A plasma protease which is expressed during supramaximal stimulation causes in vitro subcellular redistribution of lysosomal enzymes in rat exocrine pancreas.

Saluja, M.; Saluja, Ashok K.; Lerch, Markus M.; Steer, Michael L.

doi:10.1172/jci115130

Cited by 9 publications

(4 citation statements)

References 21 publications

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“…They also found in in vitro experiments that incubation of pancreas fragments with a supramaximal concentration of cerulein did not result in the redistribution of lysosomal enzymes; however, the redistribution of lysosomal hydrolases was observed when fragments were incubated with cerulein along with rat plasma obtained from cerulein-induced pancreatitis [33]. Our observation that neutrophil depletion ameliorated pancreatic injury during the early stages in ceruleininduced pancreatitis led us to conclude that neutrophils might worsen the pancreatic injury.…”

Section: Discussionsupporting

confidence: 63%

Role of Neutrophils in Cerulein-Induced Pancreatitis in Rats: Possible Involvement of Apoptosis

Fujimoto¹,

Hosotani²,

Doi³

et al. 1997

Digestion

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We investigated the role of neutrophils and the involvement of apoptosis in cerulein-induced acute pancreatitis. Male Sprague-Dawley rats were divided into 2 groups. In the control group, acute pancreatitis was induced by subcutaneous injections of cerulein. In methotrexate-treated group, the rats received intraperitoneal injections of methotrexate to produce neutrophil depletion before the injections of cerulein. The rats were sacrificed at the indicated time points until 72 h after the first injection of cerulein. Neutrophil depletion ameliorated pancreatic edema and vacuole formation in acinar cells during the early stages of cerulein-induced acute pancreatitis. Electron microscopy, DNA gel electrophoresis and in situ nick end-labeling revealed the involvement of apoptosis in acinar cells in cerulein-induced acute pancreatitis. Furthermore, the number of apoptotic acinar cells in neutrophil-depleted rats showed an about 2-fold increase during the late stages when compared with those in the control rats. Our results suggest that neutrophil depletion in cerulein-induced pancreatitis leads to amelioration of pancreatic injury during the early stage, and enhancement of apoptosis by neutrophil depletion occurs during the late stage.

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Section: Discussionsupporting

confidence: 63%

Role of Neutrophils in Cerulein-Induced Pancreatitis in Rats: Possible Involvement of Apoptosis

Fujimoto¹,

Hosotani²,

Doi³

et al. 1997

Digestion

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“…However, regardless of whether only intracellular targeting or also the mechanism of endocytosis is altered, the consequence is an intracellular colocalization of lysosomal and digestive hydrolases. Such a colocalization has previously been observed in two unrelated models of pancreatitis, and we proposed it to be a critical event for the intracellular activation of proteases in pancreatitis (30,31 ). In those studies, however, fusion of lysosomes with zymogen granules was thought to be the source of colocalization, whereas in the present investigation, uptake from the lumen appears as a novel alternative.…”

Section: Discussionsupporting

confidence: 48%

“…We have previously shown that the intracellular transport and sorting of proteins are markedly altered in early acute experimental pancreatitis (31 ) and after P-BD obstruction (32). During transport of newly synthesized enzymes through the cell, a missorting from the lysosomal into the regulated secretory pathway was observed (28).…”

Section: Discussionmentioning

confidence: 99%

Luminal endocytosis and intracellular targeting by acinar cells during early biliary pancreatitis in the opossum.

et al. 1995

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Cell necrosis in acute experimental pancreatitis is preceded by a redistribution of digestive enzymes into a lysosomal subcellular compartment. We have investigated whether endocytosis from the acinar cell lumen might contribute to this disturbance of intracellular compartmentation. In an animal model of pancreatitis involving pancreatic bile duct ligation in opossums, we have studied in vivo endocytosis of dextran 40 and ["4C]dextran 70, cationized ferritin, and horseradish peroxidase from the apical surface of acinar cells before the onset of necrosis. Marker solutions were instilled into the pancreatic duct of anesthetized animals at physiological pressure. Tissue samples obtained at intervals of up to 60 min after instillation of markers were studied by electron microscopy and electron microscope autoradiography. All markers were taken up by acinar cells in control animals and in animals with obstructed pancreatic bile ducts. Markers for membrane-mediated endocytosis (cationated ferritin and horseradish peroxidase) were transported to lysosomes in both groups. In contrast, the fluidphase tracer dextran was transported to the secretory pathway in controls but to lysosomes after duct ligation. Since dextran and luminally present secretory proteins can be expected to follow the same route after endocytosis, our findings suggest that altered intracellular targeting of endocytosed proteases might be one mechanism by which digestive zymogens reach an intracellular compartment in which premature activation can occur. This phenomenon may be a critical and early event in the pathogenesis of biliary pancreatitis. (J. Clin. Invest. 1995Invest. . 95:2222Invest. -2231

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“…The lysosom al activation hypothesis is based on two observations: (1) Cathepsin B can rapidly catalyze the conversion of trypsinogen to trypsin in vitro [57] and does so over a wide range of pH which is compatible with in vivo condi tions [58]. (2) In all experimental animal models of pan creatitis cathepsin B shifts into a zymogen granuleenriched fraction obtained by subcellular fractionation experiments [59,60], Accordingly it was proposed that early in pancreatitis cathepsin B and trypsinogen become newly colocalized in an intracellular compartment that has a greater density than lysosomes and probably corre sponds to the large cytoplasmic vacuoles observed during pancreatitis [61]. Although these experimental observa tions are undebated, their relevance as to the premature activation of trypsinogen has been questioned.…”

Section: Hypotheses For Enzyme Activationmentioning

confidence: 99%

Pathophysiology of Acute Pancreatitis

Lerch¹,

Adler²

1994

Dig Surg

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The vast majority of patients with acute pancreatitis either have gallstones or drink too much alcohol. While little is known about the action of ethanol on the exocrine pancreas, the mechanisms involved in gallstone-induced pancreatitis have recently been elucidated to an extent that allows conclusions about the pathophysiology of pancreatitis. In the following review article we will discuss the clinical and experimental studies which have shaped our understanding of biliary pancreatitis. While most of the questions regarding the association of gallstones and pancreatitis appear to be resolved, the intracellular alterations which immediately follow these triggering events and ultimately lead to acinar cell necrosis are less well understood. These early pathophysiological changes within the pancreas have been the target of an intense research interest and the subject of sometimes equally passionate controversies. We will discuss the studies that have addressed the premature and intracellular activation of digestive enzymes in acute pancreatitis and review some of the current theories and arguments which attempt to confront this issue.

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A plasma protease which is expressed during supramaximal stimulation causes in vitro subcellular redistribution of lysosomal enzymes in rat exocrine pancreas.

Abstract: The complex events by which digestive enzyme zymogens and lysosomal hydrolases are segregated from each other and differentially transported to their respective membrane-bound intracellular organelles in Invest. 1991Invest. .87:1280Invest. -1285

Cited by 9 publications

References 21 publications

Role of Neutrophils in Cerulein-Induced Pancreatitis in Rats: Possible Involvement of Apoptosis

Role of Neutrophils in Cerulein-Induced Pancreatitis in Rats: Possible Involvement of Apoptosis

Luminal endocytosis and intracellular targeting by acinar cells during early biliary pancreatitis in the opossum.

Pathophysiology of Acute Pancreatitis

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