Increased Intrapancreatic Trypsinogen Activation in Ischemia-Induced Experimental Pancreatitis

Mithöfer, Kai; Castillo, C. Fernandez-del; Frick, Thomas W.; Foitzik, Thomas; Bassi, Deomir Germano; Lewandrowski, Kent; Rattner, D. W.; Warshaw, Andrew L.

doi:10.1097/00000658-199504000-00006

Cited by 51 publications

(37 citation statements)

References 29 publications

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“…Interstitial trypsinogen activation is accepted as an early event in acute pancreatitis and plays a role in the progression to necrotizing pancreatitis [2, 4, 24, 25, 26]. In our study, high concentrations in pancreatic necroses and ascites but low values in pancreatic abscess and pleural effusion underline the role of local trypsinogen activation in the development of pancreatic necroses.…”

Section: Discussionsupporting

confidence: 61%

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Local and Systemic Zymogen Activation in Human Acute Pancreatitis

Mayer

Rau²,

Siech³

et al. 2000

Digestion

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Background: Activation of trypsinogen and phospholipase A₂ is an early event in pancreatic inflammation, but little is known about zymogen activation and the severity of human pancreatitis. Methods: Using a new fluoroimmunoassay we measured trypsinogen activation peptide (TAP) and phospholipase A₂ activation peptide (PROP) in plasma and ascites in 25 patients with acute pancreatitis. TAP, PROP, Pro-PROP and pancreatic PLA₂-I were measured in plasma for 14 days and in pancreatic necroses, ascitic fluid and pleural effusions. Results: All 16 patients with severe acute pancreatitis (SAP) had pancreatic necrosis, 10 developed systemic complications like sepsis, pulmonary or renal failure, 6 had infected necrosis, and 4 died. All 9 patients with mild pancreatitis (MAP) survived. Plasma TAP on admission was higher in patients with SAP than in those with MAP and increased in infected necroses. It did not correlate with systemic complications. Systemic PROP was not increased in complicated courses but was significantly higher in patients with MAP than in those with SAP on admission. Pro-PROP was higher in patients with SAP than in those with MAP but was not correlated with systemic complications. Plasma pancreatic PLA₂-I was increased but not different in patients with SAP and those with MAP. In patients with pancreatic necrosis, TAP and PROP were highest, while in those with post-acute pancreatic abscess, only PROP and Pro-PROP were high. In patients with pleural effusion, TAP was low and PROP/ Pro-PROP were high. Conclusion: Trypsinogen and PLA₂-I activation are early events in acute pancreatitis and the activation peptides can be detected in plasma. In the pancreas, trypsinogen activation is accompanied by PLA₂-I activation in patients with pancreatic necrosis. However, in our study, organ complications in SAP patients was not associated with increased plasma PROP.

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Section: Discussionsupporting

confidence: 61%

“…In previous studies, trypsinogen activation has been shown to be an important pathophysiologic factor in the progression of pancreatic inflammation to necrotizing pancreatitis [2, 4, 24, 25, 26, 27]. Active trypsin is difficult to measure because is it quickly complexed or denatured.…”

Section: Discussionmentioning

confidence: 99%

Local and Systemic Zymogen Activation in Human Acute Pancreatitis

Mayer

Rau²,

Siech³

et al. 2000

Digestion

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“…This cellular acidosis increases the potential for cathepsin B, which has a pH optimum of 3.8, to activate trypsinogen intracellularly [106]. Within the pancreas, this mechanism may explain the presence of activated extraluminal trypsin as a very early event in the pathogenesis of AP [107, 108]. Indeed, after hemorrhagic shock, studies directed at intracellular changes in acinar cells demonstrated marked cellular vacuolization, increased lyosomal size and fragility, and cell disruption [109].…”

Section: Ischemia/reperfusion Injury Of the Pancreasmentioning

confidence: 99%

Ischemia/Reperfusion-Induced Pancreatitis

Sakorafas

Tsiotos

Sarr³

2000

Dig Surg

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Background/Aim: The pancreas is an organ highly susceptible to ischemic damage. This discussion reviews the role of ischemia as an etiologic factor in acute pancreatitis. Methods: Literature review. Results: The susceptibility of the pancreas to ischemia/reperfusion injury has been demonstrated in experimental studies and in clinical settings such as cardiopulmonary bypass, hemorrhagic shock, and transplantation of the pancreas. Oxygen free radicals, activation of polymorphonuclear leukocytes, failure of microvascular perfusion, cellular acidosis, and disturbance of intracellular homeostasis appear to be important factors/mechanisms in the pathogenesis of ischemia/reperfusion-induced acute pancreatitis. In clinical practice, the diagnosis of ischemic pancreatitis is difficult and often delayed, especially during the postoperative period after cardiac or major vascular surgery. Conclusions: Ischemia appears to be one important factor in acute pancreatitis. The management of ischemic pancreatitis is similar to that of acute pancreatitis of any etiology.

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“…A key step for initiating many forms of pancreatitis appears to be the pathological intracellular activation of digestive zymogens (15). In vivo studies that use supramaximal concentrations (10-to 100-fold greater than that generating a maximal secretory response) of CCK or cholinergic agonists generate acute pancreatitis (9) and zymogen activation (18). Likewise, hyperstimulation of isolated pancreatic acini by CCK leads to the rapid activation of proteases and enhanced zymogen processing (15).…”

mentioning

confidence: 99%

Telenzepine-sensitive muscarinic receptors on rat pancreatic acinar cells

Schmid

Modlin

Tang

et al. 1998

American Journal of Physiology-Gastrointestinal and Liver Physi

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. Telenzepinesensitive muscarinic receptors on rat pancreatic acinar cells. Am. J. Physiol. 274 (Gastrointest. Liver Physiol. 37): G734-G741, 1998.-To identify the muscarinic subtype present on the rat pancreatic acinar cell, we examined the effects of different muscarinic receptor antagonists on amylase secretion and proteolytic zymogen processing in isolated rat pancreatic acini. Maximal zymogen processing required a concentration of carbachol 10-to 100-fold greater (10 Ϫ3 M) than that required for maximal amylase secretion (10 Ϫ5 M). Although both secretion and conversion were inhibited by the M3 antagonist 4-diphenylacetoxy-N-methyl-piperidine (4-DAMP) (50% inhibition ϳ6 ϫ 10 Ϫ7 M and 1 ϫ 10 Ϫ8 M, respectively), the most potent inhibitor was the M1 antagonist telenzepine (50% inhibition ϳ5 ϫ 10 Ϫ10 M and 1 ϫ 10 Ϫ11 M, respectively). Pirenzepine, another M1 antagonist, and the M2 antagonist methoctramine did not reduce amylase secretion or zymogen processing in concentrations up to 1 ϫ 10 Ϫ5 M. Analysis of acinar cell muscarinic receptor by PCR revealed expression of both m1 and m3 subtypes. The pancreatic acinar cell has a distinct pattern of muscarinic antagonist sensitivity (telenzepine : 4-DAMP Ͼ pirenzepine) with respect to both amylase secretion and zymogen conversion. muscarinic antagonist; 4-diphenylacetoxy-N-methyl-piperidine; carboxypeptidase A 1 ; secretion NEUROHUMORAL STIMULATION of the exocrine pancreas generates a number of physiological responses, including enhanced zymogen secretion. Recent studies suggest that cholinergic pathways may have a more important role in regulating pancreatic secretion than previously appreciated. Thus the primary action of CCK released by the intestinal nutrients may be to stimulate the cholinergic release of acetylcholine (ACh) (1, 16). The neurotransmitter then acts on muscarinic ACh receptors (mAChR) to stimulate acinar cell secretion. Cholinergic pathways may play a role in pathological processes such as the proteolytic processing of zymogens to active forms.Cholinergic stimulation may contribute to the pathogenesis of pancreatitis such as that induced by the bite of the Tityus serrulatus scorpion (22), alcohol-associated disease, and cholinesterase inhibitors (17). A key step for initiating many forms of pancreatitis appears to be the pathological intracellular activation of digestive zymogens (15). In vivo studies that use supramaximal concentrations (10-to 100-fold greater than that generating a maximal secretory response) of CCK or cholinergic agonists generate acute pancreatitis (9) and zymogen activation (18). Likewise, hyperstimulation of isolated pancreatic acini by CCK leads to the rapid activation of proteases and enhanced zymogen processing (15). The protease activation observed in isolated pancreatic acini may be relevant to the pathogenesis of acute pancreatitis.The identification of the muscarinic receptors on the pancreatic acinar cell is relevant to pancreatic physiology and pathology. Muscarinic antagonists are most often used to establish the...

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Increased Intrapancreatic Trypsinogen Activation in Ischemia-Induced Experimental Pancreatitis

Abstract: ObjectiveThe potential of pancreatic ischemia to cause acute pancreatitis as indicated by morphologic changes and ectopic trypsinogen activation was investigated.

Cited by 51 publications

References 29 publications

Local and Systemic Zymogen Activation in Human Acute Pancreatitis

Local and Systemic Zymogen Activation in Human Acute Pancreatitis

Ischemia/Reperfusion-Induced Pancreatitis

Telenzepine-sensitive muscarinic receptors on rat pancreatic acinar cells

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