ETIOPATHOGENESIS OF ACUTE PANCREATITIS

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Acute pancreatitis (AP) is a disease characterized by abdominal pain and elevations in the serum levels of amylase and lipase.27 A key feature of AP is the elaboration of an inflammatory reaction,36 which results in edema of the pancreas and extensive local and systemic effects. In the United States, approximately 80% of all causes of AP can be attributed to either gallstones or alcohol.9 Less common but significant factors in the development of AP are drugs, infections, trauma, ischemia, and genetic factors. All of the causes of AP cause a similar pattern of disease, although the severity and complications of each may be different. Thus, it is proposed that the varied causes of AP converge at a common point that initiates a cascade of events that cause pancreatitis. Moreover, it is hoped that by understanding the early events in AP, one may be able to identify the common factors in the pathogenesis of AP and design agents that reduce the severity of the disease.

Despite more than 100 years of extensive research efforts, the cellular mechanisms involved in the pathogenesis of AP are not completely characterized.36 In the last decade, with the development of animal models and advances in methodology, some of the early events in AP have been delineated.11 The discovery of the gene responsible for the development of hereditary pancreatitis has begun to provide a molecular explanation for one form of pancreatitis.12, 64 The critical role of cytokines and inflammation in the pathogenesis of the disease is appreciated. With each added piece of information, the model of pancreatitis as a cascade of pathologic events has emerged. In this article we describe these events and provide evidence from animal and human models. Several detailed reviews on the experimental models of acute pancreatitis and inflammatory reactions have been published.36, 56, 57

Section snippets

OVERVIEW

A central concept in the pathogenesis of AP is that exposure to an causal factor, such as alcohol or gallstones, initiates a cascade of pathologic events that results in the disease (Fig. 1). These events can be divided into early and late phases. The early phase seems to involve primarily the acinar cell. The activation of digestive enzymes in the acinar cell and their retention seem to play a critical role in the early phase. These activated enzymes seem to escape from the zymogen granule and

ABERRANT ZYMOGEN ACTIVATION

Chiari proposed more than 100 years ago that intrapancreatic activation of zymogens leads to pancreatic autodigestion and is a key factor in the pathogenesis of pancreatitis.36 This model is conceptually easy to accept because the pancreatic acinar cell synthesizes potent digestive zymogens that are released in response to food and are activated only after reaching the small intestine. Activation of these enzymes before reaching the small intestine seems to play a key role in disease. This

ACTIVATION OCCURS IN THE ACINAR CELL

Although evidence exists that pathologically activated enzymes can be found in the pancreatic duct and the interstitial space, most data indicate that the acinar cell is the earliest site of activation. Hyperstimulation (10 to 100 fold higher concentrations than to generate maximal enzyme secretion) with CCK or its analogue cerulein in vivo causes an increase in the tryptic activity in the pancreatic fractions enriched in zymogen granules.32 Similarly, hyperstimulation of isolated pancreatic

MECHANISM AND REGULATION OF ZYMOGEN ACTIVATION

Several different mechanisms have been proposed for the activation of zymogens; however, the two that have received the most attention are autoactivation of trypsinogen and cathepsin B activation of trypsinogen.8, 15, 16 It is unclear which of these mechanisms is the predominant one.9 The autoactivation of trypsinogen is enhanced by an acidic pH and the presence of calcium.8

Studies of zymogen activation in the acinar cell largely have been performed in isolated pancreatic acini. Using either

PROTECTIVE MECHANISMS

Because trypsinogen may undergo autoactivation [then one might wonder why the acinar cell does not undergo more self-injury], the acinar cell has evolved the following mechanisms to limit the effect of activated zymogens within the acinar cell:

  • Prevent activation of zymogens

    • Proteins are highly concentrated

    • Low pH compartment not favorable for enzyme activity

  • Block effects of active enzymes

    • Granule membranes are resistant to active enzymes

    • Enzymes are segregated

    • Active enzymes

ETHANOL AND ACTIVATION

The in vivo effects of ethanol are complex, and studies of alcoholic pancreatitis have been hampered by the lack of suitable animal models. Ethanol, however, may sensitize the pancreas to injurious effects of CCK.47 Nonoxidative ethanol metabolites also may sensitize the pancreas to injury. Finally, administration of specific CCK antagonists has been reported to ameliorate pancreatic injury caused by diet,53 bile salts,4 and ischemia,33 suggesting that CCK receptors have a more general role in

CELL AND TISSUE INJURY

The next result of premature zymogen activation and retention of the activated compounds in the acinar cell is a cell injury response.36, 56 The acinar cell releases potent substances that attract neutrophils, form free radicals, and activate platelets and complement system. Each factor has profound local and systemic effects that are responsible for the complications associated with pancreatitis. The importance of understanding these steps in the cascade of pancreatitis is their potential for

CYTOKINES IN PANCREATITIS

Early in the course of pancreatitis, serum and intrapancreatic levels of a number of cytokines are elevated.13, 37 The trypsin that is generated and released in the early course of pancreatitis has the ability to activate the complement system, thus generating the potent chemokines C3a and C5a.48, 49 A critical role for complement activation in acute pancreatitis, however, has not been shown. Proinflammatory agents attract neutrophils and macrophages, which can release more cytokines, such as

SUMMARY

Acute pancreatitis is a disease that has many causes. Each cause seems to affect the acinar cell in some way that results in the premature activation and retention of potent proteolytic enzymes. These activated enzymes then injure the acinar cell and cause the immediate release of cytokines and activate the complement system. Together, these molecules attract and sequester inflammatory cells, in particular neutrophils, which causes further secretion of cytokines, free radicals, and other

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