Department of Surgery, University of Texas Health Science Center at Houston, 6431 Fannin, MSB 4.284, Houston, TX 77030, USA.
Mol Cell Biochem. 2011 Jan;347(1-2):191-9. doi: 10.1007/s11010-010-0628-x. Epub 2010 Oct 29.
We previously demonstrated that enteral arginine increased c-Jun/activator protein-1 (AP-1) DNA-binding activity and iNOS expression in a rodent model of mesenteric ischemia/reperfusion (I/R). The objective of this study was to specifically investigate the role of AP-1 in arginine's deleterious effect on the postischemic gut. We hypothesized that AP-1 inhibition would mitigate the effects of arginine. Using a rodent model of mesenteric I/R we demonstrated that gut neutrophil infiltration, activity of c-Jun/AP-1, as well as iNOS expression were increased by I/R and further increased by arginine while lessened by inhibition of c-Jun using the pharmacologic c-Jun N-terminal kinase inhibitor, SP600125. Similar results were demonstrated using a cell culture model of oxidant stress in IEC-6 cells. Importantly, effects of SP600125 were comparable to those of c-Jun silencing. Lastly, the specific iNOS inhibitor, 1400W, had no effect on either AP-1 or c-Jun. In conclusion, SP600125 attenuated the activity of c-Jun/AP-1, iNOS expression, and neutrophil infiltration induced by arginine following mesenteric I/R. Our data suggest that AP-1 inhibition mitigates the injurious inflammatory effects of arginine in the postischemic gut. Further investigation into the pathologic role of enteral arginine in the postischemic gut is warranted.
我们之前的研究表明，在肠缺血/再灌注（I/R）的啮齿动物模型中，肠内精氨酸增加了 c-Jun/激活蛋白-1（AP-1）DNA 结合活性和 iNOS 表达。本研究的目的是专门研究 AP-1 在精氨酸对缺血后肠道的有害影响中的作用。我们假设 AP-1 抑制将减轻精氨酸的作用。我们使用肠系膜 I/R 的啮齿动物模型表明，肠道中性粒细胞浸润、c-Jun/AP-1 的活性以及 iNOS 表达在 I/R 后增加，并且在用药理学 c-Jun N 末端激酶抑制剂 SP600125 抑制 c-Jun 时进一步增加。在 IEC-6 细胞氧化应激的细胞培养模型中也得到了类似的结果。重要的是，SP600125 的作用与 c-Jun 沉默的作用相当。最后，特异性 iNOS 抑制剂 1400W 对 AP-1 或 c-Jun 均无影响。总之，SP600125 减轻了肠系膜 I/R 后精氨酸诱导的 c-Jun/AP-1 活性、iNOS 表达和中性粒细胞浸润。我们的数据表明，AP-1 抑制减轻了缺血后肠道中精氨酸的损伤性炎症作用。需要进一步研究肠内精氨酸在缺血后肠道中的病理作用。
