In pancreatic acinar cells, the Src Family of Kinases (SFK) are involved in the activation of several signaling cascades that are implicated in mediating cellular processes (growth, cytoskeletal changes, apoptosis). However the role of SFKs in various physiological responses such as enzyme secretion or in pathophysiological processes such as acute-pancreatitis is either controversial, unknown or incompletely understood. To address this, in this study, we investigated the role/mechanisms of SFK's in acute pancreatitis and enzyme-release. Enzyme-secretion was studied in rat dispersed pancreatic acini, in vitro acute-pancreatitis was induced by CCK and SFK involvement assessed using the chemical SFK inhibitor (PP2) with its inactive control, PP3, under experimental conditions markedly inhibiting SFK-activation. In acute-pancreatitis, activation occurred of trypsinogen, various MAP kinases (p42/44, JNK), transcription factors(STAT-3, NFκB, AP-1), caspases(3 ,8, 9) inducing apoptosis, LDH release reflective of necrosis, and various chemokines secreted (MCP-1, MIP-1-α, RANTES). All were inhibited by PP2, not by PP3, except caspase activation leading to apoptosis, which was increased, and trypsin-activation which was unaffected, as was CCK-induced amylase release. These results demonstrate SFK activation is playing a dual role in acute-pancreatitis, inhibiting apoptosis and promoting necrosis as well as chemokines/cytokines release inducing inflammation, leading to more severe disease, as well as not affecting secretion. Thus, our studies indicate that SFK is a key mediator of inflammation and pancreatic acinar cell death in acute pancreatitis suggesting it could be a potential therapeutic target in acute pancreatitis.
- pancreatic acini
- Copyright © 2015, American Journal of Physiology- Gastrointestinal and Liver Physiology