Annals of Biomedical Engineering

, Volume 42, Issue 2, pp 405–414 | Cite as

The Autodigestion Hypothesis for Shock and Multi-organ Failure

Article

Abstract

An important medical problem with high mortality is shock, sepsis and multi-organ failure. They have currently no treatments other than alleviation of symptoms. Shock is accompanied by strong markers for inflammation and involves a cascade of events that leads to failure in organs even if they are not involved in the initial insult. Recent evidence indicates that pancreatic digestive enzymes carried in the small intestine after mixing with ingested food are a major cause for multi-organ failure. These concentrated and relatively non-specific enzymes are usually compartmentalized inside the intestinal lumen as requirement for normal digestion. But after breakdown of the mucosal barrier they leak into the wall of the intestine and start an autodigestion process that includes destruction of villi in the intestine. Digestive enzymes also generate cytotoxic mediators, which together are transported into the systemic circulation via the portal venous system, the intestinal lymphatics and via the peritoneum. They cause various degrees of cell and organ dysfunction that can reach the point of complete organ failure. Blockade of digestive enzymes in the lumen of the intestine in experimental forms of shock serves to reduce breakdown of the mucosal barrier and autodigestion of the intestine, organ dysfunctions and mortality.

Keywords

Pancreatic digestive enzymes Trypsin Mucin Epithelium Sepsis Inflammation Unbound free fatty acids 

References

  1. 1.
    Altshuler, A. E., M. J. Morgan, S. Chien, and G. W. Schmid-Schönbein. Proteolytic activity attenuates the response of endothelial cells to fluid shear stress. Cell. Mol. Bioeng. 5:82–91, 2012.PubMedCentralPubMedCrossRefGoogle Scholar
  2. 2.
    Altshuler, A. E., A. H. Penn, J. A. Yang, G. R. Kim, and G. W. Schmid-Schönbein. Protease activity increases in plasma, peritoneal fluid, and vital organs after hemorrhagic shock in rats. PLoS ONE 7:e32672, 2012.PubMedCentralPubMedCrossRefGoogle Scholar
  3. 3.
    Arndt, H., C. W. Smith, and D. N. Granger. Leukocyte-endothelial cell adhesion in spontaneously hypertensive and normotensive rats. Hypertension 21:667–673, 1993.PubMedCrossRefGoogle Scholar
  4. 4.
    Bacsy, E., Z. Nagy, and M. Papp. Intra-acinar lipolysis, an early sign of intravital pancreatic autodigestion. Acta Med. Acad. Sci. Hung 27:331–335, 1970.PubMedGoogle Scholar
  5. 5.
    Barroso-Aranda, J., and G. W. Schmid-Schönbein. Transformation of neutrophils as indicator of irreversibility in hemorrhagic shock. Am. J. Physiol. 257:H846–H852, 1989.PubMedGoogle Scholar
  6. 6.
    Barroso-Aranda, J., B. W. Zweifach, J. C. Mathison, and G. W. Schmid-Schönbein. Neutrophil activation, tumor necrosis factor, and survival after endotoxic and hemorrhagic shock. J. Cardiovasc. Pharmacol. 25(Suppl 2):S23–S29, 1995.PubMedCrossRefGoogle Scholar
  7. 7.
    Chang, M. Mucin Disruption and Transport of Digestive Enzymes in Early Stages of Intestinal Ischemia. Ph.D. Thesis, University of California San Diego, 2012.Google Scholar
  8. 8.
    Chang, M., T. Alsaigh, E. B. Kistler, and G. W. Schmid-Schönbein. Breakdown of mucin as barrier to digestive enzymes in the ischemic rat small intestine. PLoS ONE 7:e40087, 2012.PubMedCentralPubMedCrossRefGoogle Scholar
  9. 9.
    Chang, M., E. B. Kistler, and G. W. Schmid-Schönbein. Disruption of the mucosal barrier during gut ischemia allows entry of digestive enzymes into the intestinal wall. Shock 37:297–305, 2012.PubMedCentralPubMedCrossRefGoogle Scholar
  10. 10.
    Chen, A. Y., F. A. DeLano, S. R. Valdez, J. N. Ha, H. Y. Shin, and G. W. Schmid-Schönbein. Receptor cleavage reduces the fluid shear response in neutrophils of the spontaneously hypertensive rat. Am. J. Physiol. Cell Physiol. 299:C1441–C1449, 2010.PubMedCrossRefGoogle Scholar
  11. 11.
    Chen, A. Y., J. N. Ha, F. A. Delano, and G. W. Schmid-Schönbein. Receptor cleavage and P-selectin-dependent reduction of leukocyte adhesion in the spontaneously hypertensive rat. J. Leukoc. Biol. 299:C1441–C1449, 2012.Google Scholar
  12. 12.
    Deitch, E. A., H. P. Shi, Q. Lu, E. Feketeova, and D. Z. Xu. Serine proteases are involved in the pathogenesis of trauma-hemorrhagic shock-induced gut and lung injury. Shock 19:452–456, 2003.PubMedCrossRefGoogle Scholar
  13. 13.
    Del Sorbo, L., and A. S. Slutsky. Acute respiratory distress syndrome and multiple organ failure. Curr. Opin. Crit. Care 17:1–6, 2011.PubMedCrossRefGoogle Scholar
  14. 14.
    Delano, F. A., D. B. Hoyt and G. W. Schmid-Schönbein. Pancreatic digestive enzyme blockade in the intestine increases survival after experimental shock. Sci. Transl. Med. 5:169ra11, 2013.Google Scholar
  15. 15.
    DeLano, F. A., and G. W. Schmid-Schönbein. Proteinase activity and receptor cleavage: mechanism for insulin resistance in the spontaneously hypertensive rat. Hypertension 52:415–423, 2008.PubMedCentralPubMedCrossRefGoogle Scholar
  16. 16.
    Dinarello, C. A. Proinflammatory and anti-inflammatory cytokines as mediators in the pathogenesis of septic shock. Chest 112:321S–329S, 1997.PubMedCrossRefGoogle Scholar
  17. 17.
    Doucet, J. J., D. B. Hoyt, R. Coimbra, G. W. Schmid-Schönbein, W. G. Junger, L. W. Paul, W. H. Loomis, and T. E. Hugli. Inhibition of enteral enzymes by enteroclysis with nafamostat mesilate reduces neutrophil activation and transfusion requirements after hemorrhagic shock. J. Trauma 56:501–510, 2004; discussion 510–511.Google Scholar
  18. 18.
    Fitzal, F., F. A. Delano, C. Young, H. S. Rosario, W. G. Junger, and G. W. Schmid-Schönbein. Pancreatic enzymes sustain systemic inflammation after an initial endotoxin challenge. Surgery 134:446–456, 2003.PubMedCrossRefGoogle Scholar
  19. 19.
    Fitzal, F., F. A. DeLano, C. Young, H. S. Rosario, and G. W. Schmid-Schönbein. Pancreatic protease inhibition during shock attenuates cell activation and peripheral inflammation. J. Vasc. Res. 39:320–329, 2002.PubMedCrossRefGoogle Scholar
  20. 20.
    Fitzal, F., F. A. DeLano, C. Young, and G. W. Schmid-Schönbein. Improvement in early symptoms of shock by delayed intestinal protease inhibition. Arch. Surg. 139:1008–1016, 2004.PubMedCrossRefGoogle Scholar
  21. 21.
    Hanson, P. J., A. P. Moran, and K. Butler. Paracellular permeability is increased by basal lipopolysaccharide in a primary culture of colonic epithelial cells; an effect prevented by an activator of Toll-like receptor-2. Innate Immun. 17:269–282, 2011.PubMedCrossRefGoogle Scholar
  22. 22.
    Herold, S., K. Mayer, and J. Lohmeyer. Acute lung injury: how macrophages orchestrate resolution of inflammation and tissue repair. Front. Immunol. 2:65, 2011.PubMedCentralPubMedCrossRefGoogle Scholar
  23. 23.
    Ishimaru, K., H. Mitsuoka, N. Unno, K. Inuzuka, S. Nakamura, and G. W. Schmid-Schönbein. Pancreatic proteases and inflammatory mediators in peritoneal fluid during splanchnic arterial occlusion and reperfusion. Shock 22:467–471, 2004.PubMedCrossRefGoogle Scholar
  24. 24.
    Kim, H. D., D. J. Malinoski, B. Borazjani, M. S. Patel, J. Chen, J. Slone, X. M. Nguyen, E. Steward, G. W. Schmid-Schönbein, and D. B. Hoyt. Inhibition of intraluminal pancreatic enzymes with nafamostat mesilate improves clinical outcomes after hemorrhagic shock in swine. J. Trauma 68:1078–1083, 2010.PubMedCrossRefGoogle Scholar
  25. 25.
    Kistler, E. B., T. Alsaigh, M. Chang, and G. W. Schmid-Schönbein. Impaired small-bowel barrier integrity in the presence of lumenal pancreatic digestive enzymes leads to circulatory shock. Shock 38:262–267, 2012.PubMedCentralPubMedCrossRefGoogle Scholar
  26. 26.
    Kistler, E. B., T. E. Hugli, and G. W. Schmid-Schönbein. The pancreas as a source of cardiovascular cell activating factors. Microcirculation 7:183–192, 2000.PubMedCrossRefGoogle Scholar
  27. 27.
    Kistler, E. B., A. M. Lefer, T. E. Hugli, and G. W. Schmid-Schönbein. Plasma activation during splanchnic arterial occlusion shock. Shock 14:30–34, 2000.PubMedCrossRefGoogle Scholar
  28. 28.
    Koenig, W., M. Sund, M. Frohlich, H. G. Fischer, H. Lowel, A. Doring, W. L. Hutchinson, and M. B. Pepys. C-Reactive protein, a sensitive marker of inflammation, predicts future risk of coronary heart disease in initially healthy middle-aged men: results from the MONICA (Monitoring Trends and Determinants in Cardiovascular Disease) Augsburg Cohort Study, 1984 to 1992. Circulation 99:237–242, 1999.PubMedCrossRefGoogle Scholar
  29. 29.
    Kollias, G., E. Douni, G. Kassiotis, and D. Kontoyiannis. The function of tumour necrosis factor and receptors in models of multi-organ inflammation, rheumatoid arthritis, multiple sclerosis and inflammatory bowel disease. Ann. Rheum. Dis. 58(Suppl 1):I32–I39, 1999.PubMedCrossRefGoogle Scholar
  30. 30.
    Lee, Y. T., J. Wei, Y. C. Chuang, C. Y. Chang, I. C. Chen, C. F. Weng, and G. W. Schmid-Schönbein. Successful treatment with continuous enteral protease inhibitor in a patient with severe septic shock. Transpl. Proc. 44:817–819, 2012.CrossRefGoogle Scholar
  31. 31.
    Lefer, A. M., and Y. Barenholz. Pancreatic hydrolases and the formation of a myocardial depressant factor in shock. Am. J. Physiol. 223:1103–1109, 1972.PubMedGoogle Scholar
  32. 32.
    Lefkowitz, R. B., G. W. Schmid-Schönbein, and M. J. Heller. Whole blood assay for elastase, chymotrypsin, matrix metalloproteinase-2, and matrix metalloproteinase-9 activity. Anal. Chem. 82:8251–8258, 2010.PubMedCrossRefGoogle Scholar
  33. 33.
    Li, L., and J. L. Messina. Acute insulin resistance following injury. Trends Endocrinol. Metab. 20:429–435, 2009.PubMedCentralPubMedCrossRefGoogle Scholar
  34. 34.
    Libby, P. Inflammatory mechanisms: the molecular basis of inflammation and disease. Nutr. Rev. 65:S140–S146, 2007.PubMedCrossRefGoogle Scholar
  35. 35.
    Lichtenberger, L. M. The hydrophobic barrier properties of gastrointestinal mucus. Annu. Rev. Physiol. 57:565–583, 1995.PubMedCrossRefGoogle Scholar
  36. 36.
    Marti-Carvajal, A., G. Salanti, and A. F. Cardona. Human recombinant activated protein C for severe sepsis. Cochrane Database Syst. Rev. CD004388, 2008.Google Scholar
  37. 37.
    Matthews, J. B., J. A. Smith, K. J. Tally, M. J. Menconi, H. Nguyen, and M. P. Fink. Chemical hypoxia increases junctional permeability and activates electrogenic ion transport in human intestinal epithelial monolayers. Surgery 116:150–157, 1994; discussion 157–158.Google Scholar
  38. 38.
    Mitsuoka, H., E. B. Kistler, and G. W. Schmid-Schönbein. Generation of in vivo activating factors in the ischemic intestine by pancreatic enzymes. Proc. Natl. Acad. Sci. U.S.A. 97:1772–1777, 2000.PubMedCentralPubMedCrossRefGoogle Scholar
  39. 39.
    Mitsuoka, H., E. B. Kistler, and G. W. Schmid-Schönbein. Protease inhibition in the intestinal lumen: attenuation of systemic inflammation and early indicators of multiple organ failure in shock. Shock 17:205–209, 2002.PubMedCrossRefGoogle Scholar
  40. 40.
    Mitsuoka, H., and G. W. Schmid-Schönbein. Mechanisms for blockade of in vivo activator production in the ischemic intestine and multi-organ failure. Shock 14:522–527, 2000.PubMedCrossRefGoogle Scholar
  41. 41.
    Nagai, H., H. Henrich, P. H. Wunsch, W. Fischbach, and J. Mossner. Role of pancreatic enzymes and their substrates in autodigestion of the pancreas. In vitro studies with isolated rat pancreatic acini. Gastroenterology 96:838–847, 1989.PubMedGoogle Scholar
  42. 42.
    Penn, A. H., A. E. Altshuler, J. W. Small, S. F. Taylor, K. R. Dobkins, and G. W. Schmid-Schönbein. Digested formula but not digested fresh human milk causes death of intestinal cells in vitro: implications for necrotizing enterocolitis. Pediatr. Res. 72:560–567, 2012.PubMedCentralPubMedCrossRefGoogle Scholar
  43. 43.
    Penn, A. H., T. E. Hugli, and G. W. Schmid-Schönbein. Pancreatic enzymes generate cytotoxic mediators in the intestine. Shock 27:296–304, 2007.PubMedCrossRefGoogle Scholar
  44. 44.
    Penn, A. H., and G. W. Schmid-Schönbein. The intestine as source of cytotoxic mediators in shock: free fatty acids and degradation of lipid-binding proteins. Am. J. Physiol. Heart Circ. Physiol. 294:H1779–H1792, 2008.PubMedCrossRefGoogle Scholar
  45. 45.
    Raman, K., M. Chong, G. G. Akhtar-Danesh, M. D’Mello, R. Hasso, S. Ross, F. Xu, and G. Pare. Genetic markers of inflammation and their role in cardiovascular disease. Can. J. Cardiol. 29:67–74, 2013.PubMedCrossRefGoogle Scholar
  46. 46.
    Redd, M. J., L. Cooper, W. Wood, B. Stramer, and P. Martin. Wound healing and inflammation: embryos reveal the way to perfect repair. Philos. Trans. R. Soc. Lond. B Biol. Sci. 359:777–784, 2004.PubMedCrossRefGoogle Scholar
  47. 47.
    Richter, M. D. Protease activity in mesenteric lymph following splanchnic arterial occlusion. UC San Diego, M.S. Thesis, 2012.Google Scholar
  48. 48.
    Rivers, E., B. Nguyen, S. Havstad, J. Ressler, A. Muzzin, B. Knoblich, E. Peterson, and M. Tomlanovich. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N. Engl. J. Med. 345:1368–1377, 2001.PubMedCrossRefGoogle Scholar
  49. 49.
    Rodrigues, S. F., E. D. Tran, Z. B. Fortes, and G. W. Schmid-Schönbein. Matrix metalloproteinases cleave the beta2-adrenergic receptor in spontaneously hypertensive rats. Am. J. Physiol. Heart Circ. Physiol. 299:H25–H35, 2010.PubMedCrossRefGoogle Scholar
  50. 50.
    Schmid-Schönbein, G. W. Analysis of inflammation. Annu. Rev. Biomed. Eng. 8:93–131, 2006.PubMedCrossRefGoogle Scholar
  51. 51.
    Tonelli, M., F. Sacks, M. Pfeffer, G. S. Jhangri, and G. Curhan. Biomarkers of inflammation and progression of chronic kidney disease. Kidney Int. 68:237–245, 2005.PubMedCrossRefGoogle Scholar
  52. 52.
    Tong, S., H. J. Neboori, E. D. Tran, and G. W. Schmid-Schönbein. Constitutive expression and enzymatic cleavage of ICAM-1 in the spontaneously hypertensive rat. J. Vasc. Res. 48:386–396, 2011.PubMedCrossRefGoogle Scholar
  53. 53.
    Tran, E. D., F. A. DeLano, and G. W. Schmid-Schönbein. Enhanced matrix metalloproteinase activity in the spontaneously hypertensive rat: VEGFR-2 cleavage, endothelial apoptosis, and capillary rarefaction. J. Vasc. Res. 47:423–431, 2010.PubMedCrossRefGoogle Scholar
  54. 54.
    Tran, E. D., M. Yang, A. Chen, F. A. Delano, W. L. Murfee, and G. W. Schmid-Schönbein. Matrix metalloproteinase activity causes VEGFR-2 cleavage and microvascular rarefaction in rat mesentery. Microcirculation 18:228–237, 2011.PubMedCentralPubMedCrossRefGoogle Scholar
  55. 55.
    Valdez, S. R. Serotonin 5HT-1A Receptor Density in the Brain of the Spontaneously Hypertensive Rats. San Diego, MS: Univ. Calif, 2010.Google Scholar
  56. 56.
    Waldo, S. W., H. S. Rosario, A. H. Penn, and G. W. Schmid-Schönbein. Pancreatic digestive enzymes are potent generators of mediators for leukocyte activation and mortality. Shock 20:138–143, 2003.PubMedCrossRefGoogle Scholar
  57. 57.
    Weidenbusch, M., and H. J. Anders. Tissue microenvironments define and get reinforced by macrophage phenotypes in homeostasis or during inflammation, repair and fibrosis. J. Innate Immun. 4:463–477, 2012.PubMedCrossRefGoogle Scholar
  58. 58.
    Westergaard, H., and J. M. Dietschy. Delineation of the dimensions and permeability characteristics of the two major diffusion barriers to passive mucosal uptake in the rabbit intestine. J. Clin. Invest. 54:718–732, 1974.PubMedCentralPubMedCrossRefGoogle Scholar
  59. 59.
    Zweifach, B. W. Hemorrhagic shock in germ-free rats. Ann. N. Y. Acad. Sci. 78:315–319, 1959.PubMedCrossRefGoogle Scholar

Copyright information

© Biomedical Engineering Society 2013

Authors and Affiliations

  1. 1.Department of Bioengineering, The Institute of Engineering in MedicineUniversity of California San DiegoLa JollaUSA

Personalised recommendations