Severe acute pancreatitis and reduced acinar cell apoptosis in the exocrine pancreas of mice deficient for the Cx32 gene.
OBJECTIVE
The early events leading to acinar cell injury during acute pancreatitis are poorly characterized. Signaling through gap junction channels contributes to the homeostasis of the exocrine pancreas by coordinating acinar cell activity within an acinus. To explore the role of gap junctional communication in acinar cell response to injury, we analyzed the course of acute pancreatitis induced by injection of cerulein in mice deficient for Cx32, the major gap junction protein expressed in the exocrine pancreas.


METHODS
The severity of pancreatitis was evidenced by measuring serum amylase activity, pancreatic edema, acinar cell necrosis, pancreatic tumor necrosis factor alpha concentration, and myeloperoxidase activity. Acinar cell apoptosis was detected by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL), caspase-3 activity, and Bax/Bcl-2 expression. Expression and function of connexin were evaluated by immunofluorescence and dye coupling.


RESULTS
Cx32-deficient mice exhibited a deleterious course of acute pancreatitis with increased necrosis, edema, and inflammation of the exocrine pancreas. In addition, the exocrine pancreas of Cx32-deficient mice showed a decreased number of TUNEL-positive acinar cells and decreased caspase-3 activity but no change in Bax or Bcl-2 pancreatic expression. Interestingly, chemicals known to induce apoptosis in vivo had no effect on Cx32-deficient pancreatic acinar cells.


CONCLUSIONS
Deficiency of a pancreatic connexin converts a mild reversible form of acute pancreatitis into a severe disease and decreases the sensitivity of acinar cells to apoptotic stimuli. The results show that acinar cell-to-cell communication plays a key role in the modulation of severity of acute pancreatitis.
Frossard
Jean-Louis
JL
Divisions of Gastroenterology, University Hospitals, Geneva, Switzerland.
Rubbia-Brandt
Laura
L
Wallig
Matthew A
MA
Benathan
Messod
M
Ott
Thomas
T
Morel
Philippe
P
Hadengue
Antoine
A
Suter
Susanne
S
Willecke
Klaus
K
Chanson
Marc
M
D000208:Acute Disease; D000818:Animals; D017209:Apoptosis; D002108:Ceruletide; D017630:Connexins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout / Q000235:genetics; D010179:Pancreas / Q000473:pathology / Q000503:physiopathology*; D010195:Pancreatitis / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D012720:Severity of Illness Index; D051028:bcl-2-Associated X Protein; D000097002:Gap Junction beta-1 Protein
D002108:Ceruletide; D017630:Connexins; D005978:Glutathione; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D000097002:Gap Junction beta-1 Protein; C494827:Bax protein, mouse