Vacuole-Membrane-Protein-1 Mediated Autophagy Prevents Severe Effects of Acute Pancreatitis in Transgenic Mice.

GRASSO D; ROPOLO, A; BOGGIO, V; LO RÉ, A; PARDO, R; IOVANNA, JL; VACCARO, MI

Szeged

Congreso; 41st European Pancreatic Club Meeting; 2009

European Pancreatic Club

Introduction: Autophagy is an evolutionary preserved degradation process of cytoplasmic cellular constituents which acts protecting cells against stresses. The pancreatitis-induced vacuole-membrane-protein-1 (VMP1) triggers autophagy in mammalian cells, and localizes in autophagosomes in pancreas from rats with experimental pancreatitis. Objectives: Our aim was to study the role of VMP1 mediated autophagy during acute pancreatitis. Materials and Methods: We used transgenic mice that contain the VMP1-EGFP transgene under the control of the constitutively active elastase promoter, specific from pancreas acinar cells. Pancreatitis was induced by seven intraperitoneal injections of caerulein (50 ìg/kg/h); mice were decapitated and pancreases removed after 12 h treatment. Results: Wild-type mice developed acute pancreatitis with high amylase and lipase levels in serum while enzyme levels in VMP1-transgenic mice were significantly lower. Histological analysis revealed high degree of necrosis in wild-type mice plus a markedly infiltration, expressed as number of inflammatory cells per 100 pancreatic acini and MPO activity. In contrast, almost none inflammation was seen in treated transgenic mice, without necrosis evidence either. Moreover, cleaved caspase-3 western-blot analysis and TUNEL assay revealed a significant increase of apoptosis level in pancreas from VMP1-transgenic mice. Surprisingly, trypsin activity -measured by hydrolysis of a synthetic substrate- was significantly reduced in pancreas from VMP1-transgenic mice comparing to wild-type mice undergoing acute pancreatitis. Data were confirmed using caerulein and enterokinase treatment. Results indicated that autophagy induction prevents trypsinogen activation and favors apoptosis, with a remarkable reduction in the local inflammatory response. Conclusion: We conclude that VMP1-triggered autophagic pathway in acinar cell prevents the severe effects of acute pancreatitis in mice.