Beneficial effects of cholecystokinin-receptor blockade and inhibition of proteolytic enzyme activity in experimental acute hemorrhagic pancreatitis in mice. Evidence for cholecystokinin as a major factor in the development of acute pancreatitis.

Niederau, Claus; Liddle, Rodger A.; Ferrell, Linda D.; Grendell, J. H.

doi:10.1172/jci112661

Cited by 144 publications

(71 citation statements)

References 21 publications

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“…The stained sections were coded and blindly scored by the participating pathologist (J.J.P.) according to the method of Niederau et al (15). The details of the histological scoring are presented in the legend for Table 2.…”

Section: Methodsmentioning

confidence: 99%

Activation of polyamine catabolism in transgenic rats induces acute pancreatitis

Alhonen

Parkkinen²,

Keinänen³

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

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Polyamines are required for optimal growth and function of cells. Regulation of their cellular homeostasis is therefore tightly controlled. The key regulatory enzyme for polyamine catabolism is the spermidine͞spermine N 1 -acetyltransferase (SSAT). Depletion of cellular polyamines has been associated with inhibition of growth and programmed cell death. To investigate the physiological function SSAT, we generated a transgenic rat line overexpressing the SSAT gene under the control of the inducible mouse metallothionein I promoter. Administration of zinc resulted in a marked induction of pancreatic SSAT, overaccumulation of putrescine, and appearance of N 1 -acetylspermidine with extensive depletion of spermidine and spermine in transgenic animals. The activation of pancreatic polyamine catabolism resulted in acute pancreatitis. In nontransgenic animals, an equal dose of zinc did not affect pancreatic polyamine pools, nor did it induce pancreatitis. Acetylated polyamines, products of the SSAT-catalyzed reaction, are metabolized further by the polyamine oxidase (PAO) generating hydrogen peroxide, which might cause or contribute to the pancreatic inflammatory process. Administration of specific PAO inhibitor, MDL72527 [N 1 ,N 2 -bis(2,3-butadienyl)-1,4-butanediamine], however, did not affect the histological score of the pancreatitis. Induction of SSAT by the polyamine analogue N 1 ,N 11 -diethylnorspermine reduced pancreatic polyamines levels only moderately and without signs of organ inflammation. In contrast, the combination of N 1 ,N 11 -diethylnorspermine with MDL72527 dramatically activated SSAT, causing profound depletion of pancreatic polyamines and acute pancreatitis. These results demonstrate that acute induction of SSAT leads to pancreatic inflammation, suggesting that sufficient pools of higher polyamine levels are essential to maintain pancreatic integrity. This inflammatory process is independent of the production of hydrogen peroxide by PAO.I ntracellular polyamine levels are tightly maintained by a number of mechanisms, suggesting their importance for cell function. This polyamine homeostasis is controlled by their biosynthesis, interconversion, catabolism, secretion, and uptake. Polyamine biosynthesis is regulated by the activities of ornithine and S-adenosylmethionine decarboxylases. Overexpression of ornithine decarboxylase in transgenic rodents affected spermatogenesis (1, 2), rendered animals more resistant to chemically or electrically induced seizure activity (3) and to ischemic insults (4), and enhanced skin papilloma formation (5). However, the activation of polyamine biosynthesis caused by overexpression of ornithine decarboxylase did not result in enhanced accumulation of the higher polyamines spermidine and spermine. Polyamine catabolism is controlled by the activity of spermidine͞spermine N 1 -acetyltransferase (SSAT; refs. 6 and 7). The acetylated products are oxidized further by the polyamine oxidase (PAO) to spermidine and putrescine. We recently generated transgenic mouse lines with ...

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Section: Methodsmentioning

confidence: 99%

Activation of polyamine catabolism in transgenic rats induces acute pancreatitis

Alhonen

Parkkinen²,

Keinänen³

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

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“…28 Binding of CCK to CCK receptor stimulates intracellular Ca 2＋ levels and mediates the physiologic functions such as pancreatic enzyme secretion including amylase and lipase. 29,30 The severity of pancreatitis is related to CCK level and the oxidative indices such as lipid peroxides in serum. 31 Since CCK receptor is present in pancreatic acinar cells, 32 not in pancreatic ductal cells or islet cells, 33 cerulein-induced alterations in protein expression may affect the exocrine function of pancreas by changing physiological roles of pancreatic acinar cells.…”

Section: Discussionmentioning

confidence: 99%

Membrane Proteome Analysis of Cerulein-Stimulated Pancreatic Acinar Cells: Implication for Early Event of Acute Pancreatitis

et al. 2010

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Background/Aims: Cerulein pancreatitis is similar to human edematous pancreatitis with dysregulation of the production and secretion of digestive enzymes, edema formation, cytoplasmic vacuolization and the death of acinar cells. We hypothesized that membrane proteins may be altered as the early event during the induction of acute pancreatitis. Present study aims to determine the differentially expressed proteins in the membranes of cerulein-treated pancreatic acinar cells. Methods: Pancreatic acinar AR42J cells were treated with 10 −8 M cerulein for 1 hour. Membrane proteins were isolated from the cells and separated by two-dimensional electrophoresis using pH gradients of 5-8. Membrane proteins were identified by matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF MS) analysis of the peptide digests. The differentially expressed proteins, whose expression levels were more or less than three-fold in cerulein-treated cells, were analyzed. Results: Two differentially expressed proteins (mannan-binding lectin-associated serine protease-2, heat shock protein 60) were up-regulated while four proteins (protein disulfide isomerase, γ-actin, isocitrate dehydrogenase 3, seven in absentia homolog 1A) were down-regulated by cerulein treatment in pancreatic acinar cells. These proteins are related to cell signaling, oxidative stress, and cytoskeleton arrangement. Conclusions: Oxidative stress may induce cerulein-induced cell injury and disturbances in defense mechanism in pancreatic acinar cells. (Gut Liver 2010; 4:84-93)

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“…The pancreatic parenchyma specimens were described according to the scoring scale proposed by Niederau [6] During the second operation, there was no evidence of cancer dissemination or local recurrence. All anastomoses were completely healed from a macroscopic point of view.…”

Section: Light Microscopymentioning

confidence: 99%

Pancreatic Anastomosis Healing

Hać¹,

Pęksa²,

Dobosz³

et al. 2012

OJPathology

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Background: Pancreatoduodenectomy (PD) is a complex procedure with a relatively high risk of complications. There is an increasing trend showing that the success of pancreato-enteral anastomosis depends on surgical skill and the material used. Methods: We present four cases of pancreato-enteral anastomosis resected 37 -114 days after primary surgery and the analysis of the healing process, i.e., morphology of the pancreatic parenchyma, pancreatic duct, and digestive tract mucosa, as well as the pancreatic reaction to the sewing material by microscopic morphometry. Results: Evidence of regeneration in the columnar-lined mucosa of main pancreatic ducts in all cases of pancreato-enterostomy was observed. The inflammatory foreign-body reaction around monofilament stitch was present without an evident infection. There were no microscopic signs of pancreatic duct damage. Total foreign body reaction varied between 138.1 μm and 207.3 μm. Conclusions: This observation supports the beneficial use of thin monofilament threads for pancreato-enteral anastomosis. There was no evidence of harmful action from gastric or intestinal juices on pancreatic remnant or the Wirsung duct.

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Beneficial effects of cholecystokinin-receptor blockade and inhibition of proteolytic enzyme activity in experimental acute hemorrhagic pancreatitis in mice. Evidence for cholecystokinin as a major factor in the development of acute pancreatitis.

Cited by 144 publications

References 21 publications

Activation of polyamine catabolism in transgenic rats induces acute pancreatitis

Activation of polyamine catabolism in transgenic rats induces acute pancreatitis

Membrane Proteome Analysis of Cerulein-Stimulated Pancreatic Acinar Cells: Implication for Early Event of Acute Pancreatitis

Pancreatic Anastomosis Healing

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