Exposure to Radiocontrast Agents Induces Pancreatic Inflammation by Activation of Nuclear Factor-κB, Calcium Signaling, and Calcineurin

Abstract

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.

Luteolin protects mice from severe acute pancreatitis by exerting HO-1-mediated anti-inflammatory and antioxidant effects

“…Moreover, TNFα and IL-6 increase NF-κB activity by positive feedback, further enhancing the transcription of related cytokines, which enhances the severity of the condition. It has been demonstrated that limiting NF-κB activation significantly reduces the severity of SAP (49). Antioxidants can inhibit NF-κB activation effectively, including n-acetyl-cysteine, pyrrolidine dithiocarbamate (PDTC) and ethyl acetonate, which have certain therapeutic effects.…”

New insights into the pathways initiating and driving pancreatitis

“…A radiocontrast agent induced the pathologic [Ca2+]c response in mouse and human acinar cells [48 ■ ] leading to activation of the Ca2+-dependent phosphatase calcineurin and, in turn, NF-κB. Genetic or pharmacologic inhibition of calcineurin prevented NF-κB activation, inflammation, and acinar cell injury caused by the radio-contrast agent.…”

“…Genetic or pharmacologic inhibition of calcineurin prevented NF-κB activation, inflammation, and acinar cell injury caused by the radio-contrast agent. The authors [48 ■ ] suggest using calcineurin inhibitors to prevent post-ERCP pancreatitis in patients.…”

Differential influence of tacrolimus and sirolimus on mitochondrial-dependent signaling for apoptosis in pancreatic cells

“…Arbitrary units C 12 Introduction Tacrolimus (TAC) and sirolimus (SIR) are the respective inhibitors of calcineurin and mammalian target of rapamycin (mTOR) used in the arboretum of immunosuppressive drugs to prevent the loss of graft. Although their immunosuppressive efficacy is undeniable, important side effects like nephrotoxicity, hyperlipidemia, hypertension and endocrine pancreas dysfunction have been associated with those long-term treatments [1].…”

“…A worsening of pancreatitis condition in vivo [8], the association with acute pancreatitis in pancreas-and allogenic bone marrow-transplanted patients [9,10] and impairment of pancreatic acinar cell function were reported [11]. Conversely, preventive activity against pancreatitis conditions in vivo [12,13] or anti-inflammatory properties have been evidenced [14,15]. Similarly, SIR was confirmed to promote ductal cell loss in vitro [16], but also to protect from acute pancreatitisinducing conditions in vivo and in vitro [17][18][19].…”