Early changes in pancreatic acinar cell calcium signaling after pancreatic duct obstruction.
Intracellular Ca(2+)-changes not only participate in important signaling pathways but have also been implicated in a number of disease states including acute pancreatitis. To investigate the underlying mechanisms in an experimental model mimicking human gallstone-induced pancreatitis, we ligated the pancreatic duct of Sprague-Dawley rats and NMRI mice for up to 6 h and studied intrapancreatic changes including the dynamics of [Ca(2+)](i) in isolated acini. In contrast to bile duct ligation, pancreatic duct obstruction induced intra-pancreatic trypsinogen activation, leukocytosis, hyperamylasemia, and pancreatic edema and increased lung myeloperoxidase activity. Although resting [Ca(2+)](i) in isolated acini rose by 45% to 205 +/- 7 nmol, the acetylcholine- and cholecystokinin (CCK)-stimulated calcium peaks as well as the amylase secretion declined, but neither the [Ca(2+)](i)-signaling pattern nor the amylase output in response to the Ca(2+)-ATPase inhibitor thapsigargin nor the secretin-stimulated amylase release were impaired by pancreatic duct ligation. On the single cell level pancreatic duct ligation reduced the percentage of cells in which submaximal secretagogue stimulation was followed by a physiological response (i.e. Ca(2+) oscillations) and increased the percentage of cells with a pathological response (i.e. peak plateau or absent Ca(2+) signal). Moreover, it reduced the frequency and amplitude of Ca(2+) oscillation as well as the capacitative Ca(2+) influx in response to secretagogue stimulation. Serum pancreatic enzyme elevation as well as trypsinogen activation was significantly reduced by pretreatment of animals with the calcium chelator BAPTA-AM. These experiments suggest that pancreatic duct obstruction rapidly changes the physiological response of the exocrine pancreas to a Ca(2+)-signaling pattern that has been associated with premature digestive enzyme activation and the onset of pancreatitis, both of which can be prevented by administration of an intracellular calcium chelator.
Mooren
Frank Ch
FCh
Medizinische Klinik B and Institut für Sportmedizin, Westfälische Wilhelms-Universität, 48129 Münster, Germany.
Hlouschek
Verena
V
Finkes
Till
T
Turi
Stefan
S
Weber
Ina Alexandra
IA
Singh
Jaipaul
J
Domschke
Wolfram
W
Schnekenburger
Jürgen
J
Krüger
Burkhard
B
Lerch
Markus M
MM
D000251:Adenosine Triphosphatases / Q000378:metabolism; D000681:Amylases / Q000097:blood; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002614:Chelating Agents / Q000494:pharmacology; D002766:Cholecystokinin / Q000378:metabolism; D003251:Constriction, Pathologic; D004533:Egtazic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D005434:Flow Cytometry; D008297:Male; D051379:Mice; D010179:Pancreas / Q000166:cytology* / Q000378:metabolism*; D010182:Pancreatic Diseases / Q000473:pathology; D010183:Pancreatic Ducts / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D019284:Thapsigargin / Q000378:metabolism; D013997:Time Factors; D014362:Trypsinogen / Q000378:metabolism
D002614:Chelating Agents; C070379:1,2-bis(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid acetoxymethyl ester; D004533:Egtazic Acid; D019284:Thapsigargin; D014362:Trypsinogen; D002766:Cholecystokinin; D000681:Amylases; D000251:Adenosine Triphosphatases; D002118:Calcium