A proinflammatory, antiapoptotic phenotype underlies the susceptibility to acute pancreatitis in cystic fibrosis transmembrane regulator (-/-) mice.
OBJECTIVE
Cystic fibrosis transmembrane regulator (CFTR) gene mutations are associated with pancreatic insufficiency and pancreatitis. Chronic pancreatitis, including cystic fibrosis-related disease, may exist as a continuum between acute and chronic disease and may manifest as recurrent pain. We hypothesized that cftr(m1UNC) (-/-) mice, which have no evidence of chronic pancreatitis, are susceptible to developing acute pancreatitis.


METHODS
We used a cerulein hyperstimulation model of acute pancreatitis and measured histological changes, tissue edema, neutrophil infiltration, inflammatory mediators' mRNA expression, apoptosis markers, and pancreatic trypsin and serum lipase activities. Additionally, we quantitated in vivo pancreatic secretion and pancreatic digestive enzymes.


RESULTS
Multiple proinflammatory cytokine genes were constitutively overexpressed in cftr (-/-) pancreas compared with wild-type mice. During acute pancreatitis, cftr (-/-) mice developed more severe acute pancreatitis than wild-type, as indicated by greater pancreatic edema, neutrophil infiltration, mRNA expression of multiple inflammatory mediators, and less apoptotic cell death. In contrast to wild-type mice, cftr (-/-) mice had blunted increases in pancreatic trypsin and serum lipase activities, but similar percentages of pancreatic trypsinogen activation. Finally, cftr (-/-) mice had less in vivo pancreatic secretion in response to cholecystokinin octapeptide and reduced pancreatic digestive enzyme protein and mRNA levels, thus suggesting mild pancreatic insufficiency.


CONCLUSIONS
A baseline proinflammatory state and an antiapoptotic phenotype may sensitize cftr (-/-) mice to developing more severe acute pancreatitis with an exuberant pancreatic inflammatory response. Cftr (-/-) mice have mild pancreatic insufficiency, which partially explains the blunted increase of pancreatic and serum digestive enzymes during acute pancreatitis. These findings may explain the susceptibility to acute pancreatitis in persons with classic and nonclassic cystic fibrosis.
Dimagno
Matthew J
MJ
Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, 48109, USA. mdimagno@umich.edu
Lee
Sae-Hong
SH
Hao
Yibai
Y
Zhou
Shi-Yi
SY
McKenna
Barbara J
BJ
Owyang
Chung
C
D000208:Acute Disease; D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D001483:Base Sequence; D001707:Biopsy, Needle; D003550:Cystic Fibrosis / Q000235:genetics / Q000473:pathology; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009154:Mutation; D020556:Neutrophil Infiltration; D010195:Pancreatitis / Q000235:genetics* / Q000473:pathology*; D010641:Phenotype; D011897:Random Allocation; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012680:Sensitivity and Specificity; D013045:Species Specificity
D019005:Cystic Fibrosis Transmembrane Conductance Regulator