THE INFLUENCE OF SURGICAL CASTRATION ON THE SYSTEMIC INFLAMMATORY RESPONSE INDUCED BY THE ADMINISTRATION OF LIPOPOLYSACCHARIDE TO ADULT WISTAR RATS

DOI: https://doi.org/10.29296/24999490-2018-05-04

A.M. Kosyreva, O.V. Makarova Scientific Research Institute of Human Morphology, Tsyurupy str., 3, Moscow, 117418, Russian Federation E-mail: [email protected]

Introduction. The incidence of infectious and inflammatory diseases, including sepsis, increases with the age, which is explained by the age-related decrease in the content of sex steroids. However, the features of the course of systemic inflammatory responses and the development of the immune response in individuals with low sex steroid hormones have not been studied. The aim of the study. To assess the severity of alternative and inflammatory changes in liver, lungs and immune system to the general inflammatory response induced by lipopolysaccharide in female and male Wistar rats in the remote period after the surgical castration. Methods. The systemic inflammatory response was simulated by the intraperitoneal injection of E. coli (O26:B6) lipopolysaccharide at the dose of 1.5 mg/kg in the remote period (52 days) after surgical ovari- and orchiectomy in Wistar rats. We studied morphological changes in the liver, lungs, thymus, spleen; the content of testosterone, estradiol, corticosterone, endotoxin level, the ALT and AST activity in the blood serum, the production of cytokines – IL-2, IFN-γ, TNF-α and IL-6 by ConA activated spleen cells. The informativeness of statistically significant changes of indices describing the severity of the systemic inflammatory and immune response was evaluated by the Kullback’s formula. Results. We found that the surgical ovari- and orchiectomy of mature Wistar rats, leading to a reduction of sex steroids level, impaired the course of the inflammation in lungs and gave rise in the alteration in the liver, which was accompanied by pronounced endotoxinemia and a shift in the balance of cytokine production to the proinflammatory type. The increase in endotoxin levels is most significant in the development of a systemic inflammatory response in both females and males in the remote period after the surgical castration, whereas in non-castrated animals, such hormonal changes as the decrease in estradiol in females and testosterone in males, are the most informative. Conclusion. Thus, the physiological concentrations of sex steroids have an immunoprotective effect, while the decrease in the level of testosterone and estradiol after the surgical castration of male and female Wistar rats, worsen the course of the systemic inflammatory response. Revealed data must be taken into account when developing new approaches to the therapy of infectious and inflammatory diseases in the elderly persons.
Keywords: 
castration, inflammation, lipopolysaccharide, sex steroids
Список литературы: 
  1. van Vught L.A., Scicluna B.P., Wiewel M.A., Hoogendijk A.J., Klein Klouwenberg P.M.C., Ong D.S.Y., Cremer O.L., Horn J., Franitza M., Toliat M.R., Nürnberg P., Bonten M.M.J., Schultz M.J., van der Poll T. Association of gender with outcome and host response in critically ill sepsis patients. Crit Care Med. 2017; 45 (11): 1854–1862. DOI: 10.1097/CCM.0000000000002649.
  2. Adrie C., Azoulay E., Francais A. Clec’h C., Darques L., Schwebel C., Nakache D., Jamali S., Goldgran-Toledano D., Garrouste-Orgeas M., Timsit J.F. Influence of gender on the outcome of severe sepsis: a reappraisal. Chest. 2007; 132 (6): 1786–93.
  3. Klein S.L., Roberts C.W. Sex Hormones and Immunity to Infection. Heidelberg, Germany: Springer-Verlag Berlin Heidelberg. 2010; 319.
  4. Hickey M., Emery L.I., Gregson J., Doherty D.A., Saunders C.M. The multidisciplinary management of menopausal symptoms after breast cancer: a unique model of care. Menopause. 2010; 17 (4): 727–33. DOI: 10.1097/gme.0b013e3181d672f6.
  5. Palomba H., Corrêa T.D., Silva E., Pardini A., Assuncao M.S. Comparative analysis of survival between elderly and non-elderly severe sepsis and septic shock resuscitated patients. Einstein (Sao Paulo). 2015; 13 (3): 357–63. DOI: 10.1590/S1679-45082015AO3313.
  6. Pinsky M.R., Hellstrom W.J. Hypogonadism, ADAM, and hormone replacement. Ther Adv Urol. 2010; 2 (3): 99–104. DOI: 10.1177/1756287210369805.
  7. Angstwurm M.W., Gaertner R., Schopohl J. Outcome in elderly patients with severe infection is influenced by sex hormones but not gender. Crit Care Med. 2005; 33 (12): 2786–93.
  8. Chung M.T., Lee Y.M., Shen H.H., Cheng P.Y., Huang Y.C., Lin Y.J., Huang Y.Y., Lam K.K. Activation of autophagy is involved in the protective effect of 17β-oestradiol on endotoxaemia-induced multiple organ dysfunction in ovariectomized rats. J. Cell. Mol. Med. 2017; 21 (12): 3705–17. DOI: 10.1111/jcmm.13280.
  9. Shen H.H., Huang S.Y, Cheng P.Y., Chu Y.J., Chen S.Y., Lam K.K., Lee Y.M. Involvement of HSP70 and HO-1 in the protective effects of raloxifene on multiple organ dysfunction syndrome by endotoxemia in ovariectomized rats. Menopause. 2017; 24 (8): 959–69. DOI: 10.1097/GME.0000000000000864.
  10. Ongaro L., Castrogiovanni D., Giovambattista A., Gaillard R.C., Spinedi E. Enhanced proinflammatory cytokine response to bacterial lipopolysaccharide in the adult male rat after either neonatal or prepubertal ablation of biological testosterone activity. Neuroimmunomodulation. 2011; 18 (4): 254–60. DOI: 10.1159/000324125.
  11. Torres M.B., Trentzsch H., Stewart D., Mooney M.L., Fuentes J.M., Saad D.F., Reeves R.H., De Maio A. Protection from lethal endotoxic shock after testosterone depletion is linked to chromosome X. Shock. 2005; 24 (4): 318–23.
  12. Wiechno P.J., Kowalska M., Kucharz J., Sadowska M., Michalski W., Poniatowska G., Jońska-Gmyrek J., Rzymkowska J., Nietupski K., Demkow T. Dynamics of hormonal disorders following unilateral orchiectomy for a testicular tumor. Med Oncol. 2017; 34 (5): 84. DOI: 10.1007/s12032-017-0943-0.
  13. Filippa V., Godoy D., Perez E., Mohamed F. Effects of castration on androgen receptors and gonadotropins in the pituitary of adult male viscachas. Reprod Fertil Dev. 2014; 26 (7): 991–1000. DOI: 10.1071/RD13126.
  14. Kosyreva A.M., Makarova O.V. Morfologicheskaya i immunologicheskaya harakteristika sistemnogo vospalitel`nogo otveta u ovarie`ktomirovannyh krys Vistar. Citokiny i vospalenie. 2013; 1–2: 78–82. [Kosyreva A.M., Makarova O.V. Morphology and immunology of systemic inflammatory response syndrome in ovariectomized Wistar rats. 2013; 1–2: 78–82 (in Russian)]
  15. Dashutina E.V., Bloshhickiy V.P. Razrabotka i realizaciya algoritma ocenki informativnosti priznakov pri diagnostike zabolevaniy. DonNTU., 2011. http://ea.donntu.edu.ua/handle/123456789/12855 [Dashutina E.V., Bloshhickij V.P. Razrabotka i realizacija algoritma ocenki informativnosti priznakov pri diagnostike zabolevanij. DonNTU., 2011. http://ea.donntu.edu.ua/handle/123456789/12855 (in Russian)]
  16. Kapustina S.V., Kiryakova O.V., Kapustina A.V., Lapina L.A., Stupina A.A. Vybor informativnyh priznakov dlya ocenki tyazhesti zabolevaniya. Sovremennye problemy nauki i obrazovaniya. 2015; 2(2): https://science-education.ru/ru/article/view?id=21955. [Kapustina S.V., Kirjakova O.V., Kapustina A.V., Lapina L.A., Stupina A.A. Vybor informativnyh priznakov dlja ocenki tjazhesti zabolevanija. Sovremennye problemy nauki i obrazovanija. 2015; 2–2: https://science-education.ru/ru/article/view?id=21955 (in Russian)]
  17. Zeckey C., Andruszkow H., Neunaber C., Frink M., Schirmer B., Mommsen P., Barkhausen T., Krettek C., Hildebrand F. Protective effects of finasteride on the pulmonary immune response in a combined model of trauma-hemorrhage and polymicrobial sepsis in mice. Cytokine. 2011; 56 (2): 305–11. DOI: 10.1016/j.cyto.2011.06.013
  18. Card J.W., Carey M.A., Bradbury J.A. DeGraff L.M., Morgan D.L., Moorman M.P., Flake G.P., Zeldin D.C. Gender differences in murine airway responsiveness and lipopolysaccharide-induced inflammation. J. Immunol. 2006; 177 (1): 621–30.
  19. Frink M., Hsieh Y.C., Thobe B.M. Choudhry M.A., Schwacha M.G., Bland K.I., Chaudry I.H. TLR4 regulates Kupffer cell chemokine production, systemic inflammation and lung neutrophil infiltration following trauma-hemorrhage. Mol. Immunol. 2007; 44 (10): 2625–30.
  20. Koziol-White C.J., Goncharova E.A., Cao G. Johnson M., Krymskaya V.P., Panettieri R.A. Jr. DHEA-S inhibits human neutrophil and human airway smooth muscle migration. Biochim Biophys Acta. 2012; 1822 (10): 1638–42. DOI: 10.1016/j.bbadis.2012.06.012.
  21. Lee H., Kim H., Chung Y., Kim J., Yang H. Thymocyte Differentiation is Regulated by a Change in Estradiol Levels during the Estrous Cycle in Mouse. Dev Reprod. 2013; 17 (4): 441–9. DOI: 10.12717/DR.2013.17.4.441.
  22. Olsen N.J., Kovacs W.J. Evidence that androgens modulate human thymic T cell output. J. Investig Med. 2011; 59 (1): 32–5.
  23. Giefing-Kröll C., Berger P., Lepperdinger G., Grubeck-Loebenstein B. How sex and age affect immune responses, susceptibility to infections, and response to vaccination. Aging Cell. 2015; 14 (3): 309–21. DOI: 10.1111/acel.12326.
  24. Sakiani S., Olsen N.J., Kovacs W.J. Gonadal steroids and humoral immunity. Nat Rev Endocrinol. 2013; 9 (1): 56–62. DOI: 10.1038/nrendo.2012.206.
  25. Moxley G., Stern A.G., Carlson P. Estrada E., Han J., Benson L.L. Premenopausal sexual dimorphism in lipopolysaccharide-stimulated production and secretion of tumor necrosis factor. J. Rheumatol. 2004; 31 (4): 686–94.
  26. Hotchkiss R.S., Monneret G., Payen D. Immunosuppression in sepsis: a novel understanding of the disorder and a new therapeutic approach. Lancet Infect Dis. 2013; 13 (3): 260–8. DOI: 10.1016/S1473-3099(13)70001-X.
  27. Esteban E., Ferrer R., Alsina L., Artigas A. Immunomodulation in sepsis: the role of endotoxin removal by polymyxin B-immobilized cartridge. Mediators Inflamm. 2013; 2013: 507539. DOI: 10.1155/2013/507539.
  28. Kosyreva A.M. Histophysiology of immune system and barrier organs in the late period of orchiectomy in Wistar rats. Bulletin of Experimental Biology and Medicine. 2013; 154 (4): 480–4.
  29. Kosyreva A.M., Simonova E.Yu. Histophysiology of the immune system of Wistar rats at delayed terms after ovariectomy. Bulletin of Experimental Biology and Medicine. 2013; 155 (5): 697–700.