Research Summary

Study of the pathogenic mechanisms of acinar cell injury in human acute pancreatitis.

Acute pancreatitis (AP) remains a clinical enigma without specific treatment. This potentially life-threatening disease begins as local inflammation resulting from pancreatic acinar cell injury, which eventually manifests as systemic inflammatory response syndrome (SIRS). Studies on experimental AP in murine models have demonstrated intra-acinar activation of trypsinogen to trypsin within 15-30mins of insult, which subsequently triggers a cascade of molecular events leading to acinar cell death. However, the nature of such events remains to be explored in humans. By the time the patient with AP is hospitalized, the early intra-acinar events have already occurred and it is the SIRS that is responsible for adverse outcomes. An understanding of the intra-acinar events and resulting SIRS in human AP is essential to prevent AP and develop goal-directed therapy.

We propose to elucidate the nature of human acinar cell death, zymogen/lysosomes co-localization, mechanism of acinar cell death and relationship with development of inflammation in AP. Studies will be conducted on normal human pancreatic acini isolated from resected pancreas in patients undergoing Whipple's operation/pancreatic resection for indications other than pancreatic malignancy and chronic pancreatitis. Our approach will involve studies to evaluate redistribution of cathepsins, role of cathepsins/caspases/RIP in mediating acinar cell death, intracellular calcium signalling, mitochondrial permeability and cytokine expression, employing proteomics, RT-PCR and imaging (IHC, IF).


Figure Legend: Proposed mechanism of acinar cell injury in human acute pancreatitis