期刊
PANCREAS
卷 47, 期 1, 页码 18-24出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/MPA.0000000000000953
关键词
alcohol; experimental acute pancreatitis; mitochondrial permeability transition pore (MPTP); necrosis; TRO40303
资金
- CORE, United Kingdom
- Royal College of Surgeons of England
- Liverpool China Scholarship Council
- UK National Institute for Health Research Biomedical Research Unit
- UK Medical Research Council
- Trophos
- Calcimedica
- Cypralis
- Debiopharm
- GlaxoSmithKline
- Novartis
- National Institute for Health Research [NF-SI-0515-10084] Funding Source: researchfish
Objectives Mitochondrial permeability transition pore inhibition is a promising approach to treat acute pancreatitis (AP). We sought to determine (i) the effects of the mitochondrial permeability transition pore inhibitor 3,5-seco-4-nor-cholestan-5-one oxime-3-ol (TRO40303) on murine and human pancreatic acinar cell (PAC) injury induced by fatty acid ethyl esters (FAEEs) or taurolithocholic acid-3-sulfate and (ii) TRO40303 pharmacokinetics and efficacy in experimental alcoholic AP (FAEE-AP). Methods Changes in mitochondrial membrane potential ((m)), cytosolic Ca2+ ([Ca2+](c)), and cell fate were examined in freshly isolated murine or human PACs by confocal microscopy. TRO40303 pharmacokinetics were assessed in cerulein-induced AP and therapeutic efficacy in FAEE-AP induced with palmitoleic acid and ethanol. Severity of AP was assessed by standard biomarkers and blinded histopathology. Results TRO40303 prevented loss of (m) and necrosis induced by 100 M palmitoleic acid ethyl ester or 500 M taurolithocholic acid-3-sulfate in murine and human PACs. Pharmacokinetic analysis found TRO40303 accumulated in the pancreas. A single dose of 3 mg/kg TRO40303 significantly reduced serum amylase (P = 0.043), pancreatic trypsin (P = 0.018), and histopathology scores (P = 0.0058) in FAEE-AP. Conclusions TRO40303 protects mitochondria and prevents necrotic cell death pathway activation in murine and human PACs, ameliorates the severity of FAEE-AP, and is a candidate drug for human AP.
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