Exposure to Radiocontrast Agents Induces Pancreatic Inflammation by Activation of Nuclear Factor-κB, Calcium Signaling, and Calcineurin.
Exposure to Radiocontrast Agents Induces Pancreatic Inflammation by Activation of Nuclear Factor-κB, Calcium Signaling, and Calcineurin.
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DOI：
10.1053/j.gastro.2015.05.004
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发表时间：
2015-09
期刊：
影响因子：
29.4
通讯作者：
Husain SZ
中科院分区：
文献类型：
--
作者：
Jin S;Orabi AI;Le T;Javed TA;Sah S;Eisses JF;Bottino R;Molkentin JD;Husain SZ
放射照相程序需要放射造影剂，但这些造影剂可能会通过未知的机制损伤组织。我们研究了在内窥镜逆行胰胆管造影（ERCP）过程中胰腺组织暴露于放射性对比剂是否会导致胰腺炎症，并研究了这些试剂对人类细胞系和小鼠的影响。我们将小鼠和人类腺泡细胞暴露于放射性对比剂碘海醇（欧乃派克）中，并测量细胞内 Ca2+ 的释放、钙调磷酸酶激活（使用荧光素酶报告基因）、核因子-κB（NF-κB，使用荧光素酶报告基因）的激活和细胞坏死（通过碘化丙啶摄取）。我们将放射性对比剂注入野生型小鼠（C57BL/6）的胰管中，以创建 ERCP 后胰腺炎的小鼠模型；在输注放射性对比剂之前和之后，对一些小鼠进行腹腔注射钙调神经磷酸酶抑制剂FK506。还使用了 CnAβ−/− 小鼠。该实验还在注射 AAV6-NF-κB-荧光素酶的小鼠中进行，以评估该转录因子在体内的激活情况。用碘海醇孵育小鼠和人类腺泡细胞（但不是 HEK293 或 COS7 细胞）会导致 Ca2+ 信号传导达到峰值，然后趋于稳定，同时激活转录因子 NF-κB 和 NFAT。用 BAPTA、环孢素 A 或 FK506 抑制 Ca2+ 信号传导或钙调神经磷酸酶可防止 NF-κB 激活和腺泡细胞损伤。钙调神经磷酸酶 Aβ 缺陷小鼠可免受碘海醇诱导的胰腺炎症的影响。钙调神经磷酸酶抑制剂 FK506 可防止小鼠胰腺中造影剂诱导的 NF-κB 激活；这是通过对注射 AAV6-NF-kB-荧光素酶的小鼠进行实时成像观察到的。放射性对比剂通过激活 NF-κB、Ca2+ 信号传导和钙调神经磷酸酶引起小鼠胰腺炎症。可能会开发钙调神经磷酸酶抑制剂来预防患者的 ERCP 后胰腺炎。
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. 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. 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. 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.