Figure 8. Schematic diagram illustrating how the PSCs may participate in a vicious circle amplifying necrotic PAC death in AP.

In the PACs the initial damage leading to AP may be caused by a combination of fatty acids (FA) and ethanol or by certain bile acids (for example, TLC‐S). These agents generate excessive Ca²⁺ signals in the PACs causing mitochondrial depolarization and therefore reduced mitochondrial ATP production (Gerasimenko et al. 2014). The excessive Ca²⁺ signals also cause intracellular trypsin activation. Necrosis in at least a proportion of PACs follows, releasing activated proteases, including trypsin and kallikrein into the interstitial fluid. Kallikrein catalyses the formation of BK from bradykininogen and BK in turn acts on PSCs to generate Ca²⁺ signals. Trypsin acts in the same way. These actions would amplify the direct actions of certain bile acids (e.g. taurocholate) and possibly fatty acids and ethanol on the PSCs. In these cells, Ca²⁺ signals activate the enzyme NO synthase, thereby producing NO and this gas may diffuse into neighbouring PACs and there, by mechanisms not yet understood, promote the necrotic process. This will then lead to additional protease release, further stimulating the PSCs, generating a vicious circle.