Background & Aims
Radiocontrast agents are required for radiographic procedures, but these agents can injure tissues by unknown mechanisms. We investigated whether exposure of pancreatic tissues to radiocontrast agents during endoscopic retrograde cholangiopancreatography (ERCP) causes pancreatic inflammation, and studied the effects of these agents on human cell lines and in mice.
Methods
We exposed mouse and human acinar cells to the radiocontrast agent iohexol (Omnipaque) and measured intracellular release of Ca2+, calcineurin activation (using a luciferase reporter), activation of nuclear factor-κB (NF-κB, using a luciferase reporter), and cell necrosis (via propidium iodide uptake). We infused the radiocontrast agent into the pancreatic ducts of wild type mice (C57BL/6) to create a mouse model of post-ERCP pancreatitis; some mice were given intraperitoneal injections of the calcineurin inhibitor FK506 before and after infusion of the radiocontrast agent. CnAβ−/− mice were also used. This experiment was also performed in mice given infusions of AAV6-NF-κB-luciferase, to assess activation of this transcription factor in vivo.
Results
Incubation of mouse and human acinar cells, but not HEK293 or COS7 cells, with iohexol led to a peak and then plateau in Ca2+ signaling, along with activation of the transcription factors NF-κB and NFAT. Suppressing Ca2+ signaling or calcineurin with BAPTA, cyclosporine A, or FK506 prevented activation of NF-κB and acinar cell injury. Calcineurin Aβ-deficient mice were protected against induction of pancreatic inflammation by iohexol. The calcineurin inhibitor FK506 prevented contrast-induced activation of NF-κB in pancreata of mice; this was observed by live imaging of mice given infusions of AAV6- NF-kB-luciferase.
Conclusions
Radiocontrast agents cause pancreatic inflammation in mice, via activation of NF-κB, Ca2+ signaling, and calcineurin. Calcineurin inhibitors might be developed to prevent post-ERCP pancreatitis in patients.
Background: NF-B is an important signaling molecule in the development of acute pancreatitis. Results: Adeno-associated virus-NF-B-luciferase-infused mice showed a 77-and 140-fold increase in pancreas-specific NF-B bioluminescence following caerulein and caerulein ϩ LPS pancreatitis, respectively. Conclusion: NF-B activation can be examined in a live, dynamic fashion during pancreatic inflammation. Significance: This technique offers a valuable tool to study real-time activation of NF-B in vivo.
Authors are urged to introduce these corrections into any reprints they distribute. Secondary (abstract) services are urged to carry notice of these corrections as prominently as they carried the original abstracts.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.