Induction of Apoptosis Reduces the Severity of Caerulein-Induced Pancreatitis in Mice

Saluja, Ashok K.; Hofbauer, B.; Yamaguchi, Yoshikazu; Yamanaka, Kazushi; Steer, Michael L.

doi:10.1006/bbrc.1996.0498

Cited by 43 publications

(63 citation statements)

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“…In accord with previous findings (14), biphasic stimulation͞inhibition of amylase secretion by increasing concentrations of caerulein was observed when freshly prepared pancreatic acini from wildtype NK1Rϩ͞ϩ mice was evaluated (Fig. 5).…”

Section: Resultssupporting

confidence: 90%

“…As described (14,15), wild-type mice given i.p. injections of a supramaximally stimulating dose of the secretagogue caerulein develop acute necrotizing pancreatitis.…”

Section: Resultsmentioning

confidence: 99%

“…Serum lipase activity was measured colorimetrically as described by Imamura et al (13). Acini were prepared from mouse pancreas and amylase secretion was studied as a function of caerulein treatment as described (14). Neutrophil sequestration in pancreas and lung was quantitated by measuring tissue MPO activity.…”

Section: Methodsmentioning

confidence: 99%

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Role of substance P and the neurokinin 1 receptor in acute pancreatitis and pancreatitis-associated lung injury

Bhatia

Saluja

Hofbauer

et al. 1998

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

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276

271

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Substance P, acting via the neurokinin 1 receptor (NK1R), plays an important role in mediating a variety of inf lammatory processes. However, its role in acute pancreatitis has not been previously described. We have found that, in normal mice, substance P levels in the pancreas and pancreatic acinar cell expression of NK1R are both increased during secretagogue-induced experimental pancreatitis. To evaluate the role of substance P, pancreatitis was induced in mice that genetically lack NK1R by administration of 12 hourly injections of a supramaximally stimulating dose of the secretagogue caerulein. During pancreatitis, the magnitude of hyperamylasemia, hyperlipasemia, neutrophil sequestration in the pancreas, and pancreatic acinar cell necrosis were significantly reduced in NK1R؊͞؊ mice when compared with wild-type NK1R؉͞؉ animals. Similarly, pancreatitisassociated lung injury, as characterized by intrapulmonary sequestration of neutrophils and increased pulmonary microvascular permeability, was reduced in NK1R؊͞؊ animals. These effects of NK1R deletion indicate that substance P, acting via NK1R, plays an important proinf lammatory role in regulating the severity of acute pancreatitis and pancreatitisassociated lung injury.The neuropeptide substance P has been shown to play an important role in asthma, inflammatory bowel disease, arthritis, and other inflammatory processes (1, 2). Subsequent to its release from nerve endings, substance P binds to neurokinin 1 receptors (NK1R) on effector cells, increases microvascular permeability, and promotes plasma extravasation from the intravascular to the extravascular space. Although pancreatic acinar cells are known to express NK1R and substance P has been detected within the pancreas (3-5), apparently no studies have been reported that have examined the possibility that this neuropeptide might play a role in the evolution of a pancreatic inflammatory disease such as acute pancreatitis. We have found that pancreatic levels of substance P and the expression of NK1R on pancreatic acinar cells are increased during experimental acute pancreatitis. We have also found that genetic deletion of NK1R reduces the severity of pancreatitis and pancreatitis-associated lung injury. These observations indicate that substance P, acting through NK1R, plays an important proinflammatory role in regulating the severity of acute pancreatitis and associated lung injury. MATERIALS AND METHODSAll experiments were performed according to protocols approved by the Institutional Animal Care and Use Committee of the Beth Israel Hospital. Breeding pairs of NK1R-deficient mice were generated as described (6), and the identity of their offspring as NK1R-deficient (Ϫ͞Ϫ) homozygotes was confirmed by Southern blotting (6). Animals were bred and housed in standard shoe box cages in a climate-controlled room with an ambient temperature of 23 Ϯ 2°C and a 12-h light͞12-h dark cycle. They were fed standard laboratory chow, given water ad libitum, randomly assigned to control or experimental groups, and...

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Section: Resultssupporting

confidence: 90%

“…As described (14,15), wild-type mice given i.p. injections of a supramaximally stimulating dose of the secretagogue caerulein develop acute necrotizing pancreatitis.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Role of substance P and the neurokinin 1 receptor in acute pancreatitis and pancreatitis-associated lung injury

Bhatia

Saluja

Hofbauer

et al. 1998

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

Self Cite

276

271

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“…Neutrophil infiltration augments the severity of acute pancreatitis probably by converting acinar cell apoptosis to necrosis (31). In addition, induction of apoptosis might even protect against acinar cell injury and reduce severity of caerulein-induced pancreatitis (32). However, the authors of the latter report did not calculate the apoptotic index in the pancreas of the treated groups.…”

Section: Discussionmentioning

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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“…In these models, such as pancreatitis induced in rats or mice by administration of high-dose cerulein (CR) or L-arginine (L-arg), or in mice by feeding them choline-deficient, ethionine-supplemented (CDE) diet, acinar cells have been shown to die through both necrosis and apoptosis (9,10,27,29,30,39,52,73,76,80). Of note, the severity of experimental pancreatitis directly correlates with the extent of necrosis and inversely with that of apoptosis (9,10,27,29,30,39,52,73,76,80). Thus, shifting death responses away from necrosis toward apoptosis may have a therapeutic value.…”

Section: Bcl-2 Proteins Are Key Regulators Of Mitochondrial Permeabilmentioning

confidence: 99%

Organellar Dysfunction in the Pathogenesis of Pancreatitis

Gukovsky

Pandol

Gukovskaya

2011

Antioxidants & Redox Signaling

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Significance: Acute pancreatitis is an inflammatory disease of exocrine pancreas that carries considerable morbidity and mortality; its pathophysiology remains poorly understood. During the past decade, new insights have been gained into signaling pathways and molecules that mediate the inflammatory response of pancreatitis and death of acinar cells (the main exocrine pancreas cell type). By contrast, much less is known about the acinar cell organellar damage in pancreatitis and how it contributes to the disease pathogenesis. Recent Advances: This review summarizes recent findings from our group, obtained on experimental in vivo and ex vivo models, which reveal disordering of key cellular organelles, namely, mitochondria, autophagosomes, and lysosomes, in pancreatitis. Our results indicate a critical role for mitochondrial permeabilization in determining the balance between apoptosis and necrosis in pancreatitis, and thus the disease severity. We further investigate how the mitochondrial dysfunction (and hence acinar cell death) is regulated by Ca 2+ , reactive oxygen species, and BclxL, in relation to specific properties of pancreatic mitochondria. Our results also reveal that autophagy, the principal cellular degradative, lysosome-driven pathway, is impaired in pancreatitis due to inefficient lysosomal function, and that impaired autophagy mediates two key pathological responses of pancreatitis-accumulation of vacuoles in acinar cells and the abnormal, intra-acinar activation of digestive enzymes such as trypsinogen. Critical Issues and Future Directions: The findings discussed in this review indicate critical roles for mitochondrial and autophagic/lysosomal dysfunctions in the pathogenesis of pancreatitis and delineate directions for detailed investigations into the molecular events that underlie acinar cell organellar damage. Antioxid. Redox Signal. 15, 2699-2710.

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Induction of Apoptosis Reduces the Severity of Caerulein-Induced Pancreatitis in Mice

Cited by 43 publications

References 0 publications

Role of substance P and the neurokinin 1 receptor in acute pancreatitis and pancreatitis-associated lung injury

Role of substance P and the neurokinin 1 receptor in acute pancreatitis and pancreatitis-associated lung injury

Activation of polyamine catabolism in transgenic rats induces acute pancreatitis

Organellar Dysfunction in the Pathogenesis of Pancreatitis

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