Secretin differentially sensitizes rat pancreatic acini to the effects of supramaximal stimulation with caerulein

Abstract

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.

Pancreas-specific RelA/p65 truncation increases susceptibility of acini to inflammation-associated cell death following cerulein pancreatitis

“…MAPK modules are known to be transiently activated during cerulein-induced pancreatitis (25)(26)(27)(28)(29)(30)(31). Inhibition of these modules has been associated with an improvement in the outcome during AP (27,(39)(40)(41). By analyzing these pathways in our mouse model, we also detected a prolonged activation of MAPK modules (ERK1/2 [p42/44], p38, and SAPK [p46/54]) during inflammation in the rela Δ/Δ pancreas (Figure 4).…”

Protective roles of redox-active protein thioredoxin-1 for severe acute pancreatitis

“…To assess the interaction between TRX-1 and secretory response of pancreatic acinar cells, we studied whether amylase secretion from acinar cells treated with CER could be influenced either by TRX-1 overexpression in the pancreas or treatment with rhTRX-1. Pancreatic acinar cells were obtained from the pancreas of WT or TRX-1-TG mice by collagenase treatment as described previously (2,3,34,49,52). These cells were incubated with various concentrations of CER (10 Ϫ12 -10 Ϫ7 M) for 30 min at 37°C.…”

Blockade of Multidrug Resistance-Associated Proteins Aggravates Acute Pancreatitis and Blunts Atrial Natriuretic Factor’s Beneficial Effect in Rats: Role of MRP4 (ABCC4)

“…In pancreatic acinar cells, secretin as well as other agents that increase cAMP have little effect on zymogen activation alone but sensitize the response of agents that increase intracellular calcium such as cerulein or cholecystokinin (11,12). In pancreatic acini, it was reported that a cell-permeable cAMP inhibitor (Rp-8Br-cAMP) reduces the sensitization induced by vasoactive intestinal peptide and 8Br-cAMP to low and high doses of cerulein (11).…”