Early Changes in Pancreatic Acinar Cell Calcium Signaling after Pancreatic Duct Obstruction

Abstract

Intracellular Ca2؉ -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 [ 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.Alterations in intracellular calcium signaling have previously been reported from an experimental animal model of acute pancreatitis that employs supramaximal secretagogue stimulation for the disease induction (1). Moreover, the spatial and temporal distribution of intracellular calcium signals in response to either physiological or pathological stimuli has been found to be directly related to premature digestive enzyme activation in the pancreas and to acinar cell injury (2-5). Intracellular activation of trypsinogen on the other hand can be completely prevented with agents that interfere with either the uptake of calcium, the maintenance of a calcium gradient across the plasma membrane, or the rapid release of calcium from apical intracellular stores (4, 6). All of these studies indicate clearly that the spatial and temporal distribution of intracellular calcium signals plays a critical role in the early cellular events that precede the onset of pancreatitis. The mechanism, however, that was used to induce acinar cell injury in these studies or in response to which intracellular calcium changes were characterized, supramaximal secretagogue stimulation, is not necessarily an event that is generally involved in the pathogenesis of clinical pancreatitis.In many parts of the world the most common etiological factor associated with acute pancreatitis is gallstone disease. Experimental (7) as well as clinical studies (8, 9) suggest that the onset of gallstone-induced pancreatitis requires migration of the offending stone through the biliary tract and its impaction at the duodenal papilla. Here, at the junction of the common bile duct and the pancreatic duct, the stone can impair the flow of pancreatic secretion or lead to a complete blockage of the pancreatic duct. It is now generally accepted that this impairment of pancreatic secretion (7, 10, 11), rather than a potential reflux of bile into the pancreas (13), represents the critical pathophysiological event for the development gallstoneinduced pancreatitis. To investigate whether this clinically relevant...

Postnatal developmental Histomorphological and histochemical study of the pancreas in the domestic cat (Felis Catus).

“…These findings were parallel with those found previously in different species of rabbit 7,10,14 . The presence of main pancreatic duct in domestic cats was similarly recorded in the other laboratory species such as mice, rats, guinea pigs and hamster 9,[15][16][17] . Similarly to the cat pancreas, the main duct was recorded in sheep and goats but differently these animals have also accessory duct 18 .…”

Ethanol toxicity in pancreatic acinar cells: Mediation by nonoxidative fatty acid metabolites

“…Abnormal, prolonged, global elevations of [Ca 2ϩ ] i initiate premature intracellular digestive enzyme activation and vacuolization, early changes of pancreatic acinar cell injury, both in vitro within isolated living pancreatic acinar cells exposed to hyperstimulation (11,12), TPG (11), or bile salts (19,20) and in vivo within the duct-obstructed pancreas (21). The abnormal [Ca 2ϩ ] i elevations may induce Ca 2ϩ release from zymogen granules, which prompts unfolding and premature activation of digestive enzymes (11,32).…”

“…In contrast, hyperstimulation elicits a sustained, global [Ca 2ϩ ] i rise that in turn induces pronounced premature intracellular digestive enzyme activation and vacuolization (11), nuclear factor B activation (16), cytokine expression (17,18), and acinar cell death (1,17), characteristic changes of acute pancreatitis. Similar changes are induced by naturally occurring bile salts (19,20) and pancreatic duct obstruction (21), which also induce acute pancreatitis.…”

Calcium signalling and pancreatic cell death: apoptosis or necrosis?

“…27 Furthermore, supra-maximal concentrations of CCK-induced elevation of baseline Ca 2 þ in isolated pancreatic acinar cells which was strongly linked to premature intracellular activation of trypsinogen, the hallmark of acute pancreatitis, 2,3 an effect that may involve activation of the vacuolar ATPase. 28 This action to raise cytosolic Ca 2 þ is shared by other diverse pathological stimuli that cause pancreatic injury, including non-oxidative ethanol metabolites, 11,12 duct ligation 29 and bile acids. [30][31][32] In addition, recent evidence has shown that the enzyme phosphatidylinositol 3-kinase (PI3K) mediates prolonged elevations of cytosolic Ca 2 þ , under conditions of agonist stimulation, via an inhibitory action on the sarcoendoplasmic reticulum Ca 2 þ ATPase (SERCA) pump; 33 the PI3K system has been implicated in the development of acute pancreatitis since pharmacological inhibition or knockout of this enzyme was protective in experimental animal models.…”