ETIOPATHOGENESIS OF ACUTE PANCREATITIS
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
References (64)
- et al.
Early complement system activation and neutrophil priming in acute pancreatitis: Participation of trypsin
Surgery
(1997) - et al.
Gene targeting demonstrates additive detrimental effects of interleukin 1 and tumor necrosis factor during pancreatitis
Gastroenterology
(1997) - et al.
Lysosomal enzymes and pancreatitis
Gastroenterology
(1995) - et al.
Mutations in the cationic trypsinogen gene are associated with recurrent acute and chronic pancreatitis
Gastroenterology
(1997) - et al.
Chemokine gene expression in rat pancreatic acinar cells in an early event associated with acute pancreatitis
Gastroenterology
(1997) - et al.
The activation of trypsinogen by cathepsin B
J Biol Chem
(1959) - et al.
Effect of recombinant platelet-activating factor acetylhydrolase on two models of experimental acute pancreatitis
Gastroenterology
(1998) - et al.
Evaluation of serum interleukin-6 concentration precedes acute phase response, and reflects severity in acute pancreatitis
Gastroenterology
(1991) - et al.
Isolation and partial characterization of the pancreatic secretory trypsin inhibitor in the rat
Biochim Biophys Acta
(1982) The role of cytokines in the pathogenesis of acute pancreatitis
Am J Surg
(1998)
Interleukin-1 receptor antagonist decreases severity of experimental acute pancreatitis
Surgery
Cysteine protease inhibitor, E-64d, prevents in vitro cerulein-induced trypsinogen activation
Gastroenterology
Acinar cell cytoplasmic vacuole generation in vivo and in vitro under secretagogue hyperstimulation
Gastroenterology
The role of neutrophils and platelet activating factor in mediating experimental pancreatitis
Gastroenterology
Trypsinogen-activation peptides in experimental rat pancreatitis: Prognostic implications and histopathologic correlates
Gastroenterology
Is an elevated concentration of acinar cystolic free ionised calcium the trigger for acute pancreatitis?
Lancet
Role of substance P and the neurokinin 1 receptor in acute pancreatitis and pancreatitis: Associated lung injury
Physiology
Evidence of intracellular activation of serine proteases in acute cerulein-induced pancreatitis in rats
Scand J Gastroenterol
Amelioration of cholinergic-induced pancreatitis with a selective cholecystokinin receptor antagonist
Arch Surg
Gabexate for the prevention of pancreatic damage related to endoscopic retrograde cholangiopancreatography
N Engl J Med
Gabexate for the prevention of pancreatic damage related to endoscopic retrograde cholangiopancreatography
Gastroenterology
Possible lysosomal activation of pancreatic zymogens: Activation of both human trypsinogens by cathepsin B and spontaneous acid activation of human trypsinogen 1
Biol Chem Hoppe Seyler
Acute pancreatitis
Mechanisms of intracellular zymogen activation
Zymogen proteolysis within the pancreatic acinar cell is associated with cellular injury
Am J Physiol
Endogenous cathepsin activates trypsinogen in extracts of dog pancreas
Proc Soc Exp Biol Med
Nitric oxide production regulates cGMP formation and calcium influx in pancreatic acinar cells
Am J Physiol
Pancreatic acinar cells produce, release, and respond to tumor necrosis factor-α
J Clin Invest
Tumor necrosis factor regulates cell death in caerulein-induced pancreatitis
Gastroenterology
Apical secretion of lysosomal enzymes in rabbit pancreas occurs via a secretagogue regulated pathway, and is increased after pancreatic duct obstruction
J Clin Invest
Intra-acinar cell activation of trypsinogen during caerulein-induced pancreatitis in rats
Am J Physiol
Inhibition of TNF-α improves survival in an experimental model of acute pancreatitis
Am Surg
Cited by (117)
Disparities in uptake of cholecystectomy for idiopathic pancreatitis: A nationwide retrospective cohort study
2022, Surgery (United States)Risk of Pancreatitis Following Biliary Stenting With/Without Endoscopic Sphincterotomy: A Randomized Controlled Trial
2022, Clinical Gastroenterology and HepatologyEfficacy of gabexate mesilate in preventing post endoscopic retrograde cholangiopancreatography pancreatitis: A meta-analysis of randomized clinical trials
2021, Journal of the Formosan Medical AssociationAdverse events after biliary sphincterotomy: Does the electric current mode make a difference? A systematic review and meta-analysis of randomized controlled trials
2020, Clinics and Research in Hepatology and GastroenterologyRectal nonsteroidal anti-inflammatory drugs administration is effective for the prevention of post-ERCP pancreatitis: An updated meta-analysis of randomized controlled trials
2017, PancreatologyCitation Excerpt :PEP is associated with prolonged hospitalization when mild; with severe illness, it can lead to pancreatic hemorrhage and necrosis, multi-organ failure, and even death [2]. It has been shown that ERCP-induced systemic inflammatory response is the pathophysiological event that triggers PEP [3–5]. At present, the exact pathological mechanism of PEP has not been thoroughly elucidated.
Address reprint requests to Suresh Karne, MD, PhD, Gastrointestinal Research, Building 27, 950 Campbell Avenue, West Haven Veterans Affairs, Medical Center, West Haven, CT 06516