Reactive oxygen species, Ca2+ stores and acute pancreatitis; a step closer to therapy?

- Disruption of Ca2+ homeostasis causes mitochondrial dysfunction and pancreatic damage.
- The role of oxidative stress in acute pancreatitis (AP) is unclear.
- Inhibition of acinar cell Ca2+ overload protects mitochondria and ameliorates AP.
- Prevention of MPTP formation is protective in AP.
- Clinical evaluation of new therapeutic strategies imminent.

Disruption of Ca2+ 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 Ca2+ release from internal stores, Ca2+ entry and extrusion mechanisms is necessary to avoid injury. Precipitants of AP induce Ca2+ 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 Ca2+ 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 Ca2+-dependent mitochondrial damage. Multiple approaches are indicated from preclinical findings; 1) inhibition of Ca2+ release by IP3R blockade, 2) inhibition of Ca2+ entry through Orai1 blockade and 3) prevention of MPTP formation. Clinical trials of drugs which prevent mitochondrial dysfunction induced by Ca2+ overload of pancreatic acinar cells are imminent and may provide patient benefit for a disease that currently lacks specific therapy.