Pancreatitis severity: Who calls the shots?

doi:10.1053/gast.2002.32761

Gastroenterology

Volume 122, Issue 4, April 2002, Pages 1168-1172

https://doi.org/10.1053/gast.2002.32761 Get rights and content

Abstract

GASTROENTEROLOGY 2002;122:1168-1172

Section snippets

Pancreatitis: A 3-phase disease

The recent studies using the secretagogue-induced models of pancreatitis, as well as a number of other, dissimilar, models have suggested that pancreatitis is a disease that evolves in 3 phases.⁵ The initial phase is characterized by intrapancreatic digestive enzyme activation and acinar cell injury. The second phase is characterized by an intrapancreatic inflammatory reaction and varying degrees of acinar cell necrosis. Finally, the third phase is characterized by further progression of the

Severity determinants

It has been generally believed that the ultimate severity of a pancreatitis attack is, to a great extent, determined during the early stages of its evolution, i.e., during the initial several hours when first and second phase events are unfolding. The first phase of pancreatitis appears to be similar in the otherwise dissimilar models of pancreatitis regardless of their severity and, for that reason, it is unlikely that the events that occur during that first phase are critical determinants of

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Cited by (30)

Cardiovascular manifestations of acute pancreatitis
2011, Journal of Critical Care
Citation Excerpt :
A brief presentation of the pathogenesis of AP is necessary in order to understand the various organ system dysfunctions, including the cardiac manifestations. AP is a disease that evolves in 3 phases [18]: In the first phase, there are intrapancreatic trypsinogen activation and acinar cell injury as a result of release of trypsin. The second phase is characterized by an intrapancreatic inflammatory reaction and varying degrees of acinar cell necrosis.
Acute pancreatitis (AP) is an acute inflammatory process of the pancreas that is associated with variable involvement of pancreatic/peripancreatic tissue and one or more organ systems in varying degrees. Among the multiple organ system dysfunctions in severe AP, cardiovascular and/or pulmonary manifestations are frequent. The cardiovascular system may be affected alone or with other organ systems in all stages of AP. Abnormalities of cardiac rhythm, contractility, and vasomotor tone of peripheral vessels are common cardiovascular manifestations. The pathogenetic factors of cardiac manifestations include hypovolemia and metabolic disturbances (eg, hyperkalemia, hypomagnesemia, and hypophosphatemia). Clinically, patients present with hypotension, tachycardia, and signs of systemic inflammatory response syndrome (high cardiac index, significant pulmonary shunting, decreased systemic vascular resistance, and decreased myocardial contractility). Approximately 50% of patients with AP have electrocardiographic changes, most commonly T-wave flattening and ST-segment depression. Many of the cardiac manifestations in AP are reversible with appropriate management. In AP, early onset of either multi-organ dysfunction or a sustained single-organ dysfunction is associated with poor outcome. This review highlights cardiac manifestations of AP relevant to clinical practice.
The potential effect of proteasome inhibitor PS-341 on severe acute pancreatitis detected by Positron emission tomography in ICR mice
2010, Journal of Surgical Research
Citation Excerpt :
Severe acute pancreatitis is a life threatening disease with high morbidity and mortality [1]. The exact mechanisms by which diverse etiologic factors induce an attack are still unclear, but once the disease process is initiated, the severity of the disease is largely determined by a complex network of activated inflammatory mediators [2–4]. Inhibiting these mediators and suppressing the extensive inflammatory response may provide a specific therapeutic opportunity.
Severe acute pancreatitis is a life threatening disease with a high rate of mortality, and its treatments are still controversial. The purpose of this study is to investigate the potential effects of proteasome inhibitor PS-341 on severe acute pancreatitis induced by cerulein and lipopolysaccharide in mice.
Severe acute pancreatitis was induced by seven intraperitoneal injections of 50 ug/kg cerulein at hourly intervals and one injection of 10mg/kg lipopolysaccharide in mice. Thirty min before the administration of lipopolysaccharide, mice were treated either with PS-341 or vehicle. The severity of acute pancreatitis was then evaluated by serum and pancreatic biochemical assays as well as histologic examination. Positron emission tomography (PET) was used for the first time to determine the therapeutic effects of interventions in situ.
PS-341 significantly inhibited NF-κB activation, while the pancreatic cell apoptosis was significantly enhanced, resulting in the improved parameters such as serum amylase, C-reactive protein, lactate dehydrogenase, interleukin-1β, interleukin-6, and pancreatic myeloperoxidase activity. Accordingly, pancreatic damage, including inflammatory cell infiltration, hemorrhage, and necrosis, was markedly reduced. ¹⁸F-fluorodeoxyglucose-positron emission tomography demonstrated that PS-341 significantly reduced the uptake of ¹⁸F-fluorodeoxyglucose within the pancreas.
These observations demonstrate that PS-341 was able to significantly reduce the severity of acute pancreatitis induced by cerulein and lipopolysaccharide in mice. The potential effect is associated with the inhibition of NF-κB activation and increased pancreatic cell apoptosis within the pancreas. ¹⁸F-fluorodeoxyglucose-positron emission tomography could be a sensitive and promising means in evaluating the therapeutic effect and adjusting medical interventions for pancreatitis.
Hydrogen-rich saline ameliorates the severity of l-arginine-induced acute pancreatitis in rats
2010, Biochemical and Biophysical Research Communications
Citation Excerpt :
Acute pancreatitis (AP) is a common disease with variable severity ranging from a mild and self-limiting condition to a severe form, the latter still being associated with an overall mortality rate of 10–25% [1].
Molecular hydrogen, which reacts with the hydroxyl radical, has been considered as a novel antioxidant. Here, we evaluated the protective effects of hydrogen-rich saline on the l-arginine (l-Arg)-induced acute pancreatitis (AP). AP was induced in Sprague–Dawley rats by giving two intraperitoneal injections of l-Arg, each at concentrations of 250 mg/100 g body weight, with an interval of 1 h. Hydrogen-rich saline (>0.6 mM, 6 ml/kg) or saline (6 ml/kg) was administered, respectively, via tail vein 15 min after each l-Arg administration. Severity of AP was assessed by analysis of serum amylase activity, pancreatic water content and histology. Samples of pancreas were taken for measuring malondialdehyde and myeloperoxidase. Apoptosis in pancreatic acinar cell was determined with terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling technique (TUNEL). Expression of proliferating cell nuclear antigen (PCNA) and nuclear factor kappa B (NF-κB) were detected with immunohistochemistry. Hydrogen-rich saline treatment significantly attenuated the severity of l-Arg-induced AP by ameliorating the increased serum amylase activity, inhibiting neutrophil infiltration, lipid oxidation and pancreatic tissue edema. Moreover, hydrogen-rich saline treatment could promote acinar cell proliferation, inhibit apoptosis and NF-κB activation. These results indicate that hydrogen treatment has a protective effect against AP, and the effect is possibly due to its ability to inhibit oxidative stress, apoptosis, NF-κB activation and to promote acinar cell proliferation.
Acute pancreatitis in a young girl with the Netherton syndrome
2005, Journal of Pediatric Surgery
Acute pancreatitis is uncommon in children younger than 15 years. We present the first report on the association of acute pancreatitis with the Netherton syndrome. The Netherton syndrome is an inherited skin disease characterized by ichthyosiform erythroderma, a pathognomonic hair shaft defect (“bamboo hair”), and atopic features.
A 14-year-old girl with symptoms and signs of severe acute pancreatitis was admitted to our department. A diagnostic workup could not reveal any common known cause of pancreatitis, and the cause of pancreatitis would most likely be considered idiopathic. However, based on recent reports regarding various pathophysiological mechanisms for both acute pancreatitis and the Netherton syndrome (eg, shearing the 5q locus for the respective gene-associated defects in SPINK1 and SPINK5), we speculate if a possible association may exist. Investigations on pancreatitis and the Netherton syndrome may disclose factors closely involved in the pathomechanisms of both. This notion may be of clinical importance as it adds to the number of potential life-threatening events to patients with the Netherton syndrome.
A proinflammatory, antiapoptotic phenotype underlies the susceptibility to acute pancreatitis in cystic fibrosis transmembrane regulator (-/-) mice
2005, Gastroenterology
Background & Aims: Cystic fibrosis transmembrane regulator (CFTR) gene mutations are associated with pancreatic insufficiency and pancreatitis. Chronic pancreatitis, including cystic fibrosis-related disease, may exist as a continuum between acute and chronic disease and may manifest as recurrent pain. We hypothesized that cftr^m1UNC (−/−) mice, which have no evidence of chronic pancreatitis, are susceptible to developing acute pancreatitis.Methods: We used a cerulein hyperstimulation model of acute pancreatitis and measured histological changes, tissue edema, neutrophil infiltration, inflammatory mediators’ mRNA expression, apoptosis markers, and pancreatic trypsin and serum lipase activities. Additionally, we quantitated in vivo pancreatic secretion and pancreatic digestive enzymes. Results: Multiple proinflammatory cytokine genes were constitutively overexpressed in cftr (−/−) pancreas compared with wild-type mice. During acute pancreatitis, cftr (−/−) mice developed more severe acute pancreatitis than wild-type, as indicated by greater pancreatic edema, neutrophil infiltration, mRNA expression of multiple inflammatory mediators, and less apoptotic cell death. In contrast to wild-type mice, cftr (−/−) mice had blunted increases in pancreatic trypsin and serum lipase activities, but similar percentages of pancreatic trypsinogen activation. Finally, cftr (−/−) mice had less in vivo pancreatic secretion in response to cholecystokinin octapeptide and reduced pancreatic digestive enzyme protein and mRNA levels, thus suggesting mild pancreatic insufficiency. Conclusions: A baseline proinflammatory state and an antiapoptotic phenotype may sensitize cftr (−/−) mice to developing more severe acute pancreatitis with an exuberant pancreatic inflammatory response. Cftr (−/−) mice have mild pancreatic insufficiency, which partially explains the blunted increase of pancreatic and serum digestive enzymes during acute pancreatitis. These findings may explain the susceptibility to acute pancreatitis in persons with classic and nonclassic cystic fibrosis.
Ablation of phosphoinositide 3-kinase-γ reduces the severity of acute pancreatitis
2004, American Journal of Pathology
Citation Excerpt :
In agreement with other studies that showed that PI3K signaling pathway is implicated in COX-2 up-regulation in endothelial cells52 and macrophages,53 our data suggest that PI3Kγ may have a role in mediating the increase in COX-2 expression during acute pancreatitis. Unexpectedly, and at variance from other studies,2,12,22,23,27 we did not observe thickening of the alveolar membrane or neutrophil infiltration in the cerulein model at both time points studied, may be because of variable response in different mouse strains. In this study, we observed also a significant protective effect exerted by PI3Kγ genetic ablation on several parameters of pancreatic damage in a second, noninvasive, and lethal model of experimental pancreatitis, based on the administration of a CDE diet to young female mice.26
In pancreatic acini, the G-protein-activated phosphoinositide 3-kinase-γ (PI3Kγ) regulates several key pathological responses to cholecystokinin hyperstimulation in vitro. Thus, using mice lacking PI3Kγ, we studied the function of this enzyme in vivo in two different models of acute pancreatitis. The disease was induced by supramaximal concentrations of cerulein and by feeding mice a choline-deficient/ethionine-supplemented diet. Although the secretive function of isolated pancreatic acini was identical in mutant and control samples, in both models, genetic ablation of PI3Kγ significantly reduced the extent of acinar cell injury/necrosis. In agreement with a protective role of apoptosis in pancreatitis, PI3Kγ-deficient pancreata showed an increased number of apoptotic acinar cells, as determined by terminal dUTP nick-end labeling and caspase-3 activity. In addition, neutrophil infiltration within the pancreatic tissue was also reduced, suggesting a dual action of PI3Kγ, both in the triggering events within acinar cells and in the subsequent neutrophil recruitment and activation. Finally, the lethality of the choline-deficient/ethionine-supplemented diet-induced pancreatitis was significantly reduced in mice lacking PI3Kγ. Our results thus suggest that inhibition of PI3Kγ may be of therapeutic value in acute pancreatitis.

View all citing articles on Scopus

^☆: Address requests for reprints to: Michael Steer, M.D., Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, Massachusetts 02215. Fax: (617) 667-8679; e-mail: [email protected].

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EditorialsPancreatitis severity: Who calls the shots?☆

Abstract

Section snippets

Pancreatitis: A 3-phase disease

Severity determinants

Gastroenterology

Gastroenterology

Gastroenterology

Gastroenterology

Gastroenterology

Gastroenterology

Am J Surg

Gastroenterology

Gastroenterology

Gastroenterology

Gastroenterology

Acute interstitial pancreatitis in rats induced by excessive doses of a pancreatic secretagogue

Virchows Arch A Pathol Anat Histol

Targeted disruption of the beta-chemokine receptor CCR 1 protects against pancreatitis-associated lung injury

J Clin Invest

Editorials
Pancreatitis severity: Who calls the shots?☆