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cute pancreatitis is an unpredictable disease. Most Apatients develop edema of the pancreas and quickly recoverwhatever the therapy (or lack thereof), but aminority develop severe complications with significant morbidity and mortality.When the disease is studied in experimental animal models, to distinguish between the 2 forms, it appears that all processes begin in acinar cells but then develop in different directions. The way acinar cells undergo injury and cell death seems to determine the ultimate severity. A highly regulated form of cell death is apoptosis, characterized by the activation of multiple caspases, in response to which acinar cells shrink and disintegrate into neat membrane-confined packages that are taken up by neighboring cells or macrophages. No cellular content is released and no tissue infiltrationwith inflammatory cells is triggered. Conversely,when acinar cells undergo necrosis, a process previously regarded as completely unregulated, their membranes disintegrate, their proteolytic enzymes and organelles are spilled into the interstitial space where some components act as damageassociated molecular patterns such as free adenosine triphosphate, free DNA, or released histones. Although cell death is never a good thing, a shift from necrosis to apoptosis in response to a pathologic stimulus can render experimental pancreatitis significantly less severe and thus confers a beneficial effect. Recent studies have shown that necrosis is not necessarily haphazard or spontaneous and can be tightly regulated as well. The best investigated form of regulated necrosis was termed necroptosis and involves activation of the receptorinteracting protein kinases (RIP)1/RIP3/mixed lineage kinase domain-like (MLKL) pathway. This is where Louhimo et al started. They investigated 2 reductionist, isolated, acini-based models of pancreatitis, 1 using supramaximal secretagogue stimulation and the other meant to mimic gallstone-induced pancreatitis, asking what form of cell death prevails and which role necroptosis plays. By using genetic deletion of RIP3 and a potent inhibitor of the RIP1/ RIP3 pathway, necrostatin, they found not only that necroptosis is the predominant form of acinar cell death in these models (rather than apoptosis), but that the prevention of necroptosis greatly affects the disease severity in vivo—for the better. This makes necroptosis an attractive target for the prevention of pancreatitis or at least for the reduction of its severity. In another set of experiments, Louhimo et al established that a therapy directed against necroptosis can still be effective when pancreatitis is already established, making therapy, rather than prevention, an attractive goal. A signaling mechanism reported to be involved in necrosis as well as apoptosis is that involving tumor necrosis

Necrosis, Apoptosis, Necroptosis, Pyroptosis: It Matters How Acinar Cells Die During Pancreatitis