-angiotensin system of the brain in the central mechanisms of thermoregulation in pyrogenal fever. Sistema termoregulyatsii pri adaptatsii organizma k faktoram sredy: tezisy dokladov Vsesoyuznoi konferentsii, posvyashchennoi pamyati professora A. D. Slonima, 18–20 sentyabrya 1990 goda. Tom 2 [Thermoregulation system in the adaptation of the organism to environmental factors: abstracts of reports of the All-Union conference dedicated to the memory of Professor A. D. Slonim, September 18–20, 1990. Vol. 2]. Novosibirsk, 1990, pp. 273–274 (in Russian).

36. Vismont F. I. On the participation of brain peptide hydrolases in the central mechanisms of thermoregulation during overheating and pyrogenal fever. Neiropeptidy i termoregulyatsiya: materialy Mezhdunarodnogo simpoziuma po problemam upravleniya i bioenergetiki protsessov termoregulyatsii, Minsk, 15–17 maya 1988 goda [Neuropeptides and thermoregulation: Proceedings of the International symposium on problems of control and bioenergetics of thermoregulation processes, Minsk, May 15–17, 1988]. Minsk, 1990, pp. 50–66 (in Russian).

37. Vismont F. I. On the regulatory and pathogenetic role of the proteolysis system and endogenous proteinase inhibitors in the central mechanisms of thermoregulation. Devyatyi s’’ezd Belorusskogo obshchestva fiziologov, Minsk, 5–6 sentyabrya 1996 goda: tezisy dokladov [Ninth congress of the Belarusian society of physiologists, Minsk, September 5–6, 1996: abstracts of reports]. Minsk, 1996, р. 15 (in Russian).

38. Vismont F. I., Shust O. G. On the regulatory role of brain peptide hydrolases and endogenous proteinase inhibitors in central thermoregulation processes. Rol’ neiromediatorov i regulyatornykh peptidov v protsessakh zhiznedeyatel’nosti: materialy konferentsii, posvyashchennoi150-letiyu so dnya rozhdeniya I. P. Pavlova [The role of neurotransmitters and regulatory peptides in life processes: Proceedings of the conference dedicated to the 150th anniversary of the birth of I. P. Pavlov]. Minsk, 1999, pp. 37–38 (in Russian).

39. Vismont F. I. On the role of ß-endorphin of the hypothalamic region of the brain in the central adrenergic mechanisms of heat exchange in bacterial endotoxinemia. XI s’’ezd Belorusskogo obshchestva fiziologov (Minsk, 21–22 sentyabrya 2006 goda): tezisy dokladov [XI Congress of the Belarusian society of physiologists (Minsk, September 21–22, 2006): abstracts of reports]. Minsk, 2006, р. 20 (in Russian).

40. Gurin V. N., Vismont F. I., Elkin Yu. B. On the role of neuropeptides in the central mechanisms of thermoregulation Fiziologicheski aktivnye peptidy: sbornik nauchnykh trudov [Physiologically active peptides: collection of scientific papers]. Pushchino, 1988, pp. 88–98 (in Russian).

41. Vismont F. I., Vismont A. F. To the mechanism of the neurotransmitter disregulation formation in the central structures of the body temperature regulation during bacterial endotoxemia. Meditsinskii zhurnal [Medical journal], 2011, no. 2, pp. 27–30 (in Russian).

42. Vismont F. I., Stepanenko N. N. Central neurochemical mechanisms of antipyretic action of L-arginine under endotoxin fever conditions. Vestsі Akademіі navuk Belarusі. Seryya khіmіchnykh navuk [Bulletin of the Academy of Sciences of Belarus. Chemical series], 1997, no. 2, pp. 102–106 (in Russian).

43. Vismont F. I., Vismont A. F. Formation of the “setpoint” level of body temperature regulation in endotoxin fever. Vestsі Natsyyanal’nai akademіі navuk Belarusі. Seryya medytsynskіkh navuk = Proceedings of the National Academy of Sciences of Belarus. Medical series, 2020, vol. 11, no. 1, pp. 28–37 (in Russian).

44. Gordon C. J., Heath J. E. Integration in central processing in temperature regulation. Annual Review of Physiology, 1986, no. 48, pp. 595–612. https://doi.org/10.1146/annurev.physiol.48.1.595

45. Taylor B. S., Alarcon L. H., Billiar T. R. Inducible nitric oxide synthase in the liver: regulation and function. Biochemistry (Moscow), 1998, vol. 63, no. 7, pp. 766–781.

46. Scibior D., Czeczot H. Arginine – metabolism and functions in the human organism. Postȩpy higieny i medycyny doświadczalnej = Advances in hygiene and experimental medicine, 2004, no. 58, pp. 321–332 (in Polish).

47. Gerstberger R. Nitric Oxide and body temperature control. Journal of Physiological Sciences, 1999, vol. 14, no. 1, pp. 30–36. https://doi.org/10.1152/physiologyonline.1999.14.1.30

48. Lobanova V. V., Vismont F. I. About L-arginine-NO system participation in the mechanisms of L-valine antipyretic action during endotoxine fever. Voyennaya meditsina [Military medicine], 2015, no. 4, pp. 105–107 (in Russian).

49. Lobanova V. V., Vismont F. I. To the participation of liver arginase in L-arginine-NO system activity changes, detoxification processes and body temperature in bacterial endo toxinemia. Meditsinskii zhurnal [Medical journal], 2014, no. 4, pp. 75–79 (in Russian).