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British Journal of Sports Medicine logoLink to British Journal of Sports Medicine
. 2001 Aug;35(4):223–230. doi: 10.1136/bjsm.35.4.223

Sepsis and mechanisms of inflammatory response: is exercise a good model?

R Shephard 1
PMCID: PMC1724364  PMID: 11477013

Abstract

Objectives—The immune changes induced by a bout of prolonged and vigorous exercise have been suggested to be a useful experimental model of sepsis and the inflammatory response. Available literature was reviewed to evaluate this hypothesis.

Methods—Literature describing the immune response to various patterns of exercise was compared with data on the immune changes observed during sepsis and inflammation.

Results—Although there are qualitative similarities between the immune responses to exercise and sepsis, the magnitude of the changes induced by most forms of exercise remains much smaller than in a typical inflammatory response. Indeed, the exercise induced changes in some key elements such as plasma cytokine concentrations are too small to be detected reliably by current technology.

Conclusions—If exercise is to provide a valid model of sepsis and the inflammatory response, it will be necessary to focus on subjects who are willing to exercise extremely hard, to use the pattern of exercise that has the greatest effect on the immune system, and to combine this stimulus with other psychological, environmental, or nutritional stressors.

Key Words: sepsis; inflammatory response; exercise; cytokines; endorphins; immune function

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Selected References

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  1. Alexander J. W., Boyce S. T., Babcock G. F., Gianotti L., Peck M. D., Dunn D. L., Pyles T., Childress C. P., Ash S. K. The process of microbial translocation. Ann Surg. 1990 Oct;212(4):496–512. doi: 10.1097/00000658-199010000-00012. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bone R. C., Balk R. A., Cerra F. B., Dellinger R. P., Fein A. M., Knaus W. A., Schein R. M., Sibbald W. J. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. Chest. 1992 Jun;101(6):1644–1655. doi: 10.1378/chest.101.6.1644. [DOI] [PubMed] [Google Scholar]
  3. Bosenberg A. T., Brock-Utne J. G., Gaffin S. L., Wells M. T., Blake G. T. Strenuous exercise causes systemic endotoxemia. J Appl Physiol (1985) 1988 Jul;65(1):106–108. doi: 10.1152/jappl.1988.65.1.106. [DOI] [PubMed] [Google Scholar]
  4. Brenner I. K., Natale V. M., Vasiliou P., Moldoveanu A. I., Shek P. N., Shephard R. J. Impact of three different types of exercise on components of the inflammatory response. Eur J Appl Physiol Occup Physiol. 1999 Oct;80(5):452–460. doi: 10.1007/s004210050617. [DOI] [PubMed] [Google Scholar]
  5. Brenner I. K., Severs Y. D., Rhind S. G., Shephard R. J., Shek P. N. Immune function and incidence of infection during basic infantry training. Mil Med. 2000 Nov;165(11):878–883. [PubMed] [Google Scholar]
  6. Brenner I. K., Severs Y. D., Shek P. N., Shephard R. J. Impact of heat exposure and moderate, intermittent exercise on cytolytic cells. Eur J Appl Physiol Occup Physiol. 1996;74(1-2):162–171. doi: 10.1007/BF00376509. [DOI] [PubMed] [Google Scholar]
  7. Brenner I. K., Shek P. N., Shephard R. J. Infection in athletes. Sports Med. 1994 Feb;17(2):86–107. doi: 10.2165/00007256-199417020-00002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Camus G., Deby-Dupont G., Duchateau J., Deby C., Pincemail J., Lamy M. Are similar inflammatory factors involved in strenuous exercise and sepsis? Intensive Care Med. 1994 Nov;20(8):602–610. doi: 10.1007/BF01705731. [DOI] [PubMed] [Google Scholar]
  9. Camus G., Duchateau J., Deby-Dupont G., Pincemail J., Deby C., Juchmès-Ferir A., Feron F., Lamy M. Anaphylatoxin C5a production during short-term submaximal dynamic exercise in man. Int J Sports Med. 1994 Jan;15(1):32–35. doi: 10.1055/s-2007-1021016. [DOI] [PubMed] [Google Scholar]
  10. Cannon J. G., Meydani S. N., Fielding R. A., Fiatarone M. A., Meydani M., Farhangmehr M., Orencole S. F., Blumberg J. B., Evans W. J. Acute phase response in exercise. II. Associations between vitamin E, cytokines, and muscle proteolysis. Am J Physiol. 1991 Jun;260(6 Pt 2):R1235–R1240. doi: 10.1152/ajpregu.1991.260.6.R1235. [DOI] [PubMed] [Google Scholar]
  11. Castell L. M., Poortmans J. R., Leclercq R., Brasseur M., Duchateau J., Newsholme E. A. Some aspects of the acute phase response after a marathon race, and the effects of glutamine supplementation. Eur J Appl Physiol Occup Physiol. 1997;75(1):47–53. doi: 10.1007/s004210050125. [DOI] [PubMed] [Google Scholar]
  12. Dufaux B., Order U. Complement activation after prolonged exercise. Clin Chim Acta. 1989 Jan 13;179(1):45–49. doi: 10.1016/0009-8981(89)90021-1. [DOI] [PubMed] [Google Scholar]
  13. Evans W. J., Meredith C. N., Cannon J. G., Dinarello C. A., Frontera W. R., Hughes V. A., Jones B. H., Knuttgen H. G. Metabolic changes following eccentric exercise in trained and untrained men. J Appl Physiol (1985) 1986 Nov;61(5):1864–1868. doi: 10.1152/jappl.1986.61.5.1864. [DOI] [PubMed] [Google Scholar]
  14. Fielding R. A., Manfredi T. J., Ding W., Fiatarone M. A., Evans W. J., Cannon J. G. Acute phase response in exercise. III. Neutrophil and IL-1 beta accumulation in skeletal muscle. Am J Physiol. 1993 Jul;265(1 Pt 2):R166–R172. doi: 10.1152/ajpregu.1993.265.1.R166. [DOI] [PubMed] [Google Scholar]
  15. Gannon G. A., Rhind S. G., Suzui M., Shek P. N., Shephard R. J. Circulating levels of peripheral blood leucocytes and cytokines following competitive cycling. Can J Appl Physiol. 1997 Apr;22(2):133–147. doi: 10.1139/h97-011. [DOI] [PubMed] [Google Scholar]
  16. Gannon G. A., Rhind S. G., Suzui M., Zamecnik J., Sabiston B. H., Shek P. N., Shephard R. J. beta-Endorphin and natural killer cell cytolytic activity during prolonged exercise. is there a connection? Am J Physiol. 1998 Dec;275(6 Pt 2):R1725–R1734. doi: 10.1152/ajpregu.1998.275.6.R1725. [DOI] [PubMed] [Google Scholar]
  17. Hansen J. B., Wilsgård L., Osterud B. Biphasic changes in leukocytes induced by strenuous exercise. Eur J Appl Physiol Occup Physiol. 1991;62(3):157–161. doi: 10.1007/BF00643735. [DOI] [PubMed] [Google Scholar]
  18. Iversen P. O., Arvesen B. L., Benestad H. B. No mandatory role for the spleen in the exercise-induced leucocytosis in man. Clin Sci (Lond) 1994 May;86(5):505–510. doi: 10.1042/cs0860505. [DOI] [PubMed] [Google Scholar]
  19. Jones D. A., Newham D. J., Round J. M., Tolfree S. E. Experimental human muscle damage: morphological changes in relation to other indices of damage. J Physiol. 1986 Jun;375:435–448. doi: 10.1113/jphysiol.1986.sp016126. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Jones W. G., 2nd, Minei J. P., Barber A. E., Rayburn J. L., Fahey T. J., 3rd, Shires G. T., 3rd, Shires G. T. Bacterial translocation and intestinal atrophy after thermal injury and burn wound sepsis. Ann Surg. 1990 Apr;211(4):399–405. doi: 10.1097/00000658-199004000-00004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Kappel M., Tvede N., Galbo H., Haahr P. M., Kjaer M., Linstow M., Klarlund K., Pedersen B. K. Evidence that the effect of physical exercise on NK cell activity is mediated by epinephrine. J Appl Physiol (1985) 1991 Jun;70(6):2530–2534. doi: 10.1152/jappl.1991.70.6.2530. [DOI] [PubMed] [Google Scholar]
  22. Maekawa K., Futami S., Nishida M., Terada T., Inagawa H., Suzuki S., Ono K. Effects of trauma and sepsis on soluble L-selectin and cell surface expression of L-selectin and CD11b. J Trauma. 1998 Mar;44(3):460–468. doi: 10.1097/00005373-199803000-00007. [DOI] [PubMed] [Google Scholar]
  23. Marshall J. C. The gut as a potential trigger of exercise-induced inflammatory responses. Can J Physiol Pharmacol. 1998 May;76(5):479–484. doi: 10.1139/cjpp-76-5-479. [DOI] [PubMed] [Google Scholar]
  24. Moldoveanu A. I., Shephard R. J., Shek P. N. Exercise elevates plasma levels but not gene expression of IL-1beta, IL-6, and TNF-alpha in blood mononuclear cells. J Appl Physiol (1985) 2000 Oct;89(4):1499–1504. doi: 10.1152/jappl.2000.89.4.1499. [DOI] [PubMed] [Google Scholar]
  25. Moldoveanu A. I., Shephard R. J., Shek P. N. The cytokine response to physical activity and training. Sports Med. 2001 Feb;31(2):115–144. doi: 10.2165/00007256-200131020-00004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Moore G. E., Holbein M. E., Knochel J. P. Exercise-associated collapse in cyclists is unrelated to endotoxemia. Med Sci Sports Exerc. 1995 Sep;27(9):1238–1242. [PubMed] [Google Scholar]
  27. Mosmann T. R., Coffman R. L. Heterogeneity of cytokine secretion patterns and functions of helper T cells. Adv Immunol. 1989;46:111–147. doi: 10.1016/s0065-2776(08)60652-5. [DOI] [PubMed] [Google Scholar]
  28. Murray D. R., Irwin M., Rearden C. A., Ziegler M., Motulsky H., Maisel A. S. Sympathetic and immune interactions during dynamic exercise. Mediation via a beta 2-adrenergic-dependent mechanism. Circulation. 1992 Jul;86(1):203–213. doi: 10.1161/01.cir.86.1.203. [DOI] [PubMed] [Google Scholar]
  29. Nelson J. L., Alexander J. W., Mao J. X., Vohs T., Ogle C. K. Effect of pentoxifylline on survival and intestinal cytokine messenger RNA transcription in a rat model of ongoing peritoneal sepsis. Crit Care Med. 1999 Jan;27(1):113–119. doi: 10.1097/00003246-199901000-00038. [DOI] [PubMed] [Google Scholar]
  30. Nieman D. C., Berk L. S., Simpson-Westerberg M., Arabatzis K., Youngberg S., Tan S. A., Lee J. W., Eby W. C. Effects of long-endurance running on immune system parameters and lymphocyte function in experienced marathoners. Int J Sports Med. 1989 Oct;10(5):317–323. doi: 10.1055/s-2007-1024921. [DOI] [PubMed] [Google Scholar]
  31. Nieman D. C. Exercise and resistance to infection. Can J Physiol Pharmacol. 1998 May;76(5):573–580. doi: 10.1139/cjpp-76-5-573. [DOI] [PubMed] [Google Scholar]
  32. Nieman D. C. Exercise, upper respiratory tract infection, and the immune system. Med Sci Sports Exerc. 1994 Feb;26(2):128–139. doi: 10.1249/00005768-199402000-00002. [DOI] [PubMed] [Google Scholar]
  33. Nieman D. C., Johanssen L. M., Lee J. W. Infectious episodes in runners before and after a roadrace. J Sports Med Phys Fitness. 1989 Sep;29(3):289–296. [PubMed] [Google Scholar]
  34. Northoff H., Berg A., Weinstock C. Similarities and differences of the immune response to exercise and trauma: the IFN-gamma concept. Can J Physiol Pharmacol. 1998 May;76(5):497–504. doi: 10.1139/cjpp-76-5-497. [DOI] [PubMed] [Google Scholar]
  35. Northoff H., Weinstock C., Berg A. The cytokine response to strenuous exercise. Int J Sports Med. 1994 Oct;15 (Suppl 3):S167–S171. doi: 10.1055/s-2007-1021132. [DOI] [PubMed] [Google Scholar]
  36. Ostrowski K., Rohde T., Zacho M., Asp S., Pedersen B. K. Evidence that interleukin-6 is produced in human skeletal muscle during prolonged running. J Physiol. 1998 May 1;508(Pt 3):949–953. doi: 10.1111/j.1469-7793.1998.949bp.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Ottaway C. A., Fong I. W., da Silva B., Singer W., Karrass L. Integrative aspects of a human model of endotoxemia. Can J Physiol Pharmacol. 1998 May;76(5):473–478. doi: 10.1139/cjpp-76-5-473. [DOI] [PubMed] [Google Scholar]
  38. Pedersen B. K., Ostrowski K., Rohde T., Bruunsgaard H. The cytokine response to strenuous exercise. Can J Physiol Pharmacol. 1998 May;76(5):505–511. doi: 10.1139/cjpp-76-5-505. [DOI] [PubMed] [Google Scholar]
  39. Rhind S. G., Gannon G. A., Suzui M., Shephard R. J., Shek P. N. Indomethacin inhibits circulating PGE2 and reverses postexercise suppression of natural killer cell activity. Am J Physiol. 1999 May;276(5 Pt 2):R1496–R1505. doi: 10.1152/ajpregu.1999.276.5.R1496. [DOI] [PubMed] [Google Scholar]
  40. Rhind S. G., Shek P. N., Shinkai S., Shephard R. J. Effects of moderate endurance exercise and training on in vitro lymphocyte proliferation, interleukin-2 (IL-2) production, and IL-2 receptor expression. Eur J Appl Physiol Occup Physiol. 1996;74(4):348–360. doi: 10.1007/BF02226932. [DOI] [PubMed] [Google Scholar]
  41. Round J. M., Jones D. A., Cambridge G. Cellular infiltrates in human skeletal muscle: exercise induced damage as a model for inflammatory muscle disease? J Neurol Sci. 1987 Dec;82(1-3):1–11. doi: 10.1016/0022-510x(87)90002-5. [DOI] [PubMed] [Google Scholar]
  42. Schedlowski M., Jacobs R., Stratmann G., Richter S., Hädicke A., Tewes U., Wagner T. O., Schmidt R. E. Changes of natural killer cells during acute psychological stress. J Clin Immunol. 1993 Mar;13(2):119–126. doi: 10.1007/BF00919268. [DOI] [PubMed] [Google Scholar]
  43. Severs Y., Brenner I., Shek P. N., Shephard R. J. Effects of heat and intermittent exercise on leukocyte and sub-population cell counts. Eur J Appl Physiol Occup Physiol. 1996;74(3):234–245. doi: 10.1007/BF00377446. [DOI] [PubMed] [Google Scholar]
  44. Shek P. N., Sabiston B. H., Buguet A., Radomski M. W. Strenuous exercise and immunological changes: a multiple-time-point analysis of leukocyte subsets, CD4/CD8 ratio, immunoglobulin production and NK cell response. Int J Sports Med. 1995 Oct;16(7):466–474. doi: 10.1055/s-2007-973039. [DOI] [PubMed] [Google Scholar]
  45. Shek P. N., Shephard R. J. Physical exercise as a human model of limited inflammatory response. Can J Physiol Pharmacol. 1998 May;76(5):589–597. doi: 10.1139/cjpp-76-5-589. [DOI] [PubMed] [Google Scholar]
  46. Shephard R. J., Futcher R. Physical activity and cancer: how may protection be maximized? Crit Rev Oncog. 1997;8(2-3):219–272. doi: 10.1615/critrevoncog.v8.i2-3.40. [DOI] [PubMed] [Google Scholar]
  47. Shephard R. J., Gannon G., Hay J. B., Shek P. N. Adhesion molecule expression in acute and chronic exercise. Crit Rev Immunol. 2000;20(3):245–266. [PubMed] [Google Scholar]
  48. Shephard R. J. Immune changes induced by exercise in an adverse environment. Can J Physiol Pharmacol. 1998 May;76(5):539–546. doi: 10.1139/cjpp-76-5-539. [DOI] [PubMed] [Google Scholar]
  49. Shephard R. J., Shek P. N. Cancer, immune function, and physical activity. Can J Appl Physiol. 1995 Mar;20(1):1–25. doi: 10.1139/h95-001. [DOI] [PubMed] [Google Scholar]
  50. Shephard R. J., Shek P. N. Effects of exercise and training on natural killer cell counts and cytolytic activity: a meta-analysis. Sports Med. 1999 Sep;28(3):177–195. doi: 10.2165/00007256-199928030-00003. [DOI] [PubMed] [Google Scholar]
  51. Shephard R. J., Shek P. N. Immune responses to inflammation and trauma: a physical training model. Can J Physiol Pharmacol. 1998 May;76(5):469–472. doi: 10.1139/cjpp-76-5-469. [DOI] [PubMed] [Google Scholar]
  52. Shephard R. J., Shek P. N. Immune responses to inflammation and trauma: a physical training model. Can J Physiol Pharmacol. 1998 May;76(5):469–472. doi: 10.1139/cjpp-76-5-469. [DOI] [PubMed] [Google Scholar]
  53. Shephard R. J., Shek P. N. Infectious diseases in athletes: new interest for an old problem. J Sports Med Phys Fitness. 1994 Mar;34(1):11–22. [PubMed] [Google Scholar]
  54. Shephard R. J. Special feature for the Olympics: effects of exercise on the immune system: overview of the epidemiology of exercise immunology. Immunol Cell Biol. 2000 Oct;78(5):485–495. doi: 10.1111/j.1440-1711.2000.t01-1-.x. [DOI] [PubMed] [Google Scholar]
  55. Shore S., Shinkai S., Rhind S., Shephard R. J. Immune responses to training: how critical is training volume? J Sports Med Phys Fitness. 1999 Mar;39(1):1–11. [PubMed] [Google Scholar]
  56. Smith E. M. Hormonal activities of cytokines. Chem Immunol. 1992;52:154–169. doi: 10.1159/000319388. [DOI] [PubMed] [Google Scholar]
  57. Smith J. A., Pyne D. B. Exercise, training, and neutrophil function. Exerc Immunol Rev. 1997;3:96–116. [PubMed] [Google Scholar]
  58. Verde T. J., Thomas S. G., Moore R. W., Shek P., Shephard R. J. Immune responses and increased training of the elite athlete. J Appl Physiol (1985) 1992 Oct;73(4):1494–1499. doi: 10.1152/jappl.1992.73.4.1494. [DOI] [PubMed] [Google Scholar]

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