Inhibition of acinar apoptosis occurs during acute pancreatitis in the human homologue DeltaF508 cystic fibrosis mouse.
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 DeltaF508-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 DeltaF508-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 DeltaF508-CF acini compared with WT (P < 0.05) and in WT acini pretreated with CFTR(inh)-172 compared with vehicle (P < 0.05). Cerulein-injected DeltaF508-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 DeltaF508-CF vs. WT acini at baseline (P < 0.05) and during AP (P < 0.0001). Downstream, DeltaF508-CF pancreas overexpressed the X-linked inhibitor of apoptosis compared with WT (P < 0.005). In summary, the DeltaF508-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 DeltaF508-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 DeltaF508-CF mouse differs by increasing apoptosis signaling. Impaired transduction of increased apoptosis signaling in DeltaF508-CF acini may be biologically relevant to the pathogenesis of AP associated with CFTR mutations.
DiMagno
Matthew J
MJ
Dept. of Internal Medicine, Univ. of Michigan Medical School, Ann Arbor, 48109, USA. mdimagno@umich.edu
Lee
Sae-Hong
SH
Owyang
Chung
C
Zhou
Shi-yi
SY
D000208:Acute Disease; D000818:Animals; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D002108:Ceruletide; D003550:Cystic Fibrosis / Q000150:complications* / Q000235:genetics*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics*; D004789:Enzyme Activation; D005838:Genotype; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009154:Mutation; D009336:Necrosis; D010179:Pancreas / Q000473:pathology; D010195:Pancreatitis / Q000139:chemically induced / Q000150:complications* / Q000473:pathology / Q000503:physiopathology*; D009195:Peroxidase / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D012720:Severity of Illness Index; D015398:Signal Transduction; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000235:genetics / Q000378:metabolism
D012333:RNA, Messenger; D051636:X-Linked Inhibitor of Apoptosis Protein; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D002108:Ceruletide; D009195:Peroxidase; D053148:Caspase 3