Sex and age differences of the systemic inflammatory response in experimental endotoxinemia

Abstract

The morphological and functional state of the integrative systems of the organism - endocrine, immune and nervous, in humans and animals, as well as susceptibility to diseases and the severity of their course are determined mainly by the karyotype and the content of sex steroid hormones, the concentration of which varies in individuals of different sex and age. The study evaluated differences in the systemic inflammatory response and morphological changes in the liver and lungs during experimental endotoxinemia induced by the injection of 15 mg/kg lipopolysaccharide (LPS) of E. coli in females and males Wistar rats of three age groups: newborns (2 days old), prepubertal (10 days old) and sexually mature (2-3 month old). In a day after LPS injection the severity of the inflammation was estimated by the number of neutrophils in the interalveolar septa of the lung, liver necrosis area, the activity level of liver enzymes - ALT and AST, endotoxin level, and the concentration of C-reactive protein in the blood serum. Concentration of corticosterone, estradiol and testosterone in the blood serum by ELISA. It was shown that, compared with newborn and adult Wistar rats, the most severe course of LPS-induced inflammatory response is observed in the prepubertal females and males, which are characterized by low serum concentrations of estradiol and testosterone. Despite the absence of sex differences in the concentration of steroid sex hormones in rats of the prepubertal period, the severity of the systemic inflammatory response in prepubertal males was higher than in females, as evidence by more pronounced inflammatory and pathological changes in the lung and liver, the increase of C-reactive protein in the serum. As in the prepubertal period, the severity of the inflammatory response in newborn and adult rats is more pronounced in males, which is apparently due to the genotype. The obtained data can serve as a basis for the development of new approaches to the effective personalized treatment of infectious and inflammatory diseases considering age and sex.

Keywords:lipopolysaccharide; inflammation; females and males; newborn; prepubertal; sexually mature rats

Received 18.03.2019. Accepted 16.04.2019.

For citation: Kosyreva A.M., Makarova O.V., Mikhaylova L.P., Kakturskiy L.V. Sex and age differences of the systemic inflammatory response in experimental endotoxinemia. Immunologiya. 2019; 40 (3): 28-40. doi: 10.24411/0206-4952-2019-13004. (in Russian)

Acknowledgments. The study had no sponsorship.

Conflict of interest. The authors declare no conflict of interest.

References

1. Roved J., Westerdahl H., Hasselquist D. Sex differences in immune responses: Hormonal effects, antagonistic selection, and evolutionary consequences. Horm. Behav. 2017; 88: 95-105. doi: 10.1016/j.yhbeh.2016.11.017.

2. Rainville J.R., Tsyglakova M., Hodes G.E. Deciphering sex differences in the immune system and depression. Front. Neuroendocrinol. 2018; 50: 67-90. doi: 10.1016/j.yfrne.2017.12.004.

3. Osborne B.F., Turano A., Caulfield J.I., Schwarz J.M. Sex- and region-specific differences in microglia phenotype and characterization of the peripheral immune response following early-life infection in neonatal male and female rats. Neurosci. Lett. 2019; 692: 1-9. doi: 10.1016/j.neulet.2018.10.044.

4. Bradbury N.A. All cells have a sex: studies of sex chromosome function at the cellular level. In: Legato M.J. (ed.). Principles of Gender-Specific Medicine. Gender in the Genomic Era. 3rd ed. Academic Press; Elsevier, 2017: 269-90.

5. Zore T, Palafox M, Reue K. Sex differences in obesity, lipid metabolism, and inflammation - a role for the sex chromosomes? Mol. Metab. 2018; 15: 35-44. doi: 10.1016/j.molmet.2018.04.003.

6. Arnold A.P. Y chromosome’s roles in sex differences in disease. Proc. Natl Acad. Sci. USA. 2017; 114 (15): 3787-9. doi: 10.1073/pnas.1702161114.

7. Mege J.-L., Bretelle F., Leone M. Sex and bacterial infectious diseases. New Microbes New Infect. 2018; 26 (1): s100-3. doi: 10.1016/j.nmni.2018.05.010.

8. Gubbels Bupp M.R., Jorgensen T.N. Androgen-Induced Immunosuppression. Front. Immunol. 2018; 9: 794. doi: 10.3389/fimmu.2018.00794.

9. Klein S.L., Flanagan K.L. Sex differences in immune responses. Nat. Rev. Immunol. 2016; 16 (10): 626-38. doi: 10.1038/nri.2016.90.

10. Movet G.Z. Inflammation, immunity and hypersensitivity. Moscow: Meditsina, 1975. (in Russian)

11. Chernukh A.M. Inflammation: sketches of pathology and experimental therapy. Moscow: Meditsina, 1979. (in Russian)

12. Inflammation: a guide for physicians. In: V.V. Serov, V.S. Paukov (eds). Moscow: Meditsina, 1995. (in Russian)

13. Coimbra R., Hoyt D.B., Potenza B.M., Fortlage D., et al. Does sexual dimorphism influence outcome of traumatic brain injury patients? The answer is no! J. Trauma. 2003; 54 (4): 689-700.

14. Frink M., Pape H.C., van Griensven M., Krettek C., et al. Influence of sex and age on mods and cytokines after multiple injuries. Shock. 2007; 27 (2): 151-6.

15. Lopez-Mestanza C., Andaluz-Ojeda D., Gomez-Lopez J.R., Bermejo-Martin J.F. Clinical factors influencing mortality risk in hospital-acquired sepsis. J. Hosp. Infect. 2018; 98 (2): 194-201. doi: 10.1016/j.jhin.2017.08.022.

16. Marcolini E.G., Albrecht J.S., Sethuraman K.N., Napolitano L. M. Gender disparities in trauma care. Anesthesiol. Clin. 2018. doi: 10.1016/j.anclin.2018.09.007.

17. O’Brien Z., Cass A., Cole L., Finfer S., et al. Sex and mortality in septic severe acute kidney injury. J. Crit. Care. 2019; 49: 70-6. doi: 10.1016/j.jcrc.2018.10.017.

18. Vrachnis N., Zygouris D., Iliodromiti Z., Daniilidis A., et al. Probing the impact of sex steroids and menopause-related sex steroid deprivation on modulation of immune senescence. Maturitas. 2014; 78 (3): 174-8. doi: 10.1016/j.maturitas.2014.04.014.

19. Matter M.L., Shvetsov Y.B., Dugay C., Haiman C.A., et al. High mortality due to sepsis in Native Hawaiians and African Americans: The Multiethnic Cohort. PLoS One. 2017; 12 (5): e0178374. doi: 10.1371/journal.pone.0178374.

20. Goronzy J.J., Gustafson C.E., Weyand C.M. Immune deficiencies at the extremes of age. In: R.R. Rich, W.T. Shearer, A.J. Frew, T.A. Fleisher et al. (eds). Clinical Immunology. 5th ed. Elsevier, 2019: 535-43.e1. URL: https://doi.org/10.1016/B978-0-7020-6896-6.00038-7.

21. Mohamed A.K.S., Mehta A.A., James P. Predictors of mortality of severe sepsis among adult patients in the medical Intensive Care Unit. Lung India. 2017; 34 (4): 330-5. doi: 10.4103/lungindia.lungindia_54_16.

22. Arwyn-Jones J., Brent A.J. Sepsis. Surgery (Oxford). 2019; 37 (1): 1-8. doi: 10.1016/j.mpsur.2018.11.007.

23. Voller S.M.B., Myers P.J. Neonatal sepsis. Clin. Pediatr. Emerg. Med. 2016; 17 (2): 129-33. doi: 10.1016/j.cpem.2016.03.006.

24. Wu J.H., Chen C.Y., Tsao P.N., Hsieh W.S., et al. Neonatal sepsis: a 6-year analysis in a neonatal care unit in Taiwan. Pediatr. Neonatol. 2009; 50 (3): 88-95. doi: 10.1016/S1875-9572(09)60042-5.

25. Shchegolev A.I., Mishnev O.D., Tumanova U.N., Shuvalova M. P. Neonatal sepsis as a cause of perinatal mortality in the Russian Federation. Mezhdunarodniy zhurnal prikladnikh i fundamental’nikh issledovaniy. 2016; 5: 589-94. (in Russian)

26. Shin Y.J., Ki M., Foxman B. Epidemiology of neonatal sepsis in South Korea. Pediatr. Int. 2009; 51 (2): 225-32. doi: 10.1111/j.1442-200X.2008.02685.x.

27. Spasojevic I., Obradovic B., Spasic S. Bench-to-bedside review: neonatal sepsis-redox processes in pathogenesis. Crit. Care. 2012; 16 (3): 221. doi: 10.1186/cc11183.

28. Heymann D.L. NPHIs as focal points for leadership in prevention and control of infectious diseases. J. Public Health Policy. 2008; 29 (3): 374-6. doi: 10.1057/jphp.2008.19.

29. Eshima N., Tokumaru O., Hara S., Bacal K., et al. Age-specific sex-related differences in infections: a statistical analysis of national surveillance data in Japan. PLoS One. 2012; 7 (7): e42261. doi: 10.1371/journal.pone.0042261.

30. Cheng C.C., Huang L.M., Kao C.L., Lee P.I., et al. Molecular and clinical characteristics of adenoviral infections in Taiwanese children in 2004-2005. Eur. J. Pediatr. 2008; 167 (6): 633-40. doi: 10.1007/s00431-007-0562-4.

31. Singer M. The new sepsis consensus definitions (Sepsis-3): the good, the not-so-bad, and the actually-quite-pretty. Intensive Care Med. 2016; 42 (12): 2027-9. doi: 10.1007/s00134-016-4600-4.

32. Mayr F.B., Yende S., Angus D.C. Epidemiology of severe sepsis. Virulence. 2014; 5 (1): 4-11. doi: 10.4161/viru.27372.

33. Rodriguez-Lucas C., Rodicio M.R., Costales I., Boga J.A., et al. Evaluation of Sepsis Flow Chip for identification of Gram-negative bacilli and detection of antimicrobial resistance genes directly from positive blood cultures. Diagn. Microbiol. Infect. Dis. 2018; 91 (3): 205-9. doi: 10.1016/j.diagmicrobio.2018.02.004.

34. Opota O., Croxatto A., Prod G., Greub G. Blood culture-based diagnosis of bacteraemia: state ofthe art. Clin. Microbiol. Infect. 2015; 21: 313-22. doi: 10.1016/j.cmi.2015.01.003.

35. Koch M.A. Sex bias in sepsis. Cell Host Microbe. 2018; 24 (5): 613-5. doi: 10.1016/j.chom.2018.10.014.

36. Blomkalns A.L., Stoll L.L., Shaheen W., Romig-Martin S.A., et al. Low level bacterial endotoxin activates two distinct signaling pathways in human peripheral blood mononuclear cells. J. Inflamm. (Lond.). 2011; 8: 4. doi: 10.1186/1476-9255-8-4.

37. Leveque M., Simonin-Le Jeune K., Jouneau S., Moulis S., et al. Soluble CD14 acts as a DAMP in human macrophages: origin and involvement in inflammatory cytokine/chemokine production. FASEB J. 2017; 31 (5): 1891-902. doi: 10.1096/fj.201600772R.

38. Palsson-McDermott E.M., O’Neill L.A. Signal transduction by the lipopolysaccharide receptor, Toll-like receptor-4. Immunology. 2004; 113 (2): 153-62. doi: 10.1111/j.1365-2567.2004.01976.x.

39. Mishnev O.D., Grinberg L.M., Zairat’yants O.V. Actual problems of the pathology of sepsis: 25 years in search of a consensus. Archiv patologii. 2016; 6: 3-8. doi: 10.17116/patol20167863-8. (in Russian)

40. Mishnev O.D., Tumanova U.N., Schegolev A.I. Pathology of the liver in sepsis. Mezhdunarodniy zhurnal prikladnykh i fundamental’nykh issledovaniy. 2017; 8: 267-71. (in Russian)

41. Calil I.L., Zarpelon A.C., Guerrero A.T., Alves-Filho J.C., et al. Lipopolysaccharide induces inflammatory hyperalgesia triggering a TLR4/MyD88-dependent cytokine cascade in the mice paw. PLoS One. 2014; 9 (3): e90013. doi: 10.1371/journal.pone.0090013.

42. Gregoire M., Tadie J.M., Uhel F., Gacouin A., et al. Frontline Science: HMGB1 induces neutrophil dysfunction in experimental sepsis and in patients who survive septic shock. J. Leukoc. Biol. 2017; 101 (6): 1281-7. doi: 10.1189/jlb.5HI0316-128RR.

43. Pisarev V.B., Bogomolova N.V., Novochadov V.V. Bacterial endotoxemia: a view of the pathologist. Volgograd: Izdatel’stvo Vol. GMU, 2008. (in Russian)

44. Kosyreva A.M., Simonova E.Y., Makarova O.V. Gender differences in pulmonary and immune response in acute experimental endotoxicosis. Byulleten’ eksperimental’noi biologii i meditsiny. 2012; 153 (3): 318-21. (in Russian)

45. Kosyreva A.M., Diatroptov M.E. Morphological development of systemic inflammatory response syndrome in the liver and lung of Wistar rats in the different stages of estrous cycle. Immunologiya. 2013; 34 (2): 111-4. (in Russian)

46. Kosyreva A.M., Makarova O.V., Osmolovskaya E.Yu. Age and sex-related differences in thymic morphological and functional changes in Wistar rats with systemic inflammatory response syndrome. Klinicheskaya i experimental’naya morfologiya. 2016; 3: 30-7. (in Russian)

47. Lyalikov S.A., Makarchik A.V., Evets L.V., Orekhov S.D., et al. Functional state of the endocrine system in children from different regions of Belarus. Results of five-year observation. In the book: Environmental anthropology (Yearbook). 1996: 160-7. (in Russian)

48. Moriceau S., Roth T.L., Okotoghaide T., Sullivan R.M. Corticosterone controls the developmental emergence of fear and amygdala function to predator odors in infant rat pups. Int. J. Dev. Neurosci. 2004; 22 (5-6): 415-22. doi: 10.1016/j.ijdevneu.2004.05.011.

49. Pathological anatomy of the diseases of the fetus and child : a guide. In: T.E. Ivanovskaya, B.S. Gusman (eds). Moscow: Meditsina, 1981. (in Russian)

50. Kosyreva A.M. The sex differences of morphology and immunology of SIRS of newborn Wistar rats. Int. Scholarly Res. Notices. 2014; 2017: 190749. doi: 10.1155/2014/190749.

51. Konkle A.T., McCarthy M.M. Developmental time course of estradiol, testosterone, and dihydrotestosterone levels in discrete regions of male and female rat brain. Endocrinology. 2011; 152 (1): 223-35. doi: 10.1210/en.2010-0607.

52. Karpuzoglu E., Phillips R.A., Gogal R.M., Ansar Ahmed S. IFN-gamma-inducing transcription factor, T-bet is upregulated by estrogen in murine splenocytes: role of IL-27 but not IL-12. Mol. Immunol. 2007; 44: 1808-14. doi: 10.1016/j.molimm.2006.08.005.

53. Pernis A.B. Estrogen and CD4+ T cells. Curr. Opin. Rheumatol. 2007; 19 (5): 414-20. doi: 10.1097/BOR.0b013e328277ef2a.

54. Sullivan R.M., Holman P.J. Transitions in sensitive period attachment learning in infancy: the role of corticosterone. Neurosci. Biobehav. Rev. 2010; 34 (6): 835-44. doi: 10.1016/j.neubiorev.2009.11.010.

55. Wynn J.L., Wong H.R. Pathophysiology and treatment of septic shock in neonates. Clin. Perinatol. 2010; 37 (2): 439-79. doi: 10.1016/j.clp.2010.04.002.

56. Ahmed R., Oldstone M.B., Palese P. Protective immunity and susceptibility to infectious diseases: lessons from the 1918 influenza pandemic. Nat. Immunol. 2007; 8: 1188-93. doi: 10.1038/ni1530.

57. Carvalho P.R., Feldens L., Seitz E.E., Rocha T.S., et al. Prevalence of systemic inflammatory syndromes at a tertiary pediatric intensive care unit. J. Pediatr. (Rio J.). 2005; 81 (2): 143-8.

58. Pavare J., Grope I., Gardovska D. Prevalence of systemic inflammatory response syndrome (SIRS) in hospitalized children: a point prevalence study. BMC Pediatr. 2009; 9: 25. doi: 10.1186/1471-2431-9-25.

59. Zonneveld R., Martinelli R., Shapiro N.I., Kuijpers T.W., et al. Soluble adhesion molecules as markers for sepsis and the potential pathophysiological discrepancy in neonates, children and adults. Crit. Care. 2014; 18 (2): 204. doi: 10.1186/cc13733.

60. Gentile L.F., Nacionales D.C., Lopez M.C., Vanzant E., et al. Protective immunity and defects in the neonatal and elderly immune response to sepsis. J. Immunol. 2014; 192 (7): 3156-65. doi: 10.4049/jimmunol.1301726.

61. Kosyreva A.M., Makarova O.V. The influence of surgical castration on the systemic inflammatory response induced by the administration of lipopolysaccharide to adult Wistar rats. Molekulyarnaya meditsina. 2018; 16 (5): 22-9. doi: 10.29296/24999490-2018-05-04. (in Russian)

62. Arrieta M.C., Stiemsma L.T., Amenyogbe N., Brown E.M., et al. The intestinal microbiome in early life: health and disease. Front. Immunol. 2014; 5: 427. doi: 10.3389/fimmu.2014.00427.

63. Caballero-Flores G., Sakamoto K., Zeng M.Y., Wang Y., et al. Maternal immunization confers protection to the offspring against an attaching and effacing pathogen through delivery of IgG in breast milk. Cell Host Microbe. 2019; 25 (2): 313-23.e4. doi: 10.1016/j.chom.2018.12.015.

64. Gabehart K., Correll K.A., Loader J.E., White C.W., et al. The lung response to ozone is determined by age and is partially dependent on toll-like receptor 4. Respir. Res. 2015; 16: 117. doi: 10.1186/s12931-015-0279-2.

65. Zheng G., Wu S.P., Hu Y., Smith D.E., et al. Corticosterone mediates stress-related increased intestinal permeability in a region-specific manner. Neurogastroenterol. Motil. 2013; 25 (2): e127-39. doi: 10.1111/nmo.12066.

66. Marshall J.C., Foster D., Vincent J.L., Cook D.J., et al. Diagnostic and prognostic implications of endotoxemia in critical illness: results of the MEDIC study. J. Infect. Dis. 2004; 190 (3): 52734. doi: 10.1086/422254.

67. Koch A., Meesters M.I., Scheller B., Boer C., et al. Systemic endotoxin activity correlates with clot formation: an observational study in patients with early systemic inflammation and sepsis. Crit. Care. 2013; 17 (5): R198. doi: 10.1186/cc12892.

68. Sharma A., Yang W.L., Matsuo S., Wang P. Differential alterations of tissue T-cell subsets after sepsis. Immunol. Lett. 2015; 168 (1): 41-50. doi: 10.1016/j.imlet.2015.09.005.

69. Brubaker A.L., Rendon J.L., Ramirez L., Choudhry M.A., et al. Reduced neutrophil chemotaxis and infiltration contributes to delayed resolution of cutaneous wound infection with advanced age. J. Immunol. 2013; 190 (4): 1746-57. doi: 10.4049/jimmunol.1201213.

70. Kruger P., Saffarzadeh M., Weber A.N., Rieber N., et al. Neutrophils: between host defense, immune modulation, and tissue injury. PLoS Pathog. 2015; 11 (3): e1004651. doi: 10.1371/journal.ppat.1004651.

71. Simonova E.Yu., Kosyreva A.M., Makarova O.V., Diatrop-tov M.E. Age-related changes of morphological and functional station ofthe immune system in Wistar rats. Klinicheskaya i experimental’naya morfologiya. 2014; 1 (9): 35-41. (in Russian)

All articles in our journal are distributed under the Creative Commons Attribution 4.0 International License (CC BY 4.0 license)


JOURNALS of «GEOTAR-Media»