A journey with Tony Hugli up the inflammatory cascade towards the auto-digestion hypothesis

Abstract

My association with Tony Hugli, long-term editor of Immunopharmacology and International Immunopharmacology, came about by a specific and long-standing problem in inflammation research. What is the trigger mechanism of inflammation in physiological shock? This is an important clinical problem due to the high mortality associated with physiological shock. We joined forces in the search of the answer to this question for more than a decade. Our journey eventually led to development of the hypothesis that shock may be associated with pancreatic enzymes, a set of powerful digestive enzymes that are an integral part of human digestion. The digestive enzymes need to be compartmentalized in the lumen of the intestine where they break down a broad spectrum of biological molecules into their building blocks, suitable for molecular transport across the mucosal epithelium into the circulation. The mucosal epithelial barrier is the key element for compartmentalization of the digestive enzymes. But under conditions when the mucosal barrier is compromised, the fully activated digestive enzymes in the lumen of the intestine are transported into the wall of the intestine, starting an auto-digestion process. In the process several classes of mediators are generated that by themselves have inflammatory activity and upon entry into the central circulation generate the hallmarks of inflammation and eventually cause multi-organ failure. Thus, our journey led to a new hypothesis, which is potentially of fundamental importance for death by multi-organ failure. The auto-digestion hypothesis is in line with the century old observation that the intestine plays a special role on shock -indeed it is the organ for digestion. Auto-digestion may be the prize to pay for life-long nutrition.

Oral melatonin attenuates lung inflammation and airway hyperreactivity induced by inhalation of aerosolized pancreatic fluid in rats

“…These enzymes are normally contained in the lumen of the intestine where they work by breaking down a broad spectrum of biological molecules into their building blocks suitable for transport across the mucosal epithelium and subsequently into the circulation. It has been shown that in situations of ischemia and reperfusion of the gut these powerful digestive enzymes play a central role in the destruction of the intestines and other tissues if they can no longer be compartmentalized within the intestinal lumen [5][6][7]. Under conditions where the mucosal barrier is compromised, the fully activated proteolytic enzymes initiate an auto-digestion process, initially in the intestinal wall.…”

“…Pancreatic enzymes in the pancreatic fluid (PF) may play a central role in the destruction of various tissues because of their ability to cause proteolytic and lipolytic cleavage of the extracellular domain of membrane receptors, resulting in the loss of associated cellular functions. The enzymes may also trigger mechanisms for tissue inflammation and could be the instigating event for the release of a host of strong inflammatory mediators [5][6][7]. PF is released in particularly large amounts from the pancreas after acute pancreatitis.…”

The autodigestion hypothesis: Proteolytic receptor cleavage in rheological and cardiovascular cell dysfunction1

“…Our initial hypothesis followed traditional thinking that there is a mediator in the plasma (e.g. endotoxins, complement components, reactive oxygen species, lipid mediators) that may be responsible for the activation [ 39 ]. Some of these mediators may not only serve to activate but may also be cytotoxic by themselves or as a mixture of different mediators [ 40 , 41 ].…”

“…The specific mechanism(s) by which plasma may produce cell activation remained uncertain. After years of attempts to identify the inflammatory mediators with classical biochemical approaches [ 39 ] we recognized the need for a new approach to this fundamental problem in the pathogenesis of hemorrhagic shock.…”

Transmural Intestinal Wall Permeability in Severe Ischemia after Enteral Protease Inhibition

“…The permeability increases and, as a result, intestinal contents may leak across the mucosal barrier [7] , [8] . After escape from the intestinal lumen, intestinal contents can be transported through the venous intestinal vasculature [9] , [10] , lymphatics [11] , [12] , or via the peritoneum into the systemic circulation [13] , [14] , and may be responsible for distant organ injury [12] , [15] . While many studies have investigated the transport of material into the blood and lymphatics from the intestine, few have investigated the importance of the transmural permeability in mammalian species, a route that provides direct access to peripheral organs, despite its association with poor outcome and death [11] , [14] , [16] .…”