title: Reactive oxygen species, Ca(2+) stores and acute pancreatitis; a step closer to therapy?
abstract: Disruption of Ca(2+) homeostasis can lead to severe damage of the pancreas, resulting in premature activation of digestive enzymes, vacuolisation and necrotic cell death, features typical of acute pancreatitis (AP). Therefore a fine balance between Ca(2+) release from internal stores, Ca(2+) entry and extrusion mechanisms is necessary to avoid injury. Precipitants of AP induce Ca(2+) overload of the pancreatic acinar cell that causes mitochondrial dysfunction, via formation of the mitochondrial permeability transition pore (MPTP), loss of ATP production and consequent necrosis. Oxidative stress has been shown to occur in the development of AP and may modify Ca(2+) signalling events in the acinar cell. However, the precise pathophysiological involvement is currently unclear and antioxidant therapy in the clinic has largely proved ineffective. Possible reasons for this are discussed, including evidence that ROS generation may determine cell death patterns. In contrast, recent evidence has indicated the potential for AP therapy via the prevention of Ca(2+)-dependent mitochondrial damage. Multiple approaches are indicated from preclinical findings; 1) inhibition of Ca(2+) release by IP3R blockade, 2) inhibition of Ca(2+) entry through Orai1 blockade and 3) prevention of MPTP formation. Clinical trials of drugs which prevent mitochondrial dysfunction induced by Ca(2+) overload of pancreatic acinar cells are imminent and may provide patient benefit for a disease that currently lacks specific therapy.
authors.affiliation: Department of Cellular and Molecular Physiology, Institute of Translational Medicine, and NIHR Liverpool Pancreas Biomedical Research Unit, University of Liverpool, L69 3BX, UK. Electronic address: criddle@liv.ac.uk.
authors.forename: David N
authors.initials: DN
authors.lastname: Criddle
mesh_terms: D000208:Acute Disease; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling; D004195:Disease Models, Animal; D006801:Humans; D010195:Pancreatitis / Q000378:metabolism* / Q000628:therapy*; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: D017382:Reactive Oxygen Species; D002118:Calcium
keywords: Acinar cell; Acute pancreatitis; Antioxidants; Apoptosis; Calcium; MPTP; Mitochondrial dysfunction; Necrosis; Orai; Reactive oxygen species; Store-operated calcium entry