Gender and Cell-mediated Immunity Following Trauma, Shock, and Sepsis

  • M. G. Schwacha
  • A. Samy
  • I. H. Chaudry


While improved preventative methods and patient care have decreased patient morbidity and mortality, major traumatic injury remains one of the leading causes of death for young adults (<30 years of age) in the United States. Trauma represents a severe form of injury including bone fracture, penetrating soft tissue injury, (i.e., gunshot wounds), thermal injury and protracted surgical procedures. Many forms of traumatic injury, such as penetrating soft tissue trauma, are usually associated with a subsequent loss of significant blood volume. During the initial 60-minute post-traumatic period, approximately 50% of the observed mortality is due to exsanguination or central nervous system (CNS) complications. In the subsequent 2 hours, close to 30% of the victims succumb to major internal organ damage. Unfortunately, surviving trauma patient prognosis remains dire, since these patients display a 50% mortality rate from secondary complications that include sepsis, multiple organ failure (MOF), and eventual death [1-3]. Sepsis is the major non-neurological cause of death following trauma. A significant effort in scientific and medical research has been directed towards understanding the relationship between major traumatic injury and/or shock and the predisposition to septic/infectious complications and/or MOF.


Hemorrhagic Shock Steroidogenic Enzyme Androgen Receptor Antagonist Gender Dimorphism Subsequent Sepsis 
These keywords were added by machine and not by the authors.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Baue AE, Durham R, Faist E (1998) Systemic inflammatory response syndrome (SIRS), multiple organ dysfunction syndrome (MODS), multiple organ failure (MOF): are we winning the battle? Shock 10: 79–89PubMedCrossRefGoogle Scholar
  2. 2.
    Vincent JL (2000) Update on sepsis: pathophysiology and treatment. Acta Clin Belg 55: 7987Google Scholar
  3. 3.
    Goris RJ (1989) Multiple organ failure: whole body inflammation? Schweiz Med Wochenschr 119: 347–353PubMedGoogle Scholar
  4. 4.
    Schwacha MG, Knöferl MW, Samy TSA, Ayala A, Chaudry IH (1999) The immunologic consequences of hemorrhagic shock. Crit Care Shock 2: 42–64Google Scholar
  5. 5.
    Napolitano LM, Faist E, Wichmann MW, Coimbra R (1999) Immune dysfunction in trauma. Surg Clin North Am 79: 1385–1416PubMedCrossRefGoogle Scholar
  6. 6.
    Bone RC (1992) Toward an epidemiology and natural history of SIRS (systemic inflammatory response syndrome). JAMA 268: 3452–3455PubMedCrossRefGoogle Scholar
  7. 7.
    Lahita RG, Bradlow HL, Ginzler E, Pang S, New M (1987) Low plasma androgens in women with systemic lupus erythematosus. Arthritis Rheum 30: 241–248PubMedCrossRefGoogle Scholar
  8. 8.
    Angele MK, Schwacha MG, Ayala A, Chaudry IH (2000) Effect of gender and sex hormones on immune responses following shock. Shock 14: 81–90PubMedCrossRefGoogle Scholar
  9. 9.
    Altura BM (1976) Sex and estrogens in protection against circulatory stress reactions. Am J Physiol 231: 842–847PubMedGoogle Scholar
  10. 10.
    Wichmann MW, Zellweger R, DeMaso CM, Ayala A, Chaudry IH (1996) Enhanced immune responses in females as opposed to decreased responses in males following haemorrhagic shock. Cytokine 8: 853–863PubMedCrossRefGoogle Scholar
  11. 11.
    Angele MK, Knöferl M, Schwacha MG, Cioffi WG, Bland KI, Chaudry IH (1999) Testosterone and estrogen regulate pro-and antiinflammatory cytokine release by macrophages following trauma-hemorrhage. Am J Physiol 277: C35 - C42PubMedGoogle Scholar
  12. 12.
    Adams CAJ, Magnotti LJ, Xu DZ, Lu Q, Deitch EA (2000) Acute lung injury after hemorrhagic shock is dependent on gut injury and sex. Am Surg 66: 905–912PubMedGoogle Scholar
  13. 13.
    Knöferl MW, Jarrar D, Angele MK, et al (2001) 17/3-estradiol normalizes immune responses in ovariectomized females after trauma-hemorrhage. Am J Physiol 281: C1131 - C1138Google Scholar
  14. 14.
    Knöferl MW, Diodato MI), Angele MK, et al (2000) Do female sex steroids adversely or beneficially affect the depressed immune responses in males after trauma-hemorrhage? Arch Surg 135: 425–433PubMedCrossRefGoogle Scholar
  15. 15.
    Angele MK, Xin Xu Y, Ayala A, et al (1999) Gender dimorphism in trauma-hemorrhage-induced thymocyte apoptosis. Shock 12: 316–322PubMedCrossRefGoogle Scholar
  16. 16.
    Kahlke V, Angele MK, Ayala A, et al (2000) Immune dysfunction following trauma-hemorrhage: influence of gender and age. Cytokine 12: 69–77PubMedCrossRefGoogle Scholar
  17. 17.
    Kahlke V, Angele MK, Schwacha MG, et al (2000) Reversal of sexual dimorphism in splenic T-lymphocyte responses following trauma-hemorrhage with aging. Am J Physiol 278: C509–0519Google Scholar
  18. 18.
    Schroder J, Kahlke V, Staubach KH, Zabel P, Stuber F (1998) Gender differences in human sepsis. Arch Surg 133: 1200–1205PubMedCrossRefGoogle Scholar
  19. 19.
    Wichmann MW, Inthorn D, Andress HJ, Schildberg FW (2000) Incidence and mortality of severe sepsis in surgical intensive care patients: the influence of patient gender on disease process and outcome. Intensive Care Med 26: 167–172PubMedCrossRefGoogle Scholar
  20. 20.
    Chernow B (1999) Variables affecting outcome in critically ill patients. Chest 115: 71S - 76SPubMedCrossRefGoogle Scholar
  21. 21.
    Eachempati SR, Hydo L, Barie PS (1999) Gender-based differences in outcome in patients with sepsis. Arch Surg 134: 1342–1347PubMedCrossRefGoogle Scholar
  22. 22.
    Zellweger R, Ayala A, Stein S, DeMaso CM, Chaudry IH (1997) Females in proestrus state tolerate sepsis better than males. Crit Care Med 25: 106–110PubMedCrossRefGoogle Scholar
  23. 23.
    Diodato MD, Knöferl MW, Schwacha MG, Bland KI, Chaudry IH (5–7–2001) Gender differences in the inflammatory response and survival following haemorrhage and subsequent sepsis. Cytokine 14: 162 – 169Google Scholar
  24. 24.
    Wohltmann CD, Franklin GA, Boaz PW, et al (2001) A multicenter evaluation of whether gender dimorphism affects survival after trauma. Am J Surg 181: 297–300PubMedCrossRefGoogle Scholar
  25. 25.
    Offner PJ, Moore EE, Biffl WL (1999) Male gender is a risk factor for major infections after surgery. Arch Surg 134: 935–938PubMedCrossRefGoogle Scholar
  26. 26.
    O’Keefe GE, Hunt JL, Purdue GF (2001) An evaluation of risk factors for mortality after burn trauma and the identification of gender-dependent differences in outcomes. J Am Coll Surg 192: 153–160PubMedCrossRefGoogle Scholar
  27. 27.
    Panjeshahin MR, Lari AR, Talei A, Shamsnia J, Alaghehbandan R (2001) Epidemiology and mortality of burns in the South West of Iran. Burns 27: 219–226PubMedCrossRefGoogle Scholar
  28. 28.
    Gregory MS, Duffner LA, Faunce DE, Kovacs EJ (2000) Estrogen mediates the sex difference in post-burn immunosuppression. Endocrinology 164: 129–138CrossRefGoogle Scholar
  29. 29.
    Samy TS, Schwacha MG, Cioffi WG, Bland KI, Chaudry IH (2000) Androgen and estrogen receptors in splenic T lymphocytes: effects of flutamide and trauma-hemorrhage. Shock 14: 465–470PubMedCrossRefGoogle Scholar
  30. 30.
    Olsen NJ, Kovacs WJ (1996) Gonadal steroids and immunity. Endocrin Rev 17: 369–384Google Scholar
  31. 31.
    Hu SK, Mitcho ML, Rath NC (1988) Effect of estradiol on interleukin-1 synthesis by macrophages. Int J Immunopharm 10: 247–252CrossRefGoogle Scholar
  32. 32.
    Carlsten H, Tarkowski A, Holmdahl R, Nilsson LA (1990) Oestrogen is a potent disease accelerator in SLE-prone MRL 1pr/lpr mice. Clin Exp Immunol 80: 467–473PubMedCrossRefGoogle Scholar
  33. 33.
    Svec F, Porter JR (1998) The actions of exogenous dehydroepiandrosterone in experimental animals and humans. Proc Soc Exp Biol Med 218: 174–191PubMedGoogle Scholar
  34. 34.
    Ebeling P, Koivisto VA (1994) Physiological importance of dehydroepiandrosterone. Lancet 343: 1479–1481PubMedCrossRefGoogle Scholar
  35. 35.
    Catania RA, Angele MK, Ayala A, Cioffi WG, Bland KI, Chaudry IH (1999) Dehydroepiandrosterone restores immune function following trauma-haemorrhage by a direct effect on T lymphocytes. Cytokine 11: 443–450PubMedCrossRefGoogle Scholar
  36. 36.
    Angele MK, Catania RA, Ayala A, Cioffi WG, Bland KI, Chaudry IH (1998) Dehydroepiandrosterone: an inexpensive steroid hormone that decreases the mortality due to sepsis following trauma-induced hemorrhage. Arch Surg 133: 1281–1288PubMedCrossRefGoogle Scholar
  37. 37.
    Araneo BA, Shelby J, Li GZ, Ku W, Daynes RA (1993) Administration of dehydroepiandrosterone to burned mice preserves normal immunologic competence. Arch Surg 128: 318–325PubMedCrossRefGoogle Scholar
  38. 38.
    Gala RR (1991) Prolactin and growth hormone in the regulation of the immune system (Mini review). Proc Soc Exp Biol Med 198: 513–527PubMedGoogle Scholar
  39. 39.
    Zhu XH, Zellweger R, Wichmann MW, Ayala A, Chaudry IH (1997) Effects of prolactin and metoclopramide on macrophage cytokine gene expression in late sepsis. Cytokine 9: 437–446PubMedCrossRefGoogle Scholar
  40. 40.
    Zellweger R, Wichmann MW, Ayala A, DeMaso CM, Chaudry IH (1996) Prolactin: a novel and safe immunomodulating hormone for the treatment of immunodepression following severe hemorrhage. J Surg Res 63: 53–58PubMedCrossRefGoogle Scholar
  41. 41.
    Knoferl MW, Angele MK, Ayala A, Cioffi WG, Bland KI, Chaudry IH (2000) Insight into the mechanism by which metoclopramide improves immune functions after trauma-hemorrhage. Am J Physiol 279: C72 - C80Google Scholar
  42. 42.
    Zellweger R, Zhu XH, Wichmann MW, Ayala A, DeMaso CM, Chaudry IH (1996) Prolactin administration following hemorrhagic shock improves macrophage cytokine release capacity and decreases mortality from subsequent sepsis. J Immunol 157: 5748–5754PubMedGoogle Scholar
  43. 43.
    Zellweger R, Wichmann MW, Ayala A, Chaudry IH (1998) Metoclopramide: A novel and safe immunomodulating agent for restoring the depressed macrophage function following trauma-hemorrhage. J Trauma 44: 70–77Google Scholar
  44. 44.
    Walker SE, Besch-Williford CL, Keisler DH (1994) Accelerated deaths from systemic lupus erythematosus in NZB x NZW F1 mice treated with the testosterone-blocking drug flutamide. J Lab Clin Med 124: 401–407PubMedGoogle Scholar
  45. 45.
    Angele MK, Wichmann MW, Ayala A, Cioffi WG, Chaudry IH (1997) Testosterone receptor blockade after hemorrhage in males. Restoration of the depressed immune functions and improved survival following subsequent sepsis. Arch Surg 132: 1207–1214Google Scholar
  46. 46.
    Wichmann MW, Angele MK, Ayala A, Cioffi WG, Chaudry I (1997) Flutamide: A novel agent for restoring the depressed cell-mediated immunity following soft-tissue trauma and hemorrhagic shock. Shock 8: 1–7Google Scholar
  47. 47.
    Schneider CP, Nickel EA, Samy TS, et al (2000) The aromatase inhibitor, 4-hydroxyandrostenedione, restores immune responses following trauma-hemorrhage in males and decreases mortality from subsequent sepsis. Shock 14: 347–353PubMedCrossRefGoogle Scholar
  48. 48.
    Martel C, Rheaume E, Takahashi M, et al (1992) Distribution of 17 beta-hydroxysteroid dehydrogenase gene expression and activity in rat and human tissues. J Steroid Biochem Mol Biol 41: 597–60349PubMedCrossRefGoogle Scholar
  49. 49.
    Samy TS, Knöferl MW, Zheng R, Schwacha MG, Bland KI, Chaudry IH (2001) Divergent immune responses in male and female mice after trauma-hemorrhage: dimorphic alterations in T lymphocyte steroidogenic enzyme activities. Endocrinology 142: 3519–3529PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2002

Authors and Affiliations

  • M. G. Schwacha
  • A. Samy
  • I. H. Chaudry

There are no affiliations available

Personalised recommendations