 |
 |
  |
 |
  |
 |
  |
 |
  |
 |
  |
 |
|
|
The Autodigestion Theory: Inflammation and Shock
|
|
|
|
|
The majority of human diseases have now been associated in human clinical trials with markers for inflammation (e.g. elevated levels of C-reactive protein, oxygen free radicals, cytokines and others). Inflammation consists of a cascade of events that serves to repair tissues after injury but may progresses to apoptosis and organ failure if the trigger mechanisms for the injury persists. Physiological shock is a condition that exhibits one of the most severe forms of inflammation with one of the highest levels of mortality. Over a century of exploration and microvascular research into the underlying mechanisms of shock reveals a plethora of organ pathologies. While progress has been made at the microvascular level, there is no consensus of how this destructive sequence of events plays out at the molecular level. The current bacterial translocation hypothesis does not enjoy unanimous support and several clinical trials designed to interfere with bacteria, endotoxin and their products have failed. In 2000 we postulated and tested a new hypothesis for inflammation in shock and subsequent multi-organ-failure: The Auto-Digestion HypothesisThe basic idea is as follows: Digestive enzymes are discharged from the pancreas in the form of zymogens and activated by enterokinases in the duodenal segments of the upper ileum. These powerful digestive enzymes are fully activated as part of normal digestion as they pass through the lumen of the ileum. Even though proteins, nucleotides, lipids and complex carbohydrates are degraded as part of normal nutrition, digestion of ones own intestinal tissue itself is prevented. Protection against auto-digestion is provided mostly by two special features of the epithelial brush border barrier in the intestine that prevent transport of digestive enzymes into the wall of the intestine, (a) the tight junctions between epithelial cells, and (b) mucus secretion from goblet cells that causes net outward transport away from the brush border barrier. Under shock conditions, however, the tight epithelial barrier is compromised and high molecular weight molecules, like digestive enzymes, may enter into the interstitial space of the intestinal wall. Fully activated digestive enzymes enter into the submucosal space and initiate auto-digestion of unprotected villi structure, a process that leads to their destruction. Digestive enzymes may be carried even into deeper muscle tissue layers of the intestinal wall; they can enter the portal venous circulation, the intestinal lymphatics, and may escape across the serous coat into the peritoneal fluid. A New Opportunity for InterventionBlockade of the powerful digestive enzymes in the lumen of the intestine in situations of shock serves to reduce auto-digestion of the intestine, destruction of the mucosal barrier, and minimizes inflammation in the circulation. Blockade of digestion in the intestine also prevents peripheral organ damage, i.e. multi-organ failure in experimental forms of shock (see references below). The Future OutlookCan this procedure reduce the high mortality associated with development of multi-organ-failure during shock? It needs to be tested in man. We are actively working to translate the procedure to man. Many control experiments are needed. Please contact us if you like to get involved. It could save your own life one day. | |
| Relevant Publications: | |
|
Mitsuoka, H., Kistler, E.B., Schmid-Schönbein, G.W.: Generation of in vivo activating factors in the ischemic intestine by pancreatic enzymes. Proc. Nat. Acad. Sci. U.S.A., 97:1772-1777, 2000. Mitsuoka, H., Schmid-Schönbein, G.W.: Mechanisms for blockade of in-vivo activator production in the ischemic intestine and multiorgan failure. Shock, 14:522-527, 2000 Kistler, E.B., Hugli, T.E., Schmid-Schönbein, G.W.: The pancreas as a source of cardiovascular cell activating factors. Microcirculation, 7:183-192, 2000 Kistler, E.B., Lefer, A.M., Hugli, T.E., Schmid-Schönbein, G.W.: Plasma activation during splanchnic arterial occlusion shock. Shock, 14:30-34, 2000 Schmid-Schönbein, G.W., Hugli, T.E., Kistler, E.B., Sofianos, A., Mitsuoka, H.: Pancreatic enzymes and microvascular cell activation in multiorgan failure. Microcirculation, 8:5-14, 2001. Schmid-Schönbein, G.W., Kistler, E.B., Hugli, T.E.: Mechanisms for cell activation and its consequences for biorheology and microcirculation: multiorgan failure in shock. Biorheology, 38:185-202, 2001 Mitsuoka, H., Kistler, E. B., Schmid-Schönbein, G.W.: Protease inhibition in the intestinal lumen: Attenuation of systemic inflammation and early indicators of multiple organ failure in shock. Shock, 17:205-209, 2002 Fitzal, F. , DeLano, F.A., Young, C., Rosario, H.S, Schmid-Schönbein, G.W.: Pancreatic protease inhibition during shock attenuates cell activation and peripheral inflammation. J. Vasc. Res., 39:320-329, 2002. Fitzal, F. , DeLano, F.A., Young, C., Rosario, H.S., Junger, W.G., Schmid-Schönbein, G.W.: Pancreatic enzymes sustain systemic inflammation after an initial endotoxin challenge. Surgery, 134:446-456, 2003 Waldo, S. W. , Rosario, H. S., Penn, A. H., Schmid-Schönbein, G.W.: Pancreatic digestive enzymes are potent generators of mediators for leukocyte activation and mortality. Shock, 20: 138 - 143, 2003 Kramp, W. J. , Waldo, S., Schmid-Schönbein, G.W., Hoyt, D., Coimbra, R., and Hugli, T.E.: Characterization of two classes of pancreatic shock factors: Functional differences exhibited by hydrophilic and hydrophobic shock factors. Shock, 20:356-362, 2003 Rosário, H.S., Waldo, S.W., Becker, S.A., Schmid-Schönbein, G.W.: Pancreatic trypsin increases matrix metalloproteinase-9 accumulation and activation during acute intestinal ischemia-reperfusion in the rat. Am. J. Pathol., 164:1707-1716, 2004 Doucet, J.J., Hoyt, D.B., Coimbra, R., Schmid-Schönbein, G.W., Junger, W.G., Wolf, P.L., Loomis, W.H., Hugli, T.E.: Inhibition of enteral enzymes by enteroclysis with nafamostat mesilate reduces neutrophil activation and transfusion requirements following hemorrhagic shock. Journal of Trauma, 56:501-510, 2004 Ishimaru, K., Mitsuoka, H., Unno, N., Inuzuka, K., Nakamura, S., and Schmid-Schönbein, G.W.: Pancreatic proteases and inflammatory mediators in peritoneal ascites during splanchnic arterial occlusion and reperfusion. Shock, 22:467-471, 2004 Fitzal, F., Delano, F.A., Young, C., Schmid-Schönbein, G.W.: Delayed intestinal protease inhibition after intestinal ischemia and reperfusion improves early symptoms of shock. Arch. Surg, 139:1008-1016, 2004 Schmid-Schönbein, G.W., Hugli, T.: A new hypothesis for microvascular inflammation in shock and multi-organ failure: Self-digestion by pancreatic enzymes. Microcirculation, 12:71-82, 2005 Acosta, J. A., Hoyt D. B., Schmid-Schönbein G. W., Hugli, T.E., Angaria, D. J. , Frankel, D. A., Coimbra, R.: Intraluminal pancreatic serine protease activity, mucosal permeability and shock: A review. Shock, 26: 3-9, 2006. Penn, A. H., Hugli, T. E., Schmid-Schönbein, G.W.: Pancreatic enzymes generate cytotoxic mediators in the intestine. Shock, 27:296-304, 2007 Penn, A.H., Schmid-Schönbein, G.W.: The intestine as source of cytotoxic mediators in shock: Free fatty acids and degradation of lipid-binding proteins. Am. J. Physiol. Heart Circ., 294:H1779-H1792, 2008. Penn, A.H., Kistler, E.B., Schmid-Schönbein, G.W.: Bioengineering of inflammation and cell activation: Autodigestion in shock. In: Bioengineering in Cell and Tissue Research. G. Artman, S. Chien eds., Chapter 21, Springer Verlag, Berlin, pp 511-527, 2008 Schmid-Schönbein, G.W.: Biomechanical aspects of the auto-digestion theory. Molecular & Cellular Biomechanics, 5:83-95, 2008 Malinoski, D. J., Barrios, C., Kim, H. D., Acosta, J. A., Schmid-Schönbein G. W., Hugli T. E., Coimbra, R., Hoyt D. B.: Role of pancreatic enzymes in the development of multiple organ failure after shock. J. Organ Dysfunction, in press, May 2008 |
