Pathophysiology Of Pancreatitis Research Articles

Peroxiredoxin-I Sustains Inflammation During Pancreatitis.

Peroxiredoxin-I Sustains Inflammation During Pancreatitis.

Genetics, Cell Biology, and Pathophysiology of Pancreatitis

Since the discovery of the first trypsinogen mutation in families with hereditary pancreatitis, pancreatic genetics has made rapid progress. The identification of mutations in genes involved in the digestive protease-antiprotease pathway has lent additional support to the notion that pancreatitis is a disease of autodigestion. Clinical and experimental observations have provided compelling evidence that premature intrapancreatic activation of digestive proteases is critical in pancreatitis onset. However, disease course and severity are mostly governed by inflammatory cells that drive local and systemic immune responses. In this article, we review the genetics, cell biology, and immunology of pancreatitis with a focus on protease activation pathways and other early events.

Implications of gallbladder cholesterolosis and cholesterol polyps?

BackgroundThe clinical significance of cholesterolosis has not been well established but there are some provocative, if not robust, studies of the role it may play in the pathophysiology of pancreatitis and biliary dyskinesia, as well as hypercholesterolemia. Our aim was to take advantage of a very large cholecystectomy (CCY) database to support or refute these potentially important reported associations. Materials and methodsA retrospective review of 6868 patients who underwent CCY from 2001–2013 was performed. Comparisons were made using the student t-test for continuous and chi-square analysis for categorical, variables. ResultsAmong patients for whom the CCY was the primary operation, 1053 (18%) had cholesterolosis and 4596 did not. Compared to those without cholesterolosis, those with cholesterolosis were no more likely to have elevated cholesterol levels (P = 0.64) nor low gallbladder ejection fraction (P = 0.2). To evaluate cholesterolosis as a cause of pancreatitis, all patients with gallstones were eliminated, leaving 639 patients. Among these, not only was cholesterolosis not associated with more pancreatitis, but rather there was not a single patient with or without cholesterolosis who had pancreatitis. ConclusionsDespite prior reports of associations between cholesterolosis and elevated serum cholesterol, depressed ejection fraction, and increased risk of pancreatitis, careful analysis of this current, larger data set does not support these associations. Any patient with stones or sludge, or with biliary dyskinesia, and appropriate symptoms, should be considered for CCY, with or without suspected cholesterolosis.

Acinar cell-specific knockout of the PTHrP gene decreases the proinflammatory and profibrotic responses in pancreatitis

Pancreatitis is a necroinflammatory disease with acute and chronic manifestations. Accumulated damage incurred during repeated bouts of acute pancreatitis (AP) can lead to chronic pancreatitis (CP). Pancreatic parathyroid hormone-related protein (PTHrP) levels are elevated in a mouse model of cerulein-induced AP. Here, we show elevated PTHrP levels in mouse models of pancreatitis induced by chronic cerulein administration and pancreatic duct ligation. Because acinar cells play a major role in the pathophysiology of pancreatitis, mice with acinar cell-specific targeted disruption of the Pthrp gene (PTHrP(Δacinar)) were generated to assess the role of acinar cell-secreted PTHrP in pancreatitis. These mice were generated using Cre-LoxP technology and the acinar cell-specific elastase promoter. PTHrP(Δacinar) exerted protective effects in cerulein and pancreatic duct ligation models, evident as decreased edema, histological damage, amylase secretion, pancreatic stellate cell (PSC) activation, and extracellular matrix deposition. Treating acinar cells in vitro with cerulein increased IL-6 expression and NF-κB activity; these effects were attenuated in PTHrP(Δacinar) cells, as were the cerulein- and carbachol-induced elevations in amylase secretion. The cerulein-induced upregulation of procollagen I expression was lost in PSCs from PTHrP(Δacinar) mice. PTHrP immunostaining was elevated in human CP sections. The cerulein-induced upregulation of IL-6 and ICAM-1 (human acinar cells) and procollagen I (human PSCs) was suppressed by pretreatment with the PTH1R antagonist, PTHrP (7-34). These findings establish PTHrP as a novel mediator of inflammation and fibrosis associated with CP. Acinar cell-secreted PTHrP modulates acinar cell function via its effects on proinflammatory cytokine release and functions via a paracrine pathway to activate PSCs.

The role of Ca2+ in the pathophysiology of pancreatitis

Acute pancreatitis is a human disease in which the pancreatic pro-enzymes, packaged into the zymogen granules of acinar cells, become activated and cause autodigestion. The main causes of pancreatitis are alcohol abuse and biliary disease. A considerable body of evidence indicates that the primary event initiating the disease process is the excessive release of Ca2+ from intracellular stores, followed by excessive entry of Ca2+ from the interstitial fluid. However, Ca2+ release and subsequent entry are also precisely the processes that control the physiological secretion of digestive enzymes in response to stimulation via the vagal nerve or the hormone cholecystokinin. The spatial and temporal Ca2+ signal patterns in physiology and pathology, as well as the contributions from different organelles in the different situations, are therefore critical issues. There has recently been significant progress in our understanding of both physiological stimulus–secretion coupling and the pathophysiology of acute pancreatitis. Very recently, a promising potential therapeutic development has occurred with the demonstration that the blockade of Ca2+ release-activated Ca2+ currents in pancreatic acinar cells offers remarkable protection against Ca2+ overload, intracellular protease activation and necrosis evoked by a combination of alcohol and fatty acids, which is a major trigger of acute pancreatitis.

Pathophysiology of Acute Pancreatitis: Potential Application from Experimental Models and Human Medicine to Dogs

The cellular events leading to pancreatitis have been studied extensively in experimental models. Understanding the cellular events and inciting causes of the multisystem inflammatory cascades that are activated with this disease is of vital importance to advance diagnosis and treatment of this condition. Unfortunately, the pathophysiology of pancreatitis in dogs is not well understood, and extrapolation from experimental and human medicine is necessary. The interplay of the inflammatory cascades (kinin, complement, cytokine) is extremely complex in both initiating leukocyte migration and perpetuating disease. Recently, nitric oxide (NO) and altered microcirculation of the pancreas have been proposed as major initiators of inflammation. In addition, the role of the gut is becoming increasingly explored as a cause of oxidative stress and potentiation of systemic inflammation in pancreatitis.

Serotonin regulates amylase secretion and acinar cell damage during murine pancreatitis

ObjectiveSerotonin (5-hydroxytryptamine, 5-HT) is a potent bioactive molecule involved in a variety of physiological processes. In this study, the authors analysed whether 5-HT regulates zymogen secretion in pancreatic acinar cells...

Acute and Chronic Pancreatic Inflammation

Acute and Chronic Pancreatic Inflammation

Pancreatitis

Pancreatitis, or inflammation of the pancreas, has a variety of etiologies. Severity of the disease can range from its mildest form, which resolves quickly with few complications, to its most severe form, necrotizing pancreatitis, which is associated with an increased risk for developing multiple system organ failure and mortality. Treatment of pancreatitis aims to eliminate the etiologic factors for the disease while managing its complications and preventing further disease progression. Patients with mild forms of pancreatitis may improve with symptom management, whereas those with more severe disease will need significant supportive interventions. Most patients are managed medically. Surgery may be indicated for severe pancreatitis. It is important to understand the disease process and its impact on other organ systems when caring for these patients. Accurate assessment of changes in the patient's condition can lead to interventions that can limit complications and reduce the risk of mortality. This article reviews the pathophysiology of pancreatitis, its diagnosis and treatment, associated complications and their management, and essential nursing assessment and interventions.

Pancreatitis

Pancreatitis, or inflammation of the pancreas, has a variety of etiologies. Severity of the disease can range from its mildest form, which resolves quickly with few complications, to its most severe form, necrotizing pancreatitis, which is associated with an increased risk for developing multiple system organ failure and mortality. Treatment of pancreatitis aims to eliminate the etiologic factors for the disease while managing its complications and preventing further disease progression. Patients with mild forms of pancreatitis may improve with symptom management, whereas those with more severe disease will need significant supportive interventions. Most patients are managed medically. Surgery may be indicated for severe pancreatitis. It is important to understand the disease process and its impact on other organ systems when caring for these patients. Accurate assessment of changes in the patient’s condition can lead to interventions that can limit complications and reduce the risk of mortality. This article reviews the pathophysiology of pancreatitis, its diagnosis and treatment, associated complications and their management, and essential nursing assessment and interventions.

CYTOSOLIC CATHEPSIN B INDUCES APOPTOTIC ACINAR CELL DEATH DURING PANCREATITIS

Acinar cells are the primary site of injury as pancreatitis develops, which quickly leads to acinar cell death. The intra-acinar activation of trypsinogen is the initial trigger of acinar cell injury, and there is sufficient evidence in literature to suggest that cathepsin B is responsible for intra-acinar trypsinogen activation. It is believed that the activated trypsin causes further damage to acinar cells. No other role of cathepsin B besides that in trypsinogen activation has been documented as regards the pathophysiology of pancreatitis. The aim of this study is to demonstrate that, in addition to activating trypsinogen, cathepsin B plays an important role in acinar cell death initiation. Methods: Pancreatic acinar cells were prepared 60 minutes after either single i.p. injections of caerulein (10 μg/kg), or 4 h of l-arginine (5 g/kg); trypsinogen activation, cathepsin B distribution, and caspase 3 activation were compared with acinar cells from control animals. For in vitro studies, permeabilized acinar cells were stimulated with supra-maximal caerulein for 60 minutes; cytosolic and pellet fractions were prepared by centrifugation. Trypsin activation, cathepsin B distribution, and caspase 3 activation in response to supra-maximal caerulein stimulation were compared with control animals. Results: Cytosolic cathepsin B was significantly increased in acinar cells prepared from caerulein (caerulein: 13.91 ± 2.7 vs control: 2.41 ± 0.98% of total) or L-arginine-administered animals, compared to that prepared from control animals (L-arginine: 9.23 ± 0.98 vs control: 2.27 ± 0.23% of total). This was accompanied by a significant increase in caspase-3 activity (182.67 ± 13.2% of control). In vitro studies also showed a significant redistribution of cathepsin B to the cytosolic fraction (caerulein: 20.6 ± 2.13 vs control: 2.01 ± 0.12% of total) and caspase-3 activation (233 ± 5.56% of control). In the presence of cathepsin B-specific inhibitors, caspase-3 activation was inhibited (125 ± 5.6 vs. 233 ± 5.6). There was a significant increase in apoptosis of acinar cells stimulated with supramaximal caerulein as compared to control (158.0 ± 8.4%) and this was inhibited in the presence of cathepsin B-specific inhibitors. Conclusions: In addition to its known role in trypsinogen activation, cathepsin B also plays an important role in pancreatitis by activating caspase-3 and triggering acinar cell apoptosis.

ROLE OF INTERLEUKIN 18 IN NITRIC OXIDE PRODUCTION AND PANCREATIC DAMAGE DURING ACUTE PANCREATITIS

The release of the immunomodulator, interleukin 18 (IL-18) into sera early in acute pancreatitis (AP) corresponds to disease severity. IL-18 induces nitric oxide (NO), which is involved in the pathophysiology of pancreatitis. The objective of this study was to clarify the role of IL-18 in pathogenesis and NO production during early AP using recombinant mouse (rm) IL-18 protein and IL-18 gene knockout (KO) mice. After pretreatment with phosphate-buffered saline or rmIL-18, wild-type (WT) or KO mice were injected intraperitoneally with phosphate-buffered saline (sham) or cerulein (AP) hourly for 3 h. Blood, pancreas, spleen, and liver were collected until 24 h after the first dose. Main outcome measures were serum IL-18, amylase and lipase levels, histological evaluation of the pancreas with parenchyma vacuolization of acinar cells, mRNA expression of inducible NO synthase (iNOS) in the pancreas, and spleen, liver, and plasma NO metabolite level. Serum IL-18 was significantly increased immediately after induction of AP in WT mice. Serum amylase, lipase, and the numbers of acinar cells with parenchyma vacuolization were significantly higher in the group AP/KO than in the group AP/WT, but these parameters were improved by dose-dependent pretreatment with rmIL-18 administration in both groups. Pancreatic iNOS gene expression and plasma NO metabolites were significantly increased by 6 h after the initiation of AP, but were significantly lower in the group AP/KO than in the AP/WT mice. Pretreatment with rmIL-18 also significantly increased these levels in both groups. Splenic and hepatic iNOS expression was not changed after the initiation of AP in WT mice, whereas pretreatment with rmIL-18 also increased these levels. Administration of aminoguanidine, a selective iNOS inhibitor, before AP induction abolished the protective effect of pretreatment with rmIL-18 on pancreatic injury. IL-18 appears to protect the pancreas during early induced-induced AP in mice, probably through induction of NO release from an iNOS source. IL-18 may be a target for new AP therapeutics.

Pharmacological management of pancreatitis

Pancreatitis is a common disease with substantial morbidity and mortality. Pharmacological therapy for the prevention and treatment of pancreatitis is an intense subject of investigation. The use of proteinase inhibitors such as gabexate mesylate in the prevention of post-endoscopic retrograde cholangiopancreatography pancreatitis (ERCP) has been disappointing. Initial studies using ulinastatin are promising but additional dose-response studies are needed. Somatostatin, but not octreotide, is likely to be effective in the prevention of post-ERCP pancreatitis. Rectal diclofenac might provide a simple, cheap alternative but large-scale studies are again needed. New insights into the role of proteinase-activated receptor-2 in the pancreas add to the complexity of the mechanisms involved in the pathophysiology of pancreatitis, and the development of specific agonists and antagonists of this receptor is necessary to assess their therapeutic potential in the prevention and management of pancreatitis.

ESPEN guidelines on nutrition in acute pancreatitis

This article presents a consensus of the current knowledge on physiology and pathophysiology of pancreatitis, development of common terminology and criteria to be adopted in clinical trials, and recommendations for nutrition support in mild‐to‐severe pancreatitis.

P38 Map Kinase Is Expressed in the Pancreas and Is Immediately Activated following Cerulein Hyperstimulation

Background: The pathophysiology of pancreatitis and the pancreatic stress response are not well understood. In the pancreas, mitogen-activated protein kinase (MAPK) and stress-activated protein kinase (SAPK) are reportedly regulated by secretagogue stimulation and hyperstimulation. However, no data exist on the expression and regulation of pancreatic p38 Map kinase. Aims: Pancreatic expression of p38 Map kinase and MAPK, SAPK and p38 regulation during pancreatic stress were investigated. Methods: For hyperstimulation and secretory stress, cerulein was given intravenously, while hyperthermia preconditioning stress was induced by whole body hyperthermia (42°C). Results: In addition to MAPK and SAPK, p38 Map kinase was found to be expressed in the rat pancreas. Cerulein regulated all kinases time- and dose-dependently. MAPK and p38 Map kinase showed basal activity and were further activated at low cerulein doses. SAPK had no basal activity and its activation required maximal secretory to supramaximal amounts of cerulein. Cerulein hyperstimulation, inducing pancreatitis, activated p38 more rapidly than SAPK and more strongly than MAPK. In contrast to cerulein hyperstimulation stress, hyperthermia stress only activated p38 Map kinase. Conclusions: p38 Map kinase is expressed in the pancreas and is most rapidly activated following cerulein hyperstimulation. Both SAPK and p38 Map kinase are possibly important regulators during the onset of cerulein pancreatitis.

Protease-antiprotease imbalance, hemodynamic and regional blood flow changes in experimental pancreatitis.

Pathologic proteolysis in pancreatitis is an important clue to understand the pathophysiology in pancreatitis. Impairment of pancreatic circulation is also important in the development of severe pancreatitis. In an attempt to study some of the biochemical and circulatory events in experimental pancreatitis in the pig the following experiments were undertaken. Pancreatic and splanchnic blood flow were studied in severe and mild pancreatitis with the microsphere method, together with cardiac output and mean arterial pressure. Kininogen, alpha-2-macroglobulin and alpha-1-proteinase inhibitor were measured in plasma and in peritoneal fluid. In severe pancreatitis consumption of kininogen in the peritoneal cavity was demonstrated together with a final lowering of the plasma protease inhibitors. This was accompanied by a rapid reduction of cardiac output and finally mean arterial blood pressure. Pancreatic blood flow was profoundly diminished in this group. No such changes were found in mild pancreatitis. It is concluded that pancreatic ischemia in pancreatitis is associated with protease-antiprotease imbalance.

Effects of Prostaglandin and Indomethacin on Diet-Induced Acute Pancreatitis in Mice

This study was performed to determine the effects of exogenous prostaglandin and a prostaglandin synthetase inhibitor on experimental pancreatitis in mice. An ethionine-supplemented choline-deficient diet was used to induce pancreatitis in 4-6-wk-old Swiss Webster mice. Mice were injected subcutaneously with 16,16-dimethyl prostaglandin E2 (0.1, 1.0, 10 micrograms X kg-1 X day-1), indomethacin (0.05, 0.5, 5 mg X kg-1 X day-1), or saline for 7 days. The ethionine-supplemented choline-deficient diet was introduced 24 h after the first injection, and animals ate the test diet for 48 h. A 55% mortality was observed in control animals (n = 100) treated with carrier alone. Treatment with 10 micrograms X kg-1 X day-1 of 16,16-dimethyl prostaglandin E2 significantly decreased (p less than 0.01) mortality to 12% (n = 100). Improved survival was accompanied by a significant (p less than 0.05) decrease in the pancreatic content of free chymotrypsin and a decrease in histologic damage. Treatment with 5 mg X kg-1 X day-1 of indomethacin (n = 30) significantly (p less than 0.01) increased mortality in diet-treated rats from a control rate of 55% to 100%. These studies demonstrate a protective effect of prostaglandin on the pancreas and suggest a role for endogenous prostaglandins in the pathophysiology of pancreatitis.

Complications of Pancreatitis: Medical and Surgical Management

This superbly written and well-organized monograph deals with the clinical aspects of the complications of pancreatitis, irrespective of the etiology. The 13 chapters are written by acknowledged experts, mainly surgeons. Their overall emphasis is on clinical management of all systemic and local complications, many of which are often life threatening. The pathophysiology of pancreatitis and its ramifications is covered in sufficient detail to enable the reader to follow each specific complication from development to treatment. Specific guidelines are given regarding the sequence of investigations, their use and abuse, and the available options in the treatment of each problem. Although the flavor of the book is surgical, the purely medical and metabolic aspects of the disease are also covered in depth. The book is not a technical-surgical treatise, and therapy is dealt with by emphasizing the theoretical pros and cons of each approach without belaboring the technical details. Case reports add

Functional characteristics and lysosomal integrity of the isolated perfused cat pancreas

The isolated cat pancreas perfused with a physiological salt solution plus low molecular-weight dextran functions satisfactorally for at least 2 1 2 hours. Evidence for stability and functional integrity of the preparation included measurements of vascular resistance, arterial and venous pH, PO 2, and PCO 2, pancreatic juice volumes and trypsin concentrations, and studies of acinar cell ultrastructure. Total specific β-glucuronidase activity of the unstimulated perfused pancreas was comparable to that seen in the intact cat pancreas. However, pancreozymin and secretin decreased the total β-glucuronidase activity of the perfused pancreas. Pancreozymin also increased the release of β-glucuronidase from lysosomal suspensions of liver and pancreas. β-Glucuronidase activity rose in the pancreatic juice, duodenal secretion, perfusate, and the bathing medium of the hormonally stimulated perfused pancreas concomitant with a decreased number of zymogen granules and lysosomes in the acinar cells. The data are consistent with the hypothesis that pancreozymin increases the fragility of pancreatic lysosomes liberating β-glucuronidase into the pancreatic duct, extracellular space, and intravascular compartment. Lysosomal enzymes released into the duct may have an auxiliary digestive function in the duodenum, and the increased extracellular lysosomal enzyme activity may play a role in the pathophysiology of pancreatitis or other pancreatic disease states in which the pancreatic lysosomes become compromised.