Course and spontaneous regression of acute pancreatitis in the rat

Adler, Guido; Hupp, T.; Kern, Horst F.

doi:10.1007/bf01102739

Cited by 164 publications

(80 citation statements)

References 13 publications

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“…The pathophysiology of acute pancreatitis was studied extensively with different animal models such as that of secretagogue hyperstimulation (cerulein model) and several duct ligation models as well as that induced by dibutyltin dichloride (DBTC) (9)(10)(11)(12)(13). The cerulein model serves as a paradigm for the initiating event of acute edematous pancreatitis and represents the best-characterized model of the disease to date.…”

Section: Introductionmentioning

confidence: 99%

Constitutive IKK2 activation in acinar cells is sufficient to induce pancreatitis in vivo

Baumann¹,

Wagner²,

Aleksic³

et al. 2007

J. Clin. Invest.

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111

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Activation of the inhibitor of NF-κB kinase/NF-κB (IKK/NF-κB) system and expression of proinflammatory mediators are major events in acute pancreatitis. However, the in vivo consequences of IKK activation on the onset and progression of acute pancreatitis remain unclear. Therefore, we modulated IKK activity conditionally in pancreatic acinar cells. Transgenic mice expressing the reverse tetracycline-responsive transactivator (rtTA) gene under the control of the rat elastase promoter were generated to mediate acinar cell-specific expression of IKK2 alleles. Expression of dominant-negative IKK2 ameliorated cerulein-induced pancreatitis but did not affect activation of trypsin, an initial event in experimental pancreatitis. Notably, expression of constitutively active IKK2 was sufficient to induce acute pancreatitis. This acinar cell-specific phenotype included edema, cellular infiltrates, necrosis, and elevation of serum lipase levels as well as pancreatic fibrosis. IKK2 activation caused increased expression of known NF-κB target genes, including mediators of the inflammatory response such as TNF-α and ICAM-1. Indeed, inhibition of TNF-α activity identified this cytokine as an important effector of IKK2-induced pancreatitis. Our data identify the IKK/NF-κB pathway in acinar cells as being key to the development of experimental pancreatitis and the major factor in the inflammatory response typical of this disease. IntroductionThe NF-κB transcription factors play a prominent role in controlling the integration of innate immunity into the inflammatory response and adaptive immunity. The activation and nuclear translocation of NF-κB induces the expression of a diverse range of proinflammatory genes, including chemokines, cytokines, and cell adhesion molecules, all necessary for an effective defense response to infectious agents. However, failure to terminate or resolve the inflammatory response has detrimental consequences for the organism. As NF-κB is one of the main transcriptional regulators of inflammation, pathological activation of NF-κB is often associated with chronic inflammatory diseases like rheumatoid arthritis, inflammatory bowel disease, asthma, and multiple sclerosis (1-3).NF-κB represents a family of homodimeric and heterodimeric transcription factors composed of 5 members, namely p50, p52, RelA/p65, RelB, and c-Rel. NF-κB is activated by a large number of inducers, including factors critically involved in the inflammatory response such as TNF-α, IL-1β, and microbial products. These factors activate the TNF, IL-1, Nod-like, and Toll-like receptor systems and thereby initiate signaling cascades that converge on the classical NF-κB pathway. This induces the nuclear translocation of NF-κB dimers typically composed of p50 and RelA/p65. The pivotal regulatory step in this pathway is the signal-induced phosphorylation of inhibitor of NF-κB (IκB) proteins, which are mediated by the IκB kinase (IKK) complex. In unstimulated cells, IκB proteins interact with the NF-κB proteins and inhibit their nuclear translo...

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Section: Introductionmentioning

confidence: 99%

Constitutive IKK2 activation in acinar cells is sufficient to induce pancreatitis in vivo

Baumann¹,

Wagner²,

Aleksic³

et al. 2007

J. Clin. Invest.

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111

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“…During the later peak, duct cell labeling predominates. It has been suggested that the uncommitted pancreatic stem cell is morphologically similar to the centroacinar cell, so that these labeled cells may be the precursor of both duct and acinar cells in the enlarged gland (30). Both the in vivo and in vitro studies show that after 8 weeks of raw soya flour diet, cell turnover has returned to values not greater than those observed in rats fed non-soya chow or heated soya flour.…”

Section: Indices Of Cellular Replicationmentioning

confidence: 96%

Effects of soybean flour on the pancreas of rats.

McGuinness¹,

Morgan²,

Wormsley³

1984

Environ Health Perspect

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We have reviewed the growth-promoting and carcinogenic effects of feeding raw soya flour to rats. If the raw soya flour-containing diets are fed for more than a year, about 10% of the animals develop pancreatic cancer. In addition, feeding raw soya flour markedly potentiates the action of even subthreshold amounts of pancreatic carcinogens. The raw soya flour therefore acts as a potent promoter, as well as a weak carcinogen. In view of this promotion, the rat fed raw soya flour is a sensitive model for screening pancreatic carcinogens.It is not known whether the human pancreas responds to dietary trypsin inhibitors in a manner similar to the rat. However, in view of the use of soya-based products in human nutrition-especially in infant foods-we urge that the effect of all soya-based products intended for human use be tested on the rat pancreas in long-term feeding studies, combined with subthreshold doses of azaserine to highlight any promoting activity of the product. It seems probable that if a product exerts no effect on the rat pancreas, the human pancreas will also be spared from noxious effects. Morphological Aspects Macroscopic FeaturesRaw soya flour-containing diets have been shown to produce enlargement of the rat pancreas after administration for as little as 10 to 20 days (1). The pancreatic enlargement has been shown to reflect both hypertrophy (defined as increase in cellular size and amount of protein per unit of DNA) (2) and also hyperplasia (increase in the amount of DNA and number of cells in the gland) (3). We have shown that the pancreatic growth-promoting effects continue, ifthe administration of raw soya flour is maintained, but becomes progressively more marked in an exponential manner at some time between 30 and 60 weeks of feeding raw soya flour-containing diets (4).During the period of pancreatic enlargement, the gland changes color to become dark red, reflecting increased vascularity and blood flow, as demonstrated by use of microspheres (unpublished results).Some time between 24 and 30 weeks after the start of raw soya flour-containing diets, small greyish patches become visible on the surface of the gland. Subsequently, overt nodules appear and increase in size (6). These changes correlate with the growth of the gland and with the increased secretory response to stimulants of the pancreas of these animals (7).After feeding raw soya flour-containing diets for 16 to 24 weeks, a few microscopic foci can be found scattered throughout the pancreas. The number and size of the nodules increases with the duration of feeding (4) Reversibility of Morphological ChangesThe pancreatic weights, protein content and morphological appearances revert to normal when rats are fed raw soya flour for 5 days (8), 4 weeks (9) and 6 months (unpublished observations) and then receive non-soyacontaining diets.If rats are fed raw soya flour for as long as 6 months and the diet is then changed to non-soya-containing chow, nodules are not found at death a year or more later, so that histologically the pancreas o...

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“…We initiated our evaluation of possible differences in responses to injury in the pancreas by measuring the severity of cerulein-induced pancreatitis in Itmap1 ϩ/ϩ and Itmap1 Ϫ/Ϫ mice. Repetitive administration of cerulein, a cholecystokinin analogue, induces an acute hyperstimulation pancreatitis associated with elevated serum amylase and lipase concentrations, and interstitial pancreatic edema (17)(18)(19). Cerulein-induced pancreatitis caused no mortality in either Itmap1 ϩ/ϩ or Itmap1 Ϫ/Ϫ mice.…”

Section: Generation and Characterization Of Itmap1mentioning

confidence: 99%

Protection from Pancreatitis by the Zymogen Granule Membrane Protein Integral Membrane-associated Protein-1

Imamura¹,

Asada²,

Vogt

et al. 2002

Journal of Biological Chemistry

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Pancreatitis is a common disease with substantial morbidity and mortality. To better understand the mechanisms conferring sensitivity or resistance to pancreatitis, we have initiated the analysis of novel acinar cell proteins. Integral membrane-associated protein-1 (Itmap1) is a CUB (complement subcomponents C1r/C1s, sea urchin Uegf protein, bone morphogenetic protein-1) and zona pellucida (ZP) domain-containing protein we find prominently expressed in pancreatic acinar cells. Within the acinar cell, Itmap1 localizes to zymogen granule membranes. Although roles in epithelial polarity, granule assembly, and mucosal protection have been postulated for CUB/ZP proteins, in vivo functions for these molecules have not been proven. To determine the function of Itmap1, we generated Itmap1-deficient mice. Itmap1؊/؊ mice demonstrate increased severity of secretagogue-and diet-induced pancreatitis in comparison to Itmap1 ؉/؉ mice. In contrast to previous animal models exhibiting altered severity of pancreatitis, Itmap1 deficiency results in impaired activation of trypsin, an enzyme believed critical for initiating a cascade of digestive zymogen activation during pancreatitis. Itmap1 deficiency does not alter zymogen granule size, appearance, or the composition of zymogen granule contents. Our results demonstrate that Itmap1 plays an essential role in trypsinogen activation and that both impaired and augmented trypsinogen activation can be associated with increased severity of pancreatitis.

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Course and spontaneous regression of acute pancreatitis in the rat

Cited by 164 publications

References 13 publications

Constitutive IKK2 activation in acinar cells is sufficient to induce pancreatitis in vivo

Constitutive IKK2 activation in acinar cells is sufficient to induce pancreatitis in vivo

Effects of soybean flour on the pancreas of rats.

Protection from Pancreatitis by the Zymogen Granule Membrane Protein Integral Membrane-associated Protein-1

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