期刊
GUT
卷 58, 期 3, 页码 431-442出版社
BMJ PUBLISHING GROUP
DOI: 10.1136/gut.2007.147207
关键词
-
资金
- NIH [DK059936]
- Foundation Designated Research Scholar Award in Pancreatitis
- Hirshberg Foundation
Background: Mechanisms of acinar cell death in pancreatitis are poorly understood. Cytochrome c release is a central event in apoptosis in pancreatitis. Here, we assessed the regulation of pancreatic cytochrome c release by Ca2+, mitochondrial membrane potential (Delta Psi m), and reactive oxygen species (ROS), the signals involved in acute pancreatitis. We used both isolated rat pancreatic mitochondria and intact acinar cells hyper-stimulated with cholecystokinin-8 (CCK-8; in vitro model of acute pancreatitis). Results: Micromolar amounts of Ca2+ depolarised isolated pancreatic mitochondria through a mechanism different from the classical'' (ie, liver) mitochondrial permeability transition pore (mPTP). In contrast with liver, Ca2+-induced mPTP opening caused a dramatic decrease in ROS and was not associated with pancreatic mitochondria swelling. Importantly, we found that Ca2+-induced depolarisation inhibited cytochrome c release from pancreatic mitochondria, due to blockade of ROS production. As a result, Ca2+ exerted two opposite effects on cytochrome c release: Ca2+ per se stimulated the release, whereas Ca2+-induced depolarisation inhibited it. This dual effect caused a non-monotonous dose-dependence of cytochrome c release on Ca2+. In intact acinar cells, cytochrome c release, caspase activation and apoptosis were all stimulated by ROS and Ca2+, and inhibited by depolarisation, corroborating the findings on isolated pancreatic mitochondria. Conclusions: These data implicate ROS as a key mediator of CCK-induced apoptotic responses. The results indicate a major role for mitochondria in the effects of Ca2+ and ROS on acinar cell death. They suggest that the extent of apoptosis in pancreatitis is regulated by the interplay between ROS, Delta Psi m and Ca2+. Stabilising mitochondria against loss of Delta Psi m may represent a strategy to mitigate the severity of pancreatitis.
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