title: Exposure to Radiocontrast Agents Induces Pancreatic Inflammation by Activation of Nuclear Factor-κB, Calcium Signaling, and Calcineurin.
abstract: OBJECTIVE
  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; GE Healthcare, Princeton, NJ) and measured intracellular release of Ca(2+), 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 also were used. This experiment also was performed in mice given infusions of adeno-associated virus 6-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 Ca(2+) signaling, along with activation of the transcription factors NF-κB and nuclear factor of activated T cells. Suppressing Ca(2+) 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 adeno-associated virus 6-NF-κB-luciferase.
  
  
  CONCLUSIONS
  Radiocontrast agents cause pancreatic inflammation in mice, via activation of NF-κB, Ca(2+) signaling, and calcineurin. Calcineurin inhibitors might be developed to prevent post-ERCP pancreatitis in patients.
authors.affiliation: Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
authors.forename: Shunqian
authors.initials: S
authors.lastname: Jin
authors.affiliation: Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
authors.forename: Abrahim I
authors.initials: AI
authors.lastname: Orabi
authors.affiliation: Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
authors.forename: Tianming
authors.initials: T
authors.lastname: Le
authors.affiliation: Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
authors.forename: Tanveer A
authors.initials: TA
authors.lastname: Javed
authors.affiliation: Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
authors.forename: Swati
authors.initials: S
authors.lastname: Sah
authors.affiliation: Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
authors.forename: John F
authors.initials: JF
authors.lastname: Eisses
authors.affiliation: Institute of Cellular Therapeutics, Allegheny General Hospital, Pittsburgh, Pennsylvania.
authors.forename: Rita
authors.initials: R
authors.lastname: Bottino
authors.affiliation: Department of Pediatrics, University of Cincinnati, Cincinnati Children's Hospital Medical Center, Howard Hughes Medical Institute, Cincinnati, Ohio.
authors.forename: Jeffery D
authors.initials: JD
authors.lastname: Molkentin
authors.affiliation: Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania. Electronic address: sohail.husain@chp.edu.
authors.forename: Sohail Z
authors.initials: SZ
authors.lastname: Husain
mesh_terms: D000818:Animals; D019556:COS Cells; D019703:Calcineurin / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D065095:Calcineurin Inhibitors / Q000494:pharmacology; D020013:Calcium Signaling / Q000187:drug effects; D002522:Chlorocebus aethiops; D003287:Contrast Media; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D007472:Iohexol; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D009336:Necrosis; D046790:Pancreas, Exocrine / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D010195:Pancreatitis / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D016559:Tacrolimus / Q000494:pharmacology; D013997:Time Factors
chemical_list: D065095:Calcineurin Inhibitors; D003287:Contrast Media; D016328:NF-kappa B; D007472:Iohexol; D019703:Calcineurin; C557393:protein phosphatase 3, catalytic subunit, beta isoform, mouse; D016559:Tacrolimus
keywords: Calcineurin; Calcium Signaling; PEP; Pancreatitis Pathogenesis