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

急性胰腺炎（AP）和慢性胰腺炎（CP）的特征是早期蛋白酶激活，随后出现炎症、器官损伤和难治性疼痛。介质的释放基于其对炎性细胞的血管舒张和趋化作用而引起局部炎症反应。因此，这些细胞在其颗粒中释放大量蛋白酶，通过激活蛋白酶相关受体，引发神经周围炎症反应，即所谓的“胰腺神经炎”。这些机制在AP和CP的产生和维持中起着特定的作用。在基于这些论文的研究中，在测量胰腺内蛋白酶水平后，研究了特定蛋白酶抑制剂在蛙皮素诱导的小鼠急性和慢性胰腺炎中的镇痛作用。在确定AP和CP中蛋白酶水平显着增加后，我们应用特定的抑制剂进行疼痛治疗。我们的研究结果表明，疼痛评分显着减少，以及在胰腺和背角神经元的动物的形态学变化。在翻译背景下，考虑到临床适用性，我们现在想阐明我们实验中最相关的蛋白酶镇痛作用背后的分子机制，即，组织蛋白酶S为此目的，将鉴定胰腺中在AP和CP期间上调组织蛋白酶S的细胞亚型，并且将以细胞特异性方式在AP和CP期间关闭组织蛋白酶S表达，然后分析动物的疼痛感知。我们还将研究组织蛋白酶S在体外导致神经元激活的分子途径。最后，我们将相关的细胞特异性组织蛋白酶S的表达水平与CP患者的疼痛感觉。综上所述，后续研究可以为我们的结果转化为组织蛋白酶S抑制剂治疗胰腺炎疼痛的临床应用铺平道路。

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.