Cluster of Differentiation 38 (CD38) Mediates Bile Acid-induced Acinar Cell Injury and Pancreatitis through Cyclic ADP-ribose and Intracellular Calcium Release

Abstract

Aberrant Ca2+ signals within pancreatic acinar cells are an early and critical feature in acute pancreatitis, yet it is unclear how these signals are generated. An important mediator of the aberrant Ca2+ signals due to bile acid exposure is the intracellular Ca2+ channel ryanodine receptor. One putative activator of the ryanodine receptor is the nucleotide second messenger cyclic ADP-ribose (cADPR), which is generated by an ectoenzyme ADP-ribosyl cyclase, CD38. In this study, we examined the role of CD38 and cADPR in acinar cell Ca2+ signals and acinar injury due to bile acids using pharmacologic inhibitors of CD38 and cADPR as well as mice deficient in Cd38 (Cd38−/−). Cytosolic Ca2+ signals were imaged using live time-lapse confocal microscopy in freshly isolated mouse acinar cells during perifusion with the bile acid taurolithocholic acid 3-sulfate (TLCS; 500 μm). To focus on intracellular Ca2+ release and to specifically exclude Ca2+ influx, cells were perifused in Ca2+-free medium. Cell injury was assessed by lactate dehydrogenase leakage and propidium iodide uptake. Pretreatment with either nicotinamide (20 mm) or the cADPR antagonist 8-Br-cADPR (30 μm) abrogated TLCS-induced Ca2+ signals and cell injury. TLCS-induced Ca2+ release and cell injury were reduced by 30 and 95%, respectively, in Cd38-deficient acinar cells compared with wild-type cells (p < 0.05). Cd38-deficient mice were protected against a model of bile acid infusion pancreatitis. In summary, these data indicate that CD38-cADPR mediates bile acid-induced pancreatitis and acinar cell injury through aberrant intracellular Ca2+ signaling.

From Moderately Severe to Severe Hypertriglyceridemia Induced Acute Pancreatitis: Circulating MiRNAs Play Role as Potential Biomarkers

“…Many studies found that Ca++ is overloaded in pancreatic acinar cells [17] , the sustained calcium elevation activates intracellular digestive proenzymes which leads to necrosis and toxicity [18] – [20] , resulting in necrosis and inflammation in AP [21] , [22] . Based on these previous findings, in the present study we did not focus on examining the calcium content in the pancreatic acinar cells in the pancreatic tissue of AP using animal experiments, but rather focused on investigating the relationship between the miRNAs and the calcium expression.…”

Hydrogen sulphide exacerbates acute pancreatitis by over‐activating autophagy viaAMPK/mTOR pathway

“…To stimulate AP in vitro , AR42J cells were treated with 500 μM of Na‐TC based on previous reports and our preliminary experiments. For control group, the cells were treated with an equivalent volume of PBS to that of Na‐TC administrated in AP group.…”

Role of Bile Acids and Bile Salts in Acute Pancreatitis

“…This indicates that pharmacologic blockade of CD38 and cADPR could be a therapeutic option in biliary pancreatitis. 96 Calcineurin inhibitory peptide was added to prevent BA-induced acinar cell injury because TLCS is able to cause calcineurin activation. Finally, the calcineurin inhibitors limited chymotrypsinogen activation.…”