Previously, we found that the University of North Carolina cystic fibrosis (UNC-CF) mouse had more severe experimental acute pancreatitis (AP) than wild-type (WT) mice characterized by exuberant pancreatic inflammation and impaired acinar apoptosis. Because exon 10 CFTR gene mutations exhibit different phenotypes in tissues such as the mouse lung, we tested the hypothesis that ΔF508-CF mice also develop severe AP associated with an antiapoptotic acinar phenotype, which requires indirect effects of the extracellular milieu. We used cerulein hyperstimulation models of AP. More severe pancreatitis occurred in cerulein-injected ΔF508-CF vs. WT mice based on histological severity ( P < 0.01) and greater neutrophil sequestration [ P < 0.0001; confirmed by myeloperoxidase activity ( P < 0.005)]. In dispersed acini cerulein-evoked necrosis was greater in ΔF508-CF acini compared with WT ( P < 0.05) and in WT acini pretreated with CFTRinh-172 compared with vehicle ( P < 0.05). Cerulein-injected ΔF508-CF vs. WT mice had less apoptosis based on poly(ADP-ribose) polymerase (PARP) cleavage ( P < 0.005), absent DNA laddering, and reduced terminal deoxynucleotidyltransferase biotin-dUTP nick end labeling (TUNEL) staining ( P < 0.005). Unexpectedly, caspase-3 activation was greater in ΔF508-CF vs. WT acini at baseline ( P < 0.05) and during AP ( P < 0.0001). Downstream, ΔF508-CF pancreas overexpressed the X-linked inhibitor of apoptosis compared with WT ( P < 0.005). In summary, the ΔF508-CF mutation, similar to the UNC-CF “null” mutation, causes severe AP characterized by an exuberant inflammatory response and impaired acinar apoptosis. Enhanced acinar necrosis in ΔF508-CF occurs independently of extracellular milieu and correlates with loss of CFTR-Cl conductance. Although both exon 10 models of CF inhibit acinar apoptosis execution, the ΔF508-CF mouse differs by increasing apoptosis signaling. Impaired transduction of increased apoptosis signaling in ΔF508-CF acini may be biologically relevant to the pathogenesis of AP associated with CFTR mutations.
37 Depot Medroxyprogesterone Acetate in the Management of Recurrent Acute Pancreatitis in Patients With Cystic Fibrosis Gene Mutations
