Seminars

A record of clinical trials indicates that many human diseases are accompanied by inflammation. Since inflammation is fundamentally a tissue repair mechanism, the evidence suggests that inflammatory markers in plasma, such as c-reactive protein, fibrinogen, cytokines and others, are synthesized as part of a tissue repair cascade. Our research is now focused on analysis of mechanisms that lead to tissue injury in the first place and thereby initiate inflammation.  

I will discuss the case of hemorrhagic and septic shock and multi-organ failure, conditions with high levels of inflammatory markers and high rates of mortality.  In spite of numerous clinical trials there is currently no treatment for shock other than alleviation of symptoms.  The intestine plays a central role in shock and multiorgan failure.  It has been hypothesized that bacteria in the intestine and toxins generated by them lead to inflammation and organ failure.  But clinical trials in septic patients have not confirmed this hypothesis.  

Instead, we propose that the powerful digestive enzymes, synthesized in the pancreas and discharged into the small intestine as requirement for normal digestion, play a central role in multi-organ failure.  These enzymes are non-specific, highly concentrated and fully activated in the lumen of the intestine. During normal digestion they are compartmentalized in the lumen of the intestine by the mucosal epithelial barrier.  But if this barrier becomes permeable, e.g. in an ischemic state, the digestive enzymes escape into the wall of the intestine.  In a process we designated as autodigestion they digest tissues in the wall of the intestine and generate small molecular weight fragments, which are cytotoxic, e.g. unbound free fatty acid.  Digestive enzymes also clip the ectodomain of surface receptors and so compromise their function, for example they cleave the insulin receptor causing insulin resistance.  The combination of digestive enzymes and cytotoxic fragments leaking into the central circulation causes many cell and organ dysfunctions, and ultimately may lead to full organ failure and death.  We have shown that blockade of digestive enzymes inside the lumen of the intestine serves to reduce inflammation and improve survival in multiple models of experimental shock.  

Supported by NIH Grants HL 67825 and GM 85072 and by an unrestricted gift from Leading Biosciences Inc..