Shock followed by multisystem organ failure is associated with one of the highest mortalities in hospital patients and there is currently no treatment other than alleviation of symptoms. Our objective is to determine molecular mechanisms for initial cell and organ damage and open new possibilities for intervention. In the previous funding period we tested a new hypothesis that the fully activated, non-specific pancreatic digestive enzymes play a central role in cell and organ dysfunction and death. While normally contained in the lumen of the intestine as part of digestion, the powerful digestive enzymes leak into the wall of the intestine as the mucosal epithelial barrier becomes permeable. They digest the intestinal wall and their breakdown products escape into the systemic circulation where they cause cell dysfunction and multisystem organ failure. This evidence has brought into focus that containment of the digestive enzymes inside the lumen of the small intestine is of paramount importance to prevent organ failure. Digestive enzymes do not degrade the mucosal barrier in a normal intestine. Instead, our hypothesis is that during intestinal ischemia, breakdown of the mucin barrier and opening of epithelial junctions is mediated by a set of proteases already present in the intestinal wall and different from digestive enzymes as well as by an apoptosis pathway in the epithelium. We will investigate the currently unexplored, therapeutic possibility of blocking the escape of digestive enzymes as a primary intervention in shock. Failure of the mucosal barrier also results in the translocation of the highly cytotoxic unbound free fatty acids from digestion of ingested fats and from digestion of the intestinal wall while translocation of pancreatic proteases destroys the binding proteins that act as a defense against free fatty acids. The contribution of these low molecular weight biomolecules to inflammation and multiorgan failure in shock is undefined. Furthermore, once protease activity in the systemic circulation increases, proteins in the vasculature are subject to degradation, including membrane receptors. We hypothesize that proteolytic cleavage of receptor ectodomains is a key mechanism for comorbidities in shock, e.g. proteolytic destruction of the ectodomain of adrenergic receptors leads to a reduced response to vasopressor drugs to maintain blood pressure, and ectodomain tight junction cleavage leads to elevated endothelial permeability. We will investigate these central issues for prevention of acute cell and organ damage in shock in a model of splanchnic arterial occlusion shock by the following Specific Aims: Determine the mechanisms for 1. Elevated mucosal permeability to pancreatic digestive enzymes that results in their entry into the wall of the intestine in shock; 2. damage to the intestine and systemic organs (e.g. lungs) during shock by unbound free fatty acids (FFAs); and 3. multisystem organ failure in response to shock, as measured by catecholamine hypo-responsiveness and pulmonary failure due to enzymatic (proteolytic) receptor cleavage. This work will elucidate mechanisms for acute tissue injury and consequent organ dysfunction in shock and open new opportunities to intervene with the morbidity and high mortality of critically ill patients.
Shock and multisystem organ failure are associated with high morbidity and mortality and there is no treatment available for hundreds of thousands of patients in the US alone after retraction in 2012 of a previous approach by the Food and Drug Administration. We propose a new molecular mechanism due to the powerful pancreatic digestive enzymes in the intestine and show that blockade of the digestive enzymes in the lumen of the intestine reduces morbidity and mortality in shock, including for the first time in a shock patient. As novel preventive strategies to minimize organ failure and mortality, we will identify mechanisms that prevent leaking of digestive enzymes across the normally impermeable intestine, determine the role of cytotoxic fragments generated by digestive enzymes in organ injury, as well as elucidate the mechanisms for catecholamine hypo-responsiveness to maintain blood pressure and lung failure and in shock.
|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|
|Santamaria, Marco Henry; Aletti, Federico; Li, Joyce B et al. (2017) Enteral tranexamic acid attenuates vasopressor resistance and changes in ?1-adrenergic receptor expression in hemorrhagic shock. J Trauma Acute Care Surg 83:263-270|
|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|
|Braga, D; Barcella, M; D'Avila, F et al. (2017) Preliminary profiling of blood transcriptome in a rat model of hemorrhagic shock. Exp Biol Med (Maywood) 242:1462-1470|
|Schmid-Schönbein, Geert W (2016) The autodigestion hypothesis: Proteolytic receptor cleavage in rheological and cardiovascular cell dysfunction1. Biorheology 53:179-191|
|Schmid-Schönbein, Geert W (2016) Is Matrix Metalloproteinase-8 Activity in the Mucosal Barrier a Requirement for Leakage of Cecal Material in Peritonitis? Crit Care Med 44:854-5|
|Altshuler, Angelina E; Kistler, Erik B; Schmid-Schönbein, Geert W (2016) Autodigestion: Proteolytic Degradation and Multiple Organ Failure in Shock. Shock 45:483-9|
|Aletti, Federico; Maffioli, Elisa; Negri, Armando et al. (2016) Peptidomic Analysis of Rat Plasma: Proteolysis in Hemorrhagic Shock. Shock 45:540-54|
|Alsaigh, Tom; Chang, Marisol; Richter, Michael et al. (2015) In vivo analysis of intestinal permeability following hemorrhagic shock. World J Crit Care Med 4:287-95|
|Mazor, Rafi; Schmid-Schönbein, Geert W (2015) Proteolytic receptor cleavage in the pathogenesis of blood rheology and co-morbidities in metabolic syndrome. Early forms of autodigestion. Biorheology 52:337-52|
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