69. autodigestion in hemorrhagic shock: a two-step process
Name: Asimina S Courelli
Grad Year: 2019
Hemorrhagic Shock (HS), which results from transient reduction of the blood pressure and blood flow, accounts for over 40% of patient deaths within 24 hours of hospital admission. HS is accompanied by systemic inflammation, edema, coagulation and multi-organ failure with extensive tissue damage. There is no treatment, other than alleviation of symptoms, due to the lack of understanding of the underlying tissue breakdown mechanisms. We proposed that tissue damage during HS is due to Autodigestion. Digestive enzymes (e.g. serine proteases like trypsin synthesized in the pancreas) are normally contained in the lumen of the intestine by the mucosal barrier (an epithelium with a mucin coating). But in autodigestion, the mucosal barrier fails due to reduced blood flow to the intestine. Consequently the digestive enzymes leak into the wall of the small intestine and into the circulation where they generate widespread tissue failure. Analyzing these mechanisms is essential for design of effective interventions against HS. We investigated (by mass spec analysis and immunohistochemistry) the proteases that may open the mucosal barrier to digestive enzymes and found that matrix metalloproteinases (MMP2/9) and cysteine proteases (Cathepsin B) are activated in HS. Cathepsin B is present predominantly inside the epithelial cells in a normal intestine but during HS is released into the surrounding tissue where it cleaves epithelial tight junctions and breaks down the mucin layer, thereby opens the mucosal barrier and allows escape of digestive enzymes from the lumen into the wall of the intestine. Blockade of Cathepsin B with a specific inhibitor serves to maintain the mucin layer in HS and decreases penetration of pancreatic trypsin into the intestinal mucosa. MMP2/9 is found in epithelial cells and in circulating leukocytes that accumulate in the intestinal microcirculation in HS. MMP2/9 has been detected during intestinal tissue damage and in distal organ damage (e.g. in the lung). But there is need for further analysis how this protease affects the mucosal barrier in HS. Our current analysis of the autodigestion process indicates that escape of digestive enzymes from the lumen of the intestine in hemorrhagic shock involves different families of proteases (including Cathepsin B) that have the ability to break down the mucosal barrier in the intestine and thereby allow the powerful digestive enzymes to leak into the circulation where they in turn cause organ failure and death.
Industry Application Area(s)
Life Sciences/Medical Devices & Instruments