Selective inhibition of proteases as a novel analgetic strategy in acute and chronic pancreatitis

• Applicant: Professor Dr. Ihsan Ekin Demir
• Subject Area: General and Visceral Surgery ; Gastroenterology
• Term: since 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 422377721

Acute (AP) and chronic pancreatitis (CP) are characterized by early protease activation with subsequent inflammation, organ damage and therapy-resistant pain. The release of mediators causes a local inflammatory response based on their vasodilatory and chemotactic effects on inflammatory cells. These cells consequently release an arsenal of proteases in their granules which, via the activation of protease-associated receptors, trigger a perineural inflammatory reaction, the so-called "pancreatic neuritis". These mechanisms play a specific role in the creation and maintenance of AP and CP. In the study based on these theses, after measuring the intrapancreatic protease levels, the analgesic effect of specific protease inhibitors in cerulein-induced, murine acute and chronic pancreatitis has been investigated. After identifying the significantly increased protease levels in the AP and CP, we applied specific inhibitors for pain therapy. Our results showed a significant reduction in the pain score as well as the morphological changes in the pancreata and dorsal horn neurons of the animals. In the context of a translational setting and with a view to clinical applicability, we now want to elucidate the molecular mechanism behind the analgesic effect of the most relevant protease in our experiments, i.e., cathepsin S. For this purpose, the cell subtype in the pancreas that upregulats cathepsin S during AP and CP will be identified, and the cathepsin S expression will be switched off during AP and CP in a a cell-specific manner, followed by analysis of the animals' pain perception. We will also investigate the molecular pathway through which cathepsin S leads to neuronal activation in vitro. Finally, we will correlate the level of cell-specific cathepsin S expression with the pain sensation in CP patients. In summary, the follow-up study can pave the way for the translation of our results into the clinical application of Cathepsin S inhibition for pain treatment in pancreatitis.

• DFG Programme: Research Grants
• Co-Investigator: Dr. Okan Safak