Secretin differentially sensitizes rat pancreatic acini to the effects of supramaximal stimulation with caerulein.
Supramaximal stimulation of the rat pancreas with CCK, or its analog caerulein, triggers acute pancreatitis and a number of pancreatitis-associated acinar cell changes including intracellular activation of digestive enzyme zymogens and acinar cell injury. It is generally believed that some of these various acinar cell responses to supramaximal secretagogue stimulation are interrelated and interdependent. In a recent report, Lu et al. showed that secretin, by causing generation of cAMP and activation of PKA, sensitizes acinar cells to secretagogue-induced zymogen activation, and, as a result, submaximally stimulating concentrations of caerulein can, in the presence of secretin, trigger intracellular zymogen activation. We found that secretin also sensitizes acinar cells to secretagogue-induced cell injury and to subapical F-actin redistribution but that it did not alter the caerulein concentration dependence of other pancreatitis-associated changes such as the induction of a peak plateau intracellular [Ca(2+)] rise, inhibition of secretion, activation of ERK1/2, and activation of NF-kappaB. The finding that secretin sensitizes acinar cells to both intracellular zymogen activation and cell injury is consistent with the concept that these two early events in pancreatitis are closely interrelated and, possibly, interdependent. On the other hand, the finding that, in the presence of secretin, caerulein can trigger subapical F-actin redistribution without inhibiting secretion challenges the concept that disruption of the subapical F-actin web is causally related to high-dose secretagogue-induced inhibition of secretion in pancreatic acinar cells.
Perides
G
G
Dept. of Surgery, Tufts-New England Medical Center, Boston, MA 02111, USA. gperides@tufts-nemc.org
Sharma
A
A
Gopal
A
A
Tao
X
X
Dwyer
K
K
Ligon
B
B
Steer
M L
ML
D000199:Actins / Q000378:metabolism; D000681:Amylases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002108:Ceruletide / Q000494:pharmacology*; D000242:Cyclic AMP / Q000502:physiology; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D004792:Enzyme Precursors / Q000494:pharmacology; D007546:Isoquinolines / Q000494:pharmacology; D048370:MAP Kinase Kinase 2 / Q000502:physiology; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000502:physiology; D016328:NF-kappa B / Q000502:physiology; D010179:Pancreas / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012633:Secretin / Q000494:pharmacology*; D013268:Stimulation, Chemical; D013449:Sulfonamides / Q000494:pharmacology
D000199:Actins; D017362:Cyclic AMP Response Element-Binding Protein; D004792:Enzyme Precursors; D007546:Isoquinolines; D016328:NF-kappa B; D013449:Sulfonamides; D012633:Secretin; D002108:Ceruletide; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048370:MAP Kinase Kinase 2; D000681:Amylases; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide