Citations

Abstract Background: Hemorrhagic necrotizing pancreatitis (HNP) is a highly lethal form of pancreatitis that lacks mechanism-based therapy. Intra-acinar enzyme activation is fundamental to pancreatitis initiation, yet it does not explain why only a subset of episodes progress to catastrophic hemorrhagic necrosis. Objective: To identify determinants of progression to lethal HNP and test a mechanism-based preventive intervention. Design: Using humanized trypsinogen mouse models and secretagogue regimens, we compared high-dose cerulein with low/moderate-dose cerulein and bombesin. We quantified pancreatic protease activity, performed blinded histopathologic scoring, assessed hemorrhage/vascular disruption, and evaluated enzyme localization and ductal injury by PRSS1 immunostaining. De-identified human pancreatic histology from HNP were examined. We tested a repurposed strategy using clinically approved agents for other indications: secretin to stimulate ductal fluid secretion and isosorbide mononitrate (ISMN) to promote ductal outflow via sphincter of Oddi relaxation. Results: High-dose cerulein induced robust intrapancreatic protease activation but predominantly caused edematous pancreatitis. Paradoxically, bombesin and low/moderate-dose cerulein elicited lower total pancreatic protease activity yet produced severe, frequently lethal HNP with vascular disruption and lobular ischemic necrosis. HNP was associated with intraductal enzyme accumulation and ductal injury. Secretin or ISMN alone showed limited protection, whereas combined secretin+ISMN prevented hemorrhagic necrotizing injury. Conclusion: Pancreatitis severity is determined not only by the magnitude of enzyme activation but also by where enzyme activity is exerted, implicating intraductal enzyme accumulation as a mechanistic determinant and therapeutic target in HNP. Coordinated enhancement of ductal secretion and outflow with clinically approved agents prevents HNP in vivo, supporting a translatable prevention strategy.

Fibrodysplasia ossificans progressiva (FOP) is a rare and devastating genetic disease, in which soft connective tissue is converted into heterotopic bone through an endochondral ossification process. Patients succumb early as they gradually become trapped in a second skeleton of heterotopic bone. Although the underlying genetic defect is long known, the inherent complexity of the disease has hindered the discovery of effective preventions and treatments. New developments in the gene therapy field have motivated its consideration as an attractive therapeutic option for FOP. However, the immune system's role in FOP activation and the as-yet unknown primary causative cell, are crucial issues which must be taken into account in the therapy design. While gene therapy offers a potential therapeutic solution, more knowledge about FOP is needed to enable its optimal and safe application.