Shock states are characterized by a pronounced activation of numerous cell types, which leads to an acute inflammatory reaction (1). In clinical practice, this inflammatory response affects not only the local injured tissues but also distant organs, a situation that may lead to multiple system organ failure. Many of the affected distant organs, and their vasculature, continue to show evidence of injury even after adequate resuscitation has been carried out, leading in many cases to death of the organism or severe disability (2-5).
After a century of intense investigation, numerous events have been described in the physiological, biochemical, and microcirculatory milieu of organisms in shock. These studies have attempted to define the physiological end points of resuscitation. Biochemical markers of shock have been well defined and include specific cytokines, such as tumor necrosis factor, interleukins, adhesion molecules, nitric oxide, arachidonic acid products, and oxygen free radicals. An ongoing area of investigation focuses on changes that occur at the microcirculatory level, particularly interactions between the endothelium, platelets, and neutrophils, cells that are activated by a host of inflammatory factors during shock.
Despite many advances in research, the exact mechanism by which the initial insult of shock activates an unabated systemic inflammatory response has yet to be fully elucidated. The gastrointestinal tract has been the object of close scrutiny as a possible site from which inflammatory factors and activators originate. Over the past 40 years, interest has increased in elucidating the role of the pancreas in the pathogenesis of multiorgan failure that often occurs soon after the onset of shock (6-17). The central objective of this review is to examine the hypothesis that digestive enzymes produced by the pancreas, or their products, may play a pivotal role in initiating the systemic inflammatory response. A secondary goal is to elucidate just how these enzymes may ultimately contribute to multiorgan failure and death.
PANCREATIC DIGESTIVE ENZYMES
The pancreas plays the key role in the digestion of complex food molecules into a series of basic nutrients that can more easily be absorbed in the gastrointestinal tract. This is achieved by the synthesis and secretion of powerful pancreatic enzymes into the duodenal lumen. Enzymes that digest proteins, lipids, nucleotides, and carbohydrates include proteases, lipases, nucleases, and amylases. Taken together, these enzymes will digest most food molecules required for normal nutrition. During their transit through the intestine, these enzymes are themselves degraded by the proteases, forming potentially bioactive fragments (18). Biologically active enzyme fragments coupled with the bulk of bioactive food factors (19-21) represent a "toxic" soup that constantly resides in the lumen of the intestine.
The ability of the gastrointestinal tract to prevent self-digestion depends on a compartmentalization of the digestive enzymes to the lumen of the intestine, provided by the barrier properties of the intestinal mucosa. This thin and specialized epithelial barrier (the brush border epithelium), under normal circumstances, is impermeable to molecules the size of pancreatic digestive enzymes. Injury or alteration of this protective barrier may play a key role in the initiation or prolongation of the acute inflammatory response associated with shock. This may occur because of absorption of the various bioactive breakdown products in the intestinal lumen or degradation of elements in the intestinal wall.
Table 1 summarizes the major pancreatic enzymes secreted during digestion. The major group of enzymes secreted by the pancreas that degrade proteins and other foodstuffs is classified mechanistically as serine enzymes. Prominent members of this group of proteases are trypsin, chymotrypsin, and elastase. The serine enzymes have similar catalytic sites containing an essential serine residue (SER-195) involved in hydrolytic bond cleavage. These enzymes are produced in the acinar cells of the pancreas and stored in secretory membrane-bound vesicles in an inactive form, also known as zymogens. Once secreted into the duodenal lumen, the trypsin zymogen, trypsinogen, is activated by enterokinase that is secreted by the brush border of the intestinal mucosa. The activated trypsin then activates more trypsinogen as well as the zymogen chymotrypsinogen. The activated enzymes and their zymogens are normally restricted to the intestinal tract lumen, although low levels may be found in the circulation. Increased levels of trypsin-like activity have been detected in the plasma of pigs subjected to hemorrhagic shock (16).
Trypsinogen is secreted by the human pancreas in 3 isomeric forms: cationic (trypsinogen-1), anionic (trypsinogen-2), and mesotrypsinogen (trypsinogen-3). Once activated, cationic trypsinogen and anionic trypsinogen make up more than 95% of the total trypsin in the duodenal lumen. Mesotrypsinogen accounts for less than 5% of all pancreatic trypsinogen secretion. The active form of mesotrypsinogen, mesotrypsin, is resistant to many natural inhibitors. Its role in the gastrointestinal tract may be to digest food substances rich in protease inhibitors (22).
Other pancreatic digestive enzymes include ribonuclease, deoxyribonuclease, gelatinase, amylase, and lipases. Amylase digests starch into a mixture of maltose and glucose. Lipases hydrolyze ingested fats into a mixture of free fatty acids and 2-monoglycerides. Lipase activity is enhanced by the presence of bile salts. Trypsin, chymotrypsin, and lipase, when added to organ homogenates, have been shown to stimulate cell activation and cell mortality of naive neutrophils (7). Most of the research related to intraluminal pancreatic enzyme inhibition and inflammation has focused on inhibition of proteases.
Pancreatic digestive enzymes, including active proteases, can be found in the blood in very low levels. This may be because of direct secretion into the bloodstream from the pancreas or absorption from the intestinal tract (23). To avoid the uncontrolled activity of proteases, a number of enzyme inhibitors that block their action are found in the circulation. One well-known class of protease inhibitors is the serine protease inhibitors, of which at least 30 types have been described in humans. Plasma serine protease inhibitors include alpha1-antitrypsin, antithrombin III, alpha1-antichymotrypsin, and alpha2-macroglobulin. These molecules act by binding with the proteases and blocking their active sites. Once trypsin enters the circulation, it is rapidly deactivated by alpha2-macroglobulin and alpha1-antitrypsin (24-26).
Protease inhibitors have been used both experimentally and in clinical studies for the treatment of pancreatitis. An animal study in which the protease inhibitor aprotinin was given before induction of acute pancreatitis in rats demonstrated improvement in both hemodynamics and survival (17). A clinically used serine protease inhibitor, nafamostat mesilate (FUT 175, 6-amidino-2-naphthyl p-guanidino-benzoate dimethane-sulfonate), is a synthetic molecule that not only inhibits pancreatic proteases but also has anticomplement, anticoagulation, and antifibrinolytic activity. Clinically, FUT 175 has been proven effective when applied as a continuous regional arterial infusion in patients with acute necrotizing pancreatitis (27).
MULTIPLE SYSTEM ORGAN FAILURE AND THE GUT
The ability to provide improved care for patients with critical illness over the last 30 to 40 years has led to the recognition of a clinical syndrome described as multiple system organ failure. The sequential development of multiorgan failure was extensively described by Fry et al. in 1980 (28). They established specific criteria to define organ systems failure in the lung, kidney, liver, and gastrointestinal tract. Clinical scenarios that have been described as having a causal relationship include hypovolemic shock, massive blood transfusion, chest trauma, sepsis, and pneumonia, to cite a few. The development of an unrelenting activation of neutrophils, endothelial cells, and complement seems to be the fundamental event before overt organ failure. Table 2 summarizes some of the possible mechanisms that may serve as triggers in the development of acute systemic inflammation.
Central to several of these theories is the role that the gut plays in the generation of systemic inflammatory mediators. More than a hundred years ago, gastrointestinal ulcerations were described at autopsy in patients who died after severe burns and prolonged shock (29). Approximately 50 years later, Lillehei showed that if perfusion could be maintained mechanically in the dog intestine during hemorrhagic shock, mortality could be decreased (30). This finding demonstrated that gut hypoperfusion led to increased mortality in shock models. In humans, dehydration and hypotension are well-known factors associated with hemorrhagic necrosis of the intestinal tract (31). It is also well known that during periods of shock and reperfusion, the mucosal barrier in the intestine becomes highly permeable. The exact mechanism that causes these changes is not known. Brush border enzyme activities such as gamma-glutamyltransferase, sucrase, trehalase, and aminopeptidase are reduced in ischemia (32).
It has been shown by Rosario et al. that during ischemia, proteases are able to cross the intestinal mucosal epithelial brush border (33). Once inside the submucosal space, proteases and other digestive enzymes begin to self-digest the intestinal wall. Other substances that penetrate the mucosal barrier include partially digested proteases and food products that may cause endothelial activation and release of vasoactive substances (34).
PANCREATIC ENZYMES AS A SOURCE OF INFLAMMATORY MEDIATORS
The pancreas may serve as a major source of inflammatory mediators (35). The inflammatory mediators that can be produced from homogenized pancreatic tissues are highly cytotoxic, and in vivo, they produce a rapid collapse of the circulation (36). In addition to the pancreas, many organs incubated with pancreatic enzymes (trypsin, chymotrypsin, lipases, and others) will also generate inflammatory mediators with inflammatory activity similar to homogenized pancreas (7). Thus, the distribution of these digestive enzymes or their products suggests a mechanism for eliciting an inflammatory response. The intestine is the site where digestive enzymes are activated and transported and where they remain present in high concentrations. Direct measurements show high levels of pancreatic enzyme activity in the intestine, far beyond levels encountered in other organs (7). Therefore, the hypothesis that the intestine is a major organ in which various inflammatory mediators are produced by the pancreatic digestive enzymes seems to be supported by a host of studies (1). Figure 1 shows an overall view of the interaction of shock, the pancreas, and neutrophil activation based on the pancreatic enzyme hypothesis.
PANCREATIC DUCT LIGATION
Studies dealing with the role of intraluminal pancreatic enzymes in shock have appeared in the medical literature since the late 1960s. These studies have been carried out using different animal models measuring physiological, biochemical, and inflammatory markers. Pancreatic duct ligation (PDL) has been performed by several groups in an attempt to study the effect of gut intraluminal pancreatic enzymes and shock. These studies have had varying results regarding the efficacy of PDL in protecting against the effects of shock. The first of these studies was by Glen et al. in 1972 and used a hemorrhagic model in cats. In this study, the acute and chronic effects of PDL were investigated. When hemorrhagic shock was induced 5 days after PDL, a higher percentage of cats died because of hemorrhagic pancreatitis than in those without PDL. If shock in these animals was not induced for 50 days post PDL, survival was greater in the PDL group than in the controls (37). These findings suggest that pancreatic enzymes already in the gut could be the cause of increased mortality because after 50 days, it is unlikely that enzymes would still be present in the gut lumen.
In 1992, Montgomery et al. performed PDL in pigs followed by hemorrhagic shock 3 weeks later. In their study, PDL ligation did not improve survival, intestinal vascular hemodynamics, or intramucosal tonometry. Histologic examination of the small intestine did show a delay in the development of superficial mucosal injuries in the PDL group (38). The third study was published in 2004 by Cohen et al. and demonstrated that PDL in rats immediately before hemorrhagic shock reduced shock-induced lung injury. Red blood cell injury was attenuated by PDL. The scope of ileal injury was less in the PDL group at 3 h after shock, but this protective effect was no longer present at 24 h (39).
As seen in these 3 studies, PDL leads to variable results. Although PDL prevents new secretion of pancreatic enzymes into the lumen, it does not effectively clear intraluminal enzymes or generated factors already present.
INTRALUMINAL INHIBITOR STUDIES
Early studies began in the late 1960s demonstrated that inhibition of pancreatic enzymes in the gastrointestinal tract attenuated the clinical response to shock (Table 3). An early experimental design used in several of these studies was the superior mesenteric artery (SMA) occlusion model. This involved the occlusion of the SMA for a specific period and the reestablishment of flow with the goal of creating intestinal ischemic reperfusion changes.
In 1969, Bounous used the SMA occlusion model in dogs to study the effect of intraluminal ovomucoid trypsin inhibitor on bowel ischemia and reperfusion. They noticed that blood pressure was maintained in animals receiving trypsin inhibitor. They concluded that the toxin causing hypotension seemed to be a small molecule not bacterial in origin (29). In a similar study, Bounous and McArdle described a significant reduction in chyme (intraluminal) tryptic activity in dogs after SMA occlusion and ovomucoid trypsin inhibitor. In this study, there was a rise in intraluminal acid phosphatase and B-glucorunidase activity, which the authors theorized was from the ischemic gastrointestinal mucosal cells. One conclusion of this study was that the decrease in tryptic activity was due to consumption of this enzyme during the digestion of the structural proteins of the ischemic gut (40). These studies, although able to measure certain enzymes, did not evaluate specific markers of inflammation.
A recent study by Mitsuoka et al. in 2000 using the SMA occlusion model, with and without pancreactic vascular isolation in rats, was designed to determine if systemic inflammation induced by intestinal ischemia occurred via the action of digestive enzymes in the intestinal lumen. Various measures of inflammatory cell activation were determined, including leukocyte counts, leukocyte morphology, tissue myeloperoxidase activity, spectrofluorometric serine protease activity, and tissue histology. These investigators found that pancreatic vascular isolation did not prevent leukocyte activation, an observation they attributed to active enzymes that were already in the lumen of the intestine in sufficient concentrations to cause self-digestion. In contrast, the addition of the serine protease and lipase inhibitor alpha-amidino-2-napthyl p-guanidino-benzoate dimethanesulfate (nafamostat mesilate, Futhan) into the intestinal lumen (and thereby blockade of digestion) inhibited production of inflammatory mediators, leukocyte activation, and symptoms of shock and inflammation (41). It also reduced the level of inflammatory mediators in portal venous plasma and femoral vein blood. The authors also showed that intravenous administration of pancreatic enzyme blockers was ineffective because the enzyme blockers were not administered directly into the major compartment in which the digestive enzyme activity was present, that is, the lumen of the intestine. Mitsuoka et al. showed that protection from symptoms of shock and multiple system organ failure also could be provided by an alternative enzyme inhibitor (gabexate mesilate) if administered into the lumen of the intestine to block self-digestion (42).
To clarify the mechanism by which intraluminal enzymes in combination with oxygen free radicals may initiate the inflammatory cascade, Mitsuoka et al., using an SMA occlusion model, found that adding intraluminal allopurinol (xanthase oxidase inhibitor) did not further help prevent activation of leukocytes or block the inflammatory cascade and multiple system organ failure, suggesting that blockage of the digestive enzymes by itself provided the major protection (43).
In an effort to identify the inflammatory mediators produced by the pancreatic enzymes when they act on autologous tissues, Kramp et al., in an in vitro study using pancreatic homogenates and neutrophil activation, described a possible set of mediators that linked intraluminal pancreatic enzyme inhibition to a decrease in the acute postshock inflammation. Their analysis showed multiple cell activators; some of them were peptidic, and some of them were lipid derived. Both groups of mediators, lipid and peptide, exhibit strong inflammatory activity in vivo and increased mortality in an animal model. The peptidic mediators were shown to have relatively low molecular weights, that is, less than 15 kd, with many of them even below 3000 d. Pancreatic enzyme inhibition prevented their formation (3, 9). In 2002, Fitzal et al. used an SMA rat model and the protease inhibitor gabexate mesilate to demonstrate that intraluminal administration, but not intravenous administration of this protease inhibitor, was able to improve mean arterial pressure and reduce neutrophil activation. This inhibitor also blocked the inflammatory cascade in peripheral muscle. These findings are in line with the hypothesis that pancreatic digestive enzymes produce inflammatory mediators that are generated in or derived from the intestinal tissue itself and have the ability to act on remote innocent bystander organs (44).
In 2003, Deitch et al., using a hemorrhagic rat model with trauma and intraluminal inhibition of pancreatic proteases with nafamostat mesilate, demonstrated that injury to the gut and lung could be prevented (45). This and other studies have confirmed that intravenous use of these inhibitors does not protect against lung or gut injury (44). Other hemorrhagic models of large animals using protease inhibitors have been able to show that intraluminal infusion of Futhan (nafamostat) leads to a reduction in enteral proteases, systemic leukocyte activation, and a reduction in injured mucosal villi and transfusion fluid requirements (46, 47).
Results similar to those in gut ischemia and pancreatic intraluminal blockade have been obtained in sepsis models. Fitzal et al. examined a shock model after administration of a lethal dose of endotoxin, and concomitant digestive enzyme inhibition. They demonstrated that although the endotoxin caused transient systemic inflammatory effects, the intestinal organ structure, as well as central hemodynamic parameters, recovered to the point of controls (8). This was the first evidence to suggest that even septic forms of shock may be associated with digestive enzymes. The endotoxin may be a mediator that enhances intestinal permeability (instead of just intestinal ischemia) and permits the escape of digestive enzymes from the lumen into the wall of the intestine to initiate self-digestion.
The anti-inflammatory effect of intraluminal pancreatic inhibition has been shown to be secondary to protease inhibition rather than mechanical dilution of the pancreatic enzymes. Fitzal et al. demonstrated in 2004 that the digestive protease inhibitor gabexate mesilate given intraluminally prevented further enhancement of apoptosis in cremaster muscle microcirculation above and beyond the values at the time of intestinal lavage. The delayed intestinal enzyme inhibition in this model served to recover normal femoral blood pressure as well as greatly reduced morphological damage to the intestinal mucosa (48). These results were not obtained in a group that had lavage without a protease inhibitor in the buffered solution.
EYE TO THE FUTURE
To establish this pancreas enzyme hypothesis as being clinically relevant in the prevention of systemic inflammatory response syndrome (SIRS), extended animal survival studies must be carried out with intraluminal inhibition of pancreatic enzymes. These studies will have to demonstrate not only attenuation of inflammatory markers but also a survival advantage with this therapy. Although proteases have been widely studied, inhibition of other pancreatic enzymes such as amylases, lipases, and nucleases should be explored. Broad-spectrum intraluminal enzyme inhibitors such as plasma may serve to study the role of inhibition of multiple pancreatic enzymes and activation of SIRS.
SIRS is a complex process that can be initiated by shock. Intraluminal pancreatic enzymes may be one of a group of triggers activated by shock that could lead to SIRS. The combination of intraluminal pancreatic enzyme inhibition coupled with other therapies such as variations in resuscitation models and addition of antioxidants would be an area of further investigation (49).
In conclusion, animal studies using these protease inhibitors have shown that in SMA occlusion, endotoxic shock, and acute hemorrhage models, the hemodynamic parameters are improved by inhibiting intraluminal enzymes. They have also shown that inflammatory cell activation is reduced and the end organ damage, such as in the lung and intestine, is reduced when the protease inhibitors are introduced into the intestinal lumen. This same response is not seen when the inhibitors are given intravenously, leading to the hypothesis that "shock" factors, and not protease per se, must be liberated into the circulation. These factors may include bioactive products released from the submucosal tissue, partially digested fragments from the pancreatic enzymes themselves, and inflammatory mediators generated from digested food. There is increasing evidence that pancreatic enzymes play a significant role in the acute inflammatory process resulting from gut ischemia after hemorrhagic and endotoxic shock. The complex biologic processes in shock are not all well understood, but they do seem to involve indirect involvement by the pancreatic proteases on the circulation via the generation of inflammatory mediator. Possible secondary mechanisms attributable to pancreatic enzymes include activation of membrane metalloproteases and secondary cascades such as the complement system or the thrombotic cascade. Leukocyte, platelet, and endothelial cell activation with the release of cell-derived mediators and oxygen radical products expands the systemic process.
Ultimately, the efficacy of intraluminal enzyme inhibition must be determined in a clinical setting by evaluating its contribution to patient survival.
We thank Dr Mary L. Grebenc for her editorial comments on this article.
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