INTRODUCTION
Acute pancreatitis represents a paradigm of sterile inflammation that progresses to the development of the systemic inflammatory response syndrome and multisystem organ failure. In this regard, it is relatively unique because bacterial products do not initiate and drive forward the inflammatory response. Acute pancreatitis may represent an important model as well as a clinical disease for the investigation of how the inflammatory response dictates disease outcome. It is possible that a final common inflammatory pathway may exist regardless of the initiating agent that precedes organ injury and death.
ACUTE PANCREATITIS: CLINICAL FEATURES IN HUMANS
Epidemiology
There are approximately 5000 new cases of acute pancreatitis per year in the United States with the mortality rate of 9% to 20%. The tabulated data for cause of death maintained by the Centers for Disease Control indicates that there were 8660 deaths from acute pancreatitis in the United States between 1999 and 2001 (www.cdc.gov). The most common causes of acute pancreatitis in the United States are alcohol abuse, gallstones, and idiopathic.
Clinical features
Abdominal pain is the predominant symptom of patients with acute pancreatitis. Nausea and vomiting may accompany the pain. Patients frequently have a low-grade fever, tachycardia, and hypotension.
Laboratory features
Serum amylase is the most commonly used test to diagnose acute pancreatitis. Leukocytosis, with a white blood cell count of greater than 15,000 leukocytes per microliter, is also a frequent finding. Cytokine concentrations in the serum or plasma also have prognostic value (described in greater detail below).
Complications
Of the patients who die, 60% of the mortality will occur within the first 6 days. Pulmonary complications account for a significant number of these deaths, including acute respiratory distress syndrome (1). Acute pancreatitis may be divided into three phases that are present in a continuum. The first phase is the local inflammation of the pancreas that subsequently proceeds to the second, generalized inflammation stage and systemic inflammatory response syndrome. The third and final stage occurs with the development of multiple organ damage (summarized in Fig. 1).
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FIG. 1:
The proinflammatory response to acinar cell damage is balanced by an anti-inflammatory response, resulting in the localization of the immune response to pancreatitis. Migration of proinflammatory mediators into the circulation upsets this balance, resulting in generalized inflammation and the development of a systemic inflammatory response syndrome.
On the basis of this brief overview, it is apparent that acute pancreatitis presents with three of the four diagnostic criteria for systemic inflammatory response syndrome: fever, tachycardia, and leukocytosis (2). Additionally, several prognostic factors have been identified that include indicators of organ failure. As result of these clinical observations in patients, acute pancreatitis is believed to represent a disease state where systemic inflammatory response syndrome has not been initiated by an infection.
ANIMAL MODELS
There are several animal models of acute pancreatitis (for review, see Refs. 3 and 4). The models vary in severity, ranging from those that induce pancreatic edema to those that may progress to multiorgan injury and death. The most common models are briefly described below.
Secretagogue induced
Over 100 years ago, it was reported that neural stimulation may induce damage to the exocrine pancreas. There are several secretagogues that may be used to stimulate the pancreas such as cholecystokinin. One of the most frequently used agents is a cholecystokinin analog, cerulein. This compound may be administered subcutaneously, although intravenous injection yields more reproducible results. The pancreatic damage tends to be mild.
Diet induced
A choline-deficient/ethionine-supplemented diet will induce hemorrhagic pancreatitis. The mortality may be varied by controlling the period of feeding with the defined diet. This pancreatitis evolves more slowly than other forms. Typically, female mice are used.
Bile duct ligation
Ligation of the common bile duct results in leakage of bile back into the pancreatic duct with subsequent inflammation. This model has been used in larger animals, including possums.
Duct perfusion/injection
The pancreatic duct may be directly injected or infused with substances that will induce pancreatitis. Commonly used substances include bile or sodium taurocholate. These models are very reproducible although technically challenging in mice.
POTENTIAL INFLAMMATORY MEDIATORS RESPONSIBLE FOR ACUTE PANCREATITIS
A proposed model for acute pancreatitis involves several steps (1) as shown in Figure 1. In the first step, there is acinar cell damage. The model is independent of the initiating factor for this acinar cell damage, whether it occurs secondary to alcohol abuse, biliary tract obstruction (such as occurs with cholelithiasis), or other factors. The acinar cell damage results in local activation of the immune system, including dendritic cells, macrophages, fibroblasts, T cells, and endothelial cells among others. Some patients will stop at this phase and the pancreatitis and local inflammation will resolve. However, for some unfortunate patients, the disease may progress to systemic illness. Uncontrolled local inflammation leads to systemic inflammatory response syndrome. These patients are at high risk for the development of multisystem organ failure, prolonged hospitalization, and death.
Several inflammatory molecules have been identified as potential final, common pathway mediators that induce multisystem organ failure. Among these are numerous cytokines, including tumor necrosis factor (TNF), interleukin 1β (IL-1β), IL-6, and the chemokines such as IL-8 (1, 5). Platelet-activating factor (PAF) has also been implicated, and clinical trials have been performed with PAF inhibitors (for review, see Ref. 6).
TNF
TNF was originally described as a cytokine that would induce the necrosis of tumors. Several papers have documented that infusion of TNF into experimental animals will cause tissue injury (7, 8).
Induction of TNF during acute pancreatitis-
Using the cerulein model of acute pancreatitis, it has been documented that acinar cells from the pancreas will produce TNF (9). In this study, multiple parameters were evaluated to document the presence of TNF within the acinar cells. TNF was found in isolated and in in vitro-cultured acinar cells. Furthermore, TNF mRNA and protein was found within the pancreas. Immunohistochemistry was performed that also detected the presence of TNF. Additionally, the soluble receptors for TNF were documented to be present. This exhaustive study left little room to doubt that TNF was present during acute pancreatitis. Other studies have also demonstrated the presence of TNF using the cerulein model of acute pancreatitis (10) where multiple modalities were used to document the presence of TNF. Additionally, serum levels of TNF were detectable after the induction of acute pancreatitis. Given the necrosis and tissue inflammation present within the peritoneal cavity, is possible that peritonitis and bacterial translocation were responsible for the induction of TNF. However, in endotoxin-resistant mice, it has been documented that upregulation of TNF mRNA occurs in organs distant from the pancreas (11). Elastase produced during pancreatic injury has been shown to regulate cytokine production in the nearby Kupffer cells of the liver (12). Thus, TNF nicely fits with the model of acinar cell damage progressing to local inflammation that leads to systemic inflammation.
Inhibition of TNF-
To prove a cause-and-effect relationship between increased TNF and the development of acute pancreatitis, it would be desirable to show that inhibition of TNF biological activity reduces the pathophysiology of acute pancreatitis. Studies have documented that blocking TNF in experimental animal models will improve several parameters. Using a bile infusion model of acute pancreatitis, antibody inhibition of TNF was shown to improve survival (13-15). In the choline-deficient diet model of acute pancreatitis, inhibition of TNF activity with TNF-soluble receptors improved outcome, although the timing was also critical (16). In total, each of these four separate studies demonstrate that, regardless of the model of acute pancreatitis, inhibition of the potent cytokine TNF will decrease organ injury and improve survival.
TNF in human acute pancreatitis-
Multiple studies have examined the cytokine levels in patients with acute pancreatitis and have found elevated TNF, as well as soluble receptors for TNF (17). The soluble receptors for TNF were present in greater concentrations than TNF (18). Peripheral blood mononuclear cells isolated from patients with acute pancreatitis demonstrate enhanced release of TNF, although the difference was not statistically significant in this small study (19). In 50 patients with acute pancreatitis, TNF could only be found in 18 patients (20). TNF is under very tight control and is rapidly cleared from the circulation. Thus, it is not surprising that the sustained, high levels are not present in acute pancreatitis.
IL-1β
IL-1β shares several inflammatory properties with TNF and, as indicated by the name, was the first IL to be assigned an IL number. IL-1β will also cause tissue injury when infused into experimental animals (21).
Induction of IL-1 during acute pancreatitis-
IL-1 mRNA and protein have been detected within the pancreas early in the course of experimental pancreatitis (22). The upregulation of IL-1 was shown at the level of mRNA as well as protein (23). Furthermore, the IL-1 mRNA was found not only within the pancreas, but also in distant organs (24). The induction of the IL-1 gene expression was shown to be partially dependent upon the infiltrating leukocytes (25). IL-1 mRNA was postulated to be induced by oxidant stress response genes (26), or possibly to occur in an autoregulatory feedback mechanism (27). Additionally, IL-1 has been shown to be induced in endotoxin- resistant mice, indicating that the cytokine is not merely stimulated by the presence of potential contaminating endotoxin during the acute inflammatory response (28).
Inhibition of IL-1-
There are several methods for decreasing the activity of IL-1. It is possible to block the production of IL-1 by inhibiting the enzymes necessary for the processing of the inactive precursor form of IL-1. This enzyme is referred to as the IL-1-converting enzyme (ICE) or, alternatively, has been renamed caspase 1. When inhibitors of caspase 1 were used for the treatment of acute pancreatitis in experimental animal models, there was a decrease in mortality (29). These results have been repeated by other groups (30). IL-1 has a naturally occurring antagonist that will bind to the IL-1 receptor and prevent IL-1 from binding. With the receptor occupied by the antagonist, IL-1 stimulation will not take place. When IL-1 receptor antagonist (RA) was used in the treatment of acute pancreatitis, there was a significant reduction in mortality (31, 32). These results have been repeated by other groups (33). Further support for the requirement of IL-1 is found in work where the presence of an active IL-1 receptor was necessary for the full development of pancreatitis (27). Additionally, small molecules that inhibit the production of several cytokines, including IL-1, have been shown to attenuate the severity of acute pancreatitis (34). The cytokine leptin decreased the severity of pancreatitis by inhibiting cytokine production, including IL-1 (35).
Detection of IL-1 in human disease-
IL-1β has been found in the serum or plasma of patients with acute pancreatitis (18, 36). Those patients with high levels of IL-1 were seriously ill. In addition to high levels of IL-1, the levels of IL-1 RA were also increased. In general, the levels of IL-1 RA were substantially greater than those of IL-1β (37). Interestingly, caspase 1 also processes the cytokine IL-18, and elevated levels of IL-18 have been found in patients with acute pancreatitis (38).
IL-6
IL-6 is important in the induction of synthesis of acute-phase proteins and has been used as a marker for disease severity in sepsis (39). It is controversial whether it mediates tissue injury or only represents a marker.
Induction of IL-6 during acute pancreatitis-
Several studies have documented that IL-6 is induced in the pancreas during experimental models of acute pancreatitis (22, 32). Additionally, the periacinar myofibroblasts secrete IL-6 during acute pancreatitis (40). It has also been reported that a portion of the induction of IL-6 is related to oxidative stress response genes (26).
Inhibition of IL-6-
As mentioned above, IL-6 is believed to be a marker of disease and not a direct mediator of cellular or organ injury. Although this concept is controversial, and some authors believe that IL-6 may actually mediate organ injury (41), there does not appear to be any studies performed with the blockade of IL-6 activity. However, studies have been done in IL-6 knockout mice using the cerulein model of pancreatitis. In this study, the IL-6 knockout mice had greater inflammation, indicating that endogenous IL-6 may function as an anti-inflammatory mediator in vivo (42).
Detection of IL-6 in human disease-
Consistent with its role as a marker of inflammation in experimental animals and humans, IL-6 levels have been found to closely correlate with the clinical scenario in acute pancreatitis. These findings are summarized in Table 1.
Table 1:
Correlation of plasma or serum levels of IL-6 in human acute pancreatitis
Chemokines, including IL-8
Chemokines are a group of small molecular weight cytokines that recruit and activate inflammatory cells. IL-8 was among the first described chemokines. Chemokines are divided into those with CXC sequences, which predominantly interact with neutrophils, and those with CC sequences, which are important in modulating mononuclear cells.
Induction of chemokines during acute pancreatitis-
First, it should be noted that an exact rodent homolog for the human chemokine IL-8 does not exist. There are several CXC chemokines that demonstrate similar biological activity, but there is no true rat or mouse IL-8. It has been demonstrated that human periacinar myofibroblasts can be induced to exhibit chemokine gene expression (43). Chemokines have also been produced in early acute pancreatitis induced by cerulein injection in rats (44, 45) or pancreatic duct injection of bile in rabbits (46). In some studies, both models were used to induce chemokines in rats (47). In an interesting paper, acinar cells were directly exposed to ethanol in vitro and they expressed chemokines (48).
Inhibition of chemokines-
Similar to IL-6, the role of IL-8 may be more important as a marker of disease severity rather than an actual mediator of organ injury. However, there is also the concept that mediators induced locally during acute pancreatitis may migrate systemically to cause organ injury. In this regard, antibody inhibition of the chemokines has been shown to decrease pancreatitis-associated lung injury in a rat model (49).
Detection of chemokines during human disease-
Plasma or serum levels of IL-8 have been shown to be present during acute pancreatitis. In one study, the IL-8 levels were more predictive of the prognosis of acute pancreatitis than the C-reactive protein levels (50). Other studies also documented elevations of IL-8 and its use as a diagnostic and prognostic indicator (51, 52). Additionally, peripheral blood mononuclear cells from patients with acute pancreatitis have an augmented release of proinflammatory cytokines, including IL-8 (19).
IL-10
IL-10 was originally described as an inhibitor that would decrease the production of proinflammatory cytokines. It has been postulated as a treatment of several inflammatory conditions.
Induction of IL-10 during acute pancreatitis-
During experimental pancreatitis, serum IL-10 levels become elevated, frequently in conjunction with several other cytokines (53).
Use of IL-10 to modulate acute pancreatitis-
In contrast to the previously mentioned cytokines, IL-10 blocks inflammation. Instead of blocking IL-10 to improve outcome, IL-10 is given to experimental animals to actually improve outcome. Exogenous IL-10 has been used to reduce the inflammation in experimental pancreatitis induced by cerulein (53, 54).
IL-10 in human acute pancreatitis-
Elevated levels of IL-10 have been documented in humans with pancreatitis (55). One study specifically determined that IL-10 levels were of prognostic significance (56).
Use of IL-10 in human disease-
There have been two studies investigating the use of IL-10 given before endoscopic retrograde cholangiopancreatography-induced pancreatitis. One study used a dose of 8 μm/kg in 101 patients and showed no therapeutic benefit compared with the 99 patients who received placebo (57). However, when a higher dose of 20 μm/kg was used by another group, there was a significant reduction in the incidence of pancreatitis (58). In a recent report of a clinical trial, IL-10 was not effective in reducing organ injury or days of hospital stay (59). However, there were only 15 patients enrolled in this study.
PAF
PAF is a lipid that binds to a receptor to activate cells. It is frequently upregulated at sites of inflammation. PAF serves to recruit neutrophils. Among the mediators described so far, PAF is the only one to have undergone extensive clinical trials.
Induction of PAF during acute pancreatitis-
PAF has been shown to be released into the peritoneal fluid as well as the bloodstream and the lung after the induction of acute experimental pancreatitis (60). Additionally, infusion of PAF will induce acute pancreatitis in experimental animals (61).
Inhibition of PAF-
There numerous articles where the biological activity of PAF has been inhibited to determine the role of PAF in the pathogenesis of acute pancreatitis in experimental animals. A partial listing of these papers is found in Table 2. There can be little doubt, on the basis of this extensive literature, that PAF represents a critical element in experimental acute pancreatitis.
Table 2:
Partial list of papers demonstrating the value of PAF inhibition in acute pancreatitis
Detection in human disease-
PAF is a very short-lived mediator and it may be difficult to document its presence during acute disease. However, there have been several clinical trials launched on the basis of the strong preliminary data in experimental animals indicating that inhibition of PAF could provide benefits in the treatment of acute pancreatitis. With regard to cytokine modulation, the PAF data is the most mature because large-scale clinical trials have been initiated.
All the clinical trials have used a PAF receptor antagonist (Lexipafant) that binds to and blocks the PAF receptor. These clinical trials, including the limitations, have recently been reviewed (6). In the initial trial, 83 patients were randomized to Lexipafant or placebo (62). This study showed a significant reduction in the incidence of organ failure as well as a reduction in cytokines. Another study examined 50 patients and again documented a reduction in organ failure (63). A larger trial enrolled 290 patients who were randomized to placebo or Lexipafant (64). This study showed that Lexipafant did not improve organ injury compared with placebo. However, 44% of the patients had pre-existing organ injury upon enrollment into the study. Consequently, there was limited ability to document an improvement. The results from human clinical trials of Lexipafant provided conflicting data and were confounded by design issues within the studies, such as the inclusion of patients that experienced organ failure before admission to the studies and inclusion difficulties using APACHE scores. Such issues within the human trials highlight the necessity of careful human trial study design and data interpretation when transitioning from animal models to the human clinical setting.
Other noncytokine mediators
Substance P, a neuropeptide acting through neurokinin 1 receptors (NK1R), was found to act in a proinflammatory manner in a cerulein-induced model of pancreatitis using NK1R-deficient mice (65). Deletion of the NK1R gene resulted in reduced severity of pancreatitis and subsequent lung injury. Additionally, a role has been suggested for higher polyamine levels in a study using a transgenic rat cell line that overexpressed spermidine/spermine N1-acetyltransferase. When zinc was used to induce pancreatic spermidine/spermine N1-acetyltransferase activities in transgenic mice, spermidine and spermine pools were reduced with onset of pancreatitis (66).
CONCLUSIONS
Acute pancreatitis induces a strong inflammatory response in experimental animal models and in humans. Many of the traditional hallmarks of acute inflammation are present in the disease. Included among these are increases in the peripheral blood white count, fever, and tachycardia. Several cytokines are also increased, including TNF, IL-1β, IL-6, and IL-8. Clinical trials have been initiated with PAF receptor antagonists, but despite initial optimism, the large-scale clinical trial failed to show efficacy. Animal models appear to be appropriate for the study of acute pancreatitis, but clinical trials will need to be carefully designed to test immunomodulatory therapy for the treatment of the disease.
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