| Intracellular activation of trypsinogen in transgenic mice induces acute but not chronic pancreatitis. | |
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MedLine Citation:
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PMID: 21471572 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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Background and aims Premature intra-acinar activation of trypsinogen is widely considered key for both the initiation of acute pancreatitis and the development of chronic pancreatitis. However, the biological consequences of intracellular trypsinogen activation have not been directly examined. To do so, a new mouse model was developed. Methods Mice were engineered to conditionally express an endogenously activated trypsinogen within pancreatic acinar cells (PACE-tryp(on)). Hallmarks of pancreatitis were determined and findings were correlated to the level (zygosity) and extent (temporal and spatial) of conditional PACE-tryp(on) expression. Furthermore, the impact of acinar cell death in PACE-tryp(on) mice was assessed and compared with a model of selective diphtheria toxin (DT)-mediated induction of acinar apoptosis. Results Initiation of acute pancreatitis was observed with high (homozygous), but not low (heterozygous) levels of PACE-tryp(on) expression. Subtotal (maximal-rapid induction) but not limited (gradual-repetitive induction) conditional PACE-tryp(on) expression was associated with systemic complications and mortality. Rapid caspase-3 activation and apoptosis with delayed necrosis was observed, and loss of acinar cells led to replacement with fatty tissue. Chronic inflammation or fibrosis did not develop. Selective depletion of pancreatic acinar cells by apoptosis using DT evoked similar consequences. Conclusions Intra-acinar activation of trypsinogen is sufficient to initiate acute pancreatitis. However, the primary response to intracellular trypsin activity is rapid induction of acinar cell death via apoptosis which facilitates resolution of the acute inflammation rather than causing chronic pancreatitis. This novel model provides a powerful tool to improve our understanding of basic mechanisms occurring during pancreatitis. |
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Authors:
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Sebastian Gaiser; Jaroslaw Daniluk; Yan Liu; Lilian Tsou; Jun Chu; Woojin Lee; Daniel S Longnecker; Craig D Logsdon; Baoan Ji |
Publication Detail:
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Type: JOURNAL ARTICLE Date: 2011-4-6 |
Journal Detail:
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Title: Gut Volume: - ISSN: 1468-3288 ISO Abbreviation: - Publication Date: 2011 Apr |
Date Detail:
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Created Date: 2011-4-7 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 2985108R Medline TA: Gut Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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