The pancreatic proteases as new analgesic targets in acute and chronic pancreatitis

Introduction and targets Acute (AP) and chronic pancreatitis (CP) are characterized by early protease activation with subsequent inflammation, tissue damage and therapy-resistant pain. These mechanisms are triggered by a perineural inflammatory response via proteinase-activated receptors. Additionally to inflammation analysis, there is need for a study illuminating the role of all major protease families with their specific subtypes and isoforms in pancreatic pain development in AP and CP.

Methods Here, we performed the quantification of the intrapancreatic protease levels in AP and CP with the subsequent selective inhibition of proteases for the prevention of tissue destruction and pain therapy. For this purpose, AP and CP were induced by intraperitoneal cerulein administration in C57BL/6J mice. The observation period was 12 h in AP and 8 weeks in CP. After quantification of relative protease levels, specific inhibitors were continuously administered subcutaneously via implanted osmotic pumps. The abdominal pain reaction was examined via standardized mechanosensitivity, using “von Frey” test.

Results We have shown, that intrapancreatic protease levels in AP or CP showed a significantly altered profile compared to healthy controls. In detail, the expression of cysteine protease Cathepsin S was three times higher in AP and CP. Furthermore, there was an increase of ADAM9, MMP2, MMP3 and MMP9. As a proof of concept, we selectively inhibited the elevated protease-subtypes and measured the abdominal mechanosensitivity with Von-Frey-Score (scale from 0 to 20). Here we were able to show, that treated mice with CP had a significantly lower pain level. Compared to placebo mice (Von-Frey Score 11,2), treatment with SB3CT (inhibitor of MMP-2 and MMP-9) decreased pain to 9,13, APC366 (inhibits mast cell tryptase) to 8,33, SB366791 (TRPV1 antagonist) to 8,67 and LY3000328 (inhibitor of Cathespin S) to 3,40.

Conclusion Selective protease inhibition ameliorates the severity of acute and chronic pancreatitis and attenuates the activation of sensoric neurons in the dorsal root ganglia via protease-associated receptors. Thus, protease inhibition may lead to a significant improvement of pain therapy in the clinical treatment of acute and chronic pancreatitis.

Publication History

Article published online:
07 September 2021