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Pancreas. 2019 Apr;48(4):459-470. doi: 10.1097/MPA.0000000000001298.

Recent Insights Into the Pathogenic Mechanism of Pancreatitis: Role of Acinar Cell Organelle Disorders.

Author information

1
Department of Nutritional Sciences, University of Wisconsin, Madison, WI.
2
Division of Digestive and Liver Diseases, Cedars-Sinai Medical Center, Los Angeles.
3
Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, University of California San Diego School of Medicine, La Jolla.
4
Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University School of Medicine, Stanford, CA.

Abstract

Acute pancreatitis (AP) is a potentially lethal inflammatory disease that lacks specific therapy. Damaged pancreatic acinar cells are believed to be the site of AP initiation. The primary function of these cells is the synthesis, storage, and export of digestive enzymes. Beginning in the endoplasmic reticulum and ending with secretion of proteins stored in zymogen granules, distinct pancreatic organelles use ATP produced by mitochondria to move and modify nascent proteins through sequential vesicular compartments. Compartment-specific accessory proteins concentrate cargo and promote vesicular budding, targeting, and fusion. The autophagy-lysosomal-endosomal pathways maintain acinar cell homeostasis by removing damaged/dysfunctional organelles and recycling cell constituents for substrate and energy. Here, we discuss studies in experimental and genetic AP models, primarily from our groups, which show that acinar cell injury is mediated by distinct mechanisms of organelle dysfunction involved in protein synthesis and trafficking, secretion, energy generation, and autophagy. These early AP events (often first manifest by abnormal cytosolic Ca signaling) in the acinar cell trigger the inflammatory and cell death responses of pancreatitis. Manifestations of acinar cell organelle disorders are also prominent in human pancreatitis. Our findings suggest that targeting specific mediators of organelle dysfunction could reduce disease severity.

PMID:
30973461
PMCID:
PMC6461375
[Available on 2020-04-01]
DOI:
10.1097/MPA.0000000000001298
[Indexed for MEDLINE]

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