Inhibition of hedgehog signaling ameliorates severity of chronic pancreatitis in experimental mouse models

Chronic pancreatitis (CP) is a fibro-inflammatory disease of the pancreas with no specific cure. Research highlighting the pathogenesis and especially the therapeutic aspect remains limited. Aberrant activation of developmental pathways in adults has been implicated in several diseases. Hedgehog pathway is a notable embryonic signaling pathway, known to promote fibrosis of various organs when overactivated. The aim of this study is to explore the role of the Hedgehog pathway in the progression of CP and evaluate its inhibition as a novel therapeutic strategy against CP. CP was induced in mice by repeated injections of l-arginine or caerulein in two separate models. Mice were administered with the FDA-approved pharmacological Hedgehog pathway inhibitor, vismodegib during or after establishing the disease condition to inhibit Hedgehog signaling. Various parameters of CP were analyzed to determine the effect of Hedgehog pathway inhibition on the severity and progression of the disease. Our study shows that Hedgehog signaling was overactivated during CP and its inhibition was effective in improving the histopathological parameters associated with CP. Vismodegib administration not only halted the progression of CP but was also able to resolve already-established fibrosis. In addition, inhibition of Hedgehog signaling resulted in the reversal of pancreatic stellate cell activation ex vivo. Findings from our study justify conducting clinical trials using vismodegib against CP and, thus, could lead to the development of a novel therapeutic strategy for the treatment of CP.NEW & NOTEWORTHY Hedgehog signaling is activated in human and experimental models of CP. Inhibition of Hedgehog signaling using an FDA-approved inhibitor, vismodegib, leads to the resolution of fibrosis and improves CP. This study has immense and immediate translational benefits.

chronic pancreatitis; fibrosis; hedgehog signaling; inflammation; recurrent acute pancreatitis.