One of the important unresolved issues in physiological shock is understanding the mechanism leading to formation of an inflammatory cascade. Shock is accompanied by cell activation in the microcirculation, leukocyte infiltration, cell dysfunction, apoptosis and organ failure. We recently obtained evidence that pancreatic enzymes serve as a powerful source for generation of humoral inflammatory mediators in the ischemic intestine. Blockade of pancreatic enzymes in the lumen of the ischemic intestine leads to high levels of protection against inflammation and multi-organ failure. Our results point to an important role for pancreatic serine proteinases. In accordance with this evidence we hypothesize that pancreatic digestive enzymes in the intestine can escape across the brush border cell barrier during ischemia and thereafter produce humoral inflammatory mediators by digestion of extracellular matrix proteins and other cellular components.
Our Specific Aims are (1) to identify specific pancreatic enzyme activities which contribute to humoral microvascular activator production in hemorrhagic shock by enzyme blockade in the lumen of the ischemic intestine and by introduction of purified pancreatic enzymes into the lumen of the small intestine; (2) to examine the pancreatic enzyme localization in the tissue before and after intestinal ischemia and determine the production of inflammatory mediator production in the interstitial space of the small intestine; (3) to examine molecular mechanisms for initiation of inflammation in a peripheral organ after activator production by pancreatic enzymes in the intestine; and (4) to purify and characterize selected inflammatory mediators produced by pancreatic enzymes from homogenates of pancreas as an ubiquitous source of inflammatory mediators and from digests of purified extracellular matrix proteins (including fibronectin, vitronectin, and collagen I, III and IV) with serine proteinases. We will study, using state of the art digital in-vivo microscopy, transport and action of pancreatic enzymes in combination with biochemical identification of inflammatory mediators in the rat shock model. Biochemical identification of the inflammatory mediators is facilitated by availability of large quantities of starting material from harvested rat and pig pancreatic tissue. Understanding the trigger mechanisms for inflammation in shock will lead to new treatment modalities in man.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL067825-02
Application #
6527995
Study Section
Cardiovascular and Renal Study Section (CVB)
Program Officer
Hoke, Tracey R
Project Start
2001-09-30
Project End
2006-07-31
Budget Start
2002-08-05
Budget End
2003-07-31
Support Year
2
Fiscal Year
2002
Total Cost
$297,877
Indirect Cost
Name
University of California San Diego
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
077758407
City
La Jolla
State
CA
Country
United States
Zip Code
92093
DeLano, Frank A; Chow, Jason; Schmid-Schönbein, Geert W (2017) Volatile Decay Products in Breath During Peritonitis Shock are Attenuated by Enteral Blockade of Pancreatic Digestive Proteases. Shock 48:571-575
Aletti, Federico; Gambarotta, Nicolò; Penn, Alexander H et al. (2017) Heart period and blood pressure characteristics in splanchnic arterial occlusion shock-induced collapse. J Clin Monit Comput 31:167-175
Schmid-Schönbein, Geert W; Chang, Marisol (2014) The autodigestion hypothesis for shock and multi-organ failure. Ann Biomed Eng 42:405-14
DeLano, Frank A; Hoyt, David B; Schmid-Schönbein, Geert W (2013) Pancreatic digestive enzyme blockade in the intestine increases survival after experimental shock. Sci Transl Med 5:169ra11
Chang, Marisol; Kistler, Erik B; Schmid-Schönbein, Geert W (2012) Disruption of the mucosal barrier during gut ischemia allows entry of digestive enzymes into the intestinal wall. Shock 37:297-305
Penn, Alexander H; Schmid-Schonbein, Geert W (2011) Severe intestinal ischemia can trigger cardiovascular collapse and sudden death via a parasympathetic mechanism. Shock 36:251-62
Schmid-Schönbein, Geert W; Penn, Alex; Kistler, Erik (2011) The Autodigestion Hypothesis in Shock and Multi-Organ Failure: Degrading Protease Activity. Bol Soc Port Hemorreol Microcirc 26:6-15
Schmid-Schönbein, Geert W (2009) 2008 Landis Award lecture. Inflammation and the autodigestion hypothesis. Microcirculation 16:289-306
Schmid-Schonbein, Geert W (2008) Biomechanical aspects of the auto-digestion theory. Mol Cell Biomech 5:83-95
Penn, Alexander H; Schmid-Schonbein, Geert W (2008) 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:H1779-92

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