Targeted Inhibition of Pancreatic Acinar Cell Calcineurin Is a Novel Strategy to Prevent Post-ERCP Pancreatitis

Abstract

Background and Aims There is a pressing need to develop effective preventative therapies for post-ERCP pancreatitis (PEP). We demonstrated that early PEP events are induced through the calcium-activated phosphatase calcineurin and that global calcineurin deletion abolishes PEP in mice. A crucial question is whether acinar cell calcineurin controls the initiation of PEP in vivo. Methods We used a mouse model of PEP and examined the effects of in vivo acinar cell-specific calcineurin deletion by either generating a conditional knockout line or infusing a novel AAV-Ela-iCre into the pancreatic duct of a calcineurin floxed line. Results We found that PEP is dependent on acinar cell calcineurin in vivo, and this led us to determine that calcineurin inhibitors, infused within the radiocontrast, can largely prevent PEP. Conclusions These results provide impetus for launching clinical trials to test the efficacy of intraductal calcineurin inhibitors to prevent PEP.

Recent Insights Into the Pathogenic Mechanism of Pancreatitis

“…We and others showed that healthy human acinar cells isolated from cadaveric tissue retain their morphology and functional characteristics, which has allowed examination of early pancreatitis responses to a number of stressors, e.g., bile salts. 72,98,100,113,126,127 We characterized physiologic and pathophysiologic responses of the human acinar cell preparations and found them similar to those observed in mouse ex-vivo models. 126 In particular, disordered organelle responses: the ER stress, aberrant Ca 2+ signal, mitochondrial depolarization, and impaired autophagy -are all prominent in ex-vivo pancreatitis on human acinar cells.…”

Pancreatitis is an FGF21-deficient state that is corrected by replacement therapy

“…ERCP was performed as previously described (17)(18)(19). Female Swiss Webster mice were used for these experiments, which were performed at the University of Pittsburgh.…”

Location, Location, Location . . . It Is Important in Pancreatitis, Too

“…To this end, Orabi et al, 3 in this issue of Cellular and Molecular Gastroenterology and Hepatology , evaluated the role of calcineurin in an animal model of endoscopic retrograde cholangiopancreatography (ERCP)-induced pancreatitis. This group previously reported that pancreatitis produced by injection of either bile acids or radiocontrast into the pancreatic duct activated calcineurin and nuclear factor-κB and was ameliorated by pharmacologic calcineurin inhibition or global deletion of the calcineurin gene in mice 4 …”

“…Was calcineurin in T cells or acinar cells important for pancreatitis? To address this question, Orabi et al 3 deleted the calcineurin gene specifically in acinar cells in conditional knockout mice or with an acinar cell–specific viral targeting vector. Their results showed that calcineurin in the pancreas mediated acute pancreatitis.…”

“…The real value of the study by Orabi et al 3 was proving that it is calcineurin in acinar cells that mediates ERCP pancreatitis. The therapeutic implication is that systemic administration of calcineurin inhibitors is unnecessary.…”