Pancreatitis

Notes: Oppliger, S

Hartnack, S

Riond, B

Reusch, C E

Kook, P H

eng

2013/07/31 06:00

J Vet Intern Med. 2013 Sep-Oct;27(5):1077-82. doi: 10.1111/jvim.12150. Epub 2013 Jul 26.

URL: http://www.ncbi.nlm.nih.gov/pubmed/23888903

Author Address: Clinic for Small Animal Internal Medicine, Vetsuisse Faculty, University of Zurich, Zurich, Switzerland.

 

 

Reference Type:  Journal Article

Record Number: 5025Author: Orabi, A. I., Muili, K. A., Javed, T. A., Jin, S., Jayaraman, T., Lund, F. E. and Husain, S. Z.

Year: 2013

Title: Cluster of differentiation 38 (CD38) mediates bile acid-induced acinar cell injury and pancreatitis through cyclic ADP-ribose and intracellular calcium release

Journal: J Biol Chem

Volume: 288

Issue: 38

Pages: 27128-37

Date: Sep 20

Short Title: Cluster of differentiation 38 (CD38) mediates bile acid-induced acinar cell injury and pancreatitis through cyclic ADP-ribose and intracellular calcium release

Alternate Journal: The Journal of biological chemistry

ISSN: 1083-351X (Electronic)

0021-9258 (Linking)

DOI: 10.1074/jbc.M113.494534

PMCID: 3779711

Accession Number: 23940051

Keywords: Acinar Cells/*metabolism/pathology

Animals

Antigens, CD38/genetics/*metabolism

Bile Acids and Salts/*toxicity

Calcium/metabolism

Calcium Signaling/*drug effects/genetics

Cyclic ADP-Ribose/genetics/*metabolism

Humans

L-Lactate Dehydrogenase/genetics/metabolism

Membrane Glycoproteins/genetics/*metabolism

Mice

Mice, Knockout

Pancreatitis/chemically induced/genetics/*metabolism/pathology

Abstract: Aberrant Ca(2+) 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 Ca(2+) signals due to bile acid exposure is the intracellular Ca(2+) 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 Ca(2+) signals and acinar injury due to bile acids using pharmacologic inhibitors of CD38 and cADPR as well as mice deficient in Cd38 (Cd38(-/-)). Cytosolic Ca(2+) 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 muM). To focus on intracellular Ca(2+) release and to specifically exclude Ca(2+) influx, cells were perifused in Ca(2+)-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 muM) abrogated TLCS-induced Ca(2+) signals and cell injury. TLCS-induced Ca(2+) 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 Ca(2+) signaling.

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