Contribution of Interaction between Nitric Oxide and Cyclooxygenases to the Production of Prostaglandins in Carrageenan-induced Inflammation
Contribution of Interaction between Nitric Oxide and Cyclooxygenases to the Production of Prostaglandins in Carrageenan-induced Inflammation
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DOI：
10.1097/00000542-200410000-00025
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发表时间：
2004-10
期刊：
影响因子：
8.8
通讯作者：
M. Toriyabe;K. Omote;T. Kawamata;A. Namiki
中科院分区：
文献类型：
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作者：
M. Toriyabe;K. Omote;T. Kawamata;A. Namiki
背景：一氧化氮（NO）和前列腺素（pg）是促进炎症反应和疼痛产生的重要介质。本研究旨在探讨外周释放NO对角叉菜胶诱导炎症中环氧合酶（COX）表达/激活和pg生成的影响。方法：将微透析探针植入大鼠后爪皮下。测定透析液中NO代谢物、PGE2和PGI2代谢物6-酮- pgf1的浓度。在透析导管灌注过程中，用改良林格氏液或ng -一甲基乙酸精氨酸注入后爪足底表面卡拉胶。此外，我们还检测了选择性COX-1抑制剂SC-560和选择性COX-2抑制剂NS-398对NO、PGE2和6-酮- pgf1生成的影响。Western blotting检测炎症部位皮肤COX-1和COX-2的表达。结果：卡拉胶注射导致NO、PGE2、PGI2浓度升高，而ng -一甲基乙酸精氨酸完全抑制了这些升高。SC-560有效抑制了前2 h PGE2和PGI2浓度的升高，NS-398抑制了卡拉胶后3-6 h PGE2和PGI2浓度的升高。Western blot分析显示，涂上角叉菜胶后皮肤中COX-1和COX-2的浓度均升高。角叉菜胶作用后3和6小时，皮肤中COX-1表达上调，ng -单甲基-l-精氨酸醋酸酯未抑制COX-1表达。在使用卡拉胶3和6小时后，皮肤中COX-2的表达也有所上调，但在ng -单甲基-l-精氨酸醋酸酯处理的大鼠中，COX-2被完全抑制。结论：本研究结果提示NO在卡拉胶早期激活COX-1，在后期上调COX-2在皮肤中的表达，导致炎症部位产生PGE2和PGI2，从而加剧炎症过程。
Background:Nitric oxide (NO) and prostaglandins (PGs) are crucial mediators contributing to generation of inflammatory responses and pain. This study was designed to investigate the effects of peripherally released NO on cyclooxygenase (COX) expression/activation and production of PGs in carrageenan-induced inflammation. Methods:A microdialysis probe was implanted subcutaneously into the skin of hind paws of rats. The concentrations of NO metabolites, PGE2, and 6-keto-PGF1 (metabolite of PGI2) in the dialysate were measured. Carrageenan was injected into the plantar surface of the hind paw during perfusion of the dialysis catheter with modified Ringer’s solution or NG-monomethyl-l-arginine acetate. In addition, the effects of the selective COX-1 inhibitor SC-560 and the selective COX-2 inhibitor NS-398 on the production of NO, PGE2, and 6-keto-PGF1 were examined. Western blotting was performed to evaluate the expression of COX-1 and COX-2 in the skin at the site of the inflammation. Results:Carrageenan injection resulted in increases in the concentrations of NO, PGE2, and PGI2, and these increases were completely suppressed by NG-monomethyl-l-arginine acetate. SC-560 effectively inhibited the increase in PGE2 and PGI2 concentrations for the first 2 h, and NS-398 inhibited 3–6 h after carrageenan. Western blot analysis showed that the concentrations of both COX-1 and COX-2 in the skin increased after carrageenan. The up-regulation of COX-1 in the skin was observed 3 and 6 h after carrageenan and was not suppressed in the rats treated with NG-monomethyl-l-arginine acetate. The up-regulation of COX-2 in the skin was also observed 3 and 6 h after carrageenan and was completely suppressed in the rats treated with NG-monomethyl-l-arginine acetate. Conclusion:The results of the current study suggest that NO activates COX-1 in the early phase of carrageenan and up-regulates COX-2 expression in the late phase in the skin, resulting in production of PGE2 and PGI2 at the site of inflammation, which would contribute to exacerbation of the inflammatory process.