Toriyabe Masaki, Omote Keiichi, Kawamata Tomoyuki, Namiki Akiyoshi
Department of Anesthesiology, Sapporo Medical University School of Medicine, South-1 West-16, Chuo-ku, Sapporo, Hokkaido 060-8543, Japan.
Anesthesiology. 2004 Oct;101(4):983-90. doi: 10.1097/00000542-200410000-00025.
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.
A microdialysis probe was implanted subcutaneously into the skin of hind paws of rats. The concentrations of NO metabolites, PGE2, and 6-keto-PGF1alpha (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 N-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-PGF1alpha 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.
Carrageenan injection resulted in increases in the concentrations of NO, PGE2, and PGI2, and these increases were completely suppressed by N-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 N-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 N-monomethyl-L-arginine acetate.
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.
一氧化氮（NO）和前列腺素（PGs）是导致炎症反应和疼痛产生的关键介质。本研究旨在探究外周释放的NO对角叉菜胶诱导的炎症中环氧合酶（COX）表达/激活及PGs产生的影响。
将微透析探针皮下植入大鼠后爪皮肤。测量透析液中NO代谢产物、前列腺素E2（PGE2）和6-酮-前列腺素F1α（前列环素I2（PGI2）的代谢产物）的浓度。在使用改良林格氏液或N-单甲基-L-精氨酸醋酸盐灌注透析导管期间，将角叉菜胶注射到后爪的足底表面。此外，还研究了选择性COX-1抑制剂SC-560和选择性COX-2抑制剂NS-398对NO、PGE2和6-酮-前列腺素F1α产生的影响。采用蛋白质免疫印迹法评估炎症部位皮肤中COX-1和COX-2的表达。
注射角叉菜胶导致NO、PGE2和PGI2浓度升高，而N-单甲基-L-精氨酸醋酸盐可完全抑制这些升高。SC-560在最初2小时有效抑制了PGE2和PGI2浓度的升高，NS-398在角叉菜胶注射后3 - 6小时发挥抑制作用。蛋白质免疫印迹分析显示，角叉菜胶注射后皮肤中COX-1和COX-2的浓度均升高。角叉菜胶注射后3小时和6小时观察到皮肤中COX-1上调，在用N-单甲基-L-精氨酸醋酸盐处理的大鼠中未被抑制。角叉菜胶注射后3小时和6小时也观察到皮肤中COX-2上调，在用N-单甲基-L-精氨酸醋酸盐处理的大鼠中被完全抑制。
本研究结果表明，在角叉菜胶诱导的炎症早期，NO激活COX-1，在后期上调皮肤中COX-2的表达，导致炎症部位产生PGE2和PGI2，这可能会加剧炎症过程。
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