Journal
GUT
Volume 65, Issue 8, Pages 1333-1346Publisher
BMJ PUBLISHING GROUP
DOI: 10.1136/gutjnl-2014-308553
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Funding
- US Veterans Administration Merit Review
- NIH [R01DK59936, R01AA19730]
- Southern California Research Center for Alcoholic Liver and Pancreatic Diseases
- American Gastroenterological Association Foundation Designated Research Scholar Award in Pancreatitis
- Russian Federation BR grant [09-04-00739]
- UK/China Postgraduate Research Scholarship for Excellence
- Liverpool China Scholarship Council Award
- CORE, UK
- UK Medical Research Council
- Royal College of Surgeons of England
- UK NIHR Biomedical Research Unit Funding Scheme
- Academy of Medical Sciences (AMS) [AMS-SGCL10-Mukherjee] Funding Source: researchfish
- Cancer Research UK [8968, 15957] Funding Source: researchfish
- Medical Research Council [MR/J002771/1, G19/22] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0510-10126, CL-2012-07-001] Funding Source: researchfish
- MRC [G19/22, MR/J002771/1] Funding Source: UKRI
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Objective Acute pancreatitis is caused by toxins that induce acinar cell calcium overload, zymogen activation, cytokine release and cell death, yet is without specific drug therapy. Mitochondrial dysfunction has been implicated but the mechanism not established. Design We investigated the mechanism of induction and consequences of the mitochondrial permeability transition pore (MPTP) in the pancreas using cell biological methods including confocal microscopy, patch clamp technology and multiple clinically representative disease models. Effects of genetic and pharmacological inhibition of the MPTP were examined in isolated murine and human pancreatic acinar cells, and in hyperstimulation, bile acid, alcoholic and choline-deficient, ethionine-supplemented acute pancreatitis. Results MPTP opening was mediated by toxin-induced inositol trisphosphate and ryanodine receptor calcium channel release, and resulted in diminished ATP production, leading to impaired calcium clearance, defective autophagy, zymogen activation, cytokine production, phosphoglycerate mutase 5 activation and necrosis, which was prevented by intracellular ATP supplementation. When MPTP opening was inhibited genetically or pharmacologically, all biochemical, immunological and histopathological responses of acute pancreatitis in all four models were reduced or abolished. Conclusions This work demonstrates the mechanism and consequences of MPTP opening to be fundamental to multiple forms of acute pancreatitis and validates the MPTP as a drug target for this disease.
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