Involvement of leukotriene B4 in substance P-induced itch-associated response in mice
Involvement of leukotriene B4 in substance P-induced itch-associated response in mice
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DOI：
10.1046/j.0022-202x.2001.01585.x
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发表时间：
2001-12-01
影响因子：
6.5
通讯作者：
Kuraishi, Y
中科院分区：
文献类型：
--
作者：
Andoh, T;Katsube, N;Kuraishi, Y
皮内注射P物质可增强人类受试者的瘙痒感觉和小鼠的瘙痒相关反应。抗组胺药不能抑制P物质诱导的小鼠瘙痒相关反应。因此，P物质诱导的瘙痒相关反应的机制尚不清楚。在这项研究中，我们展示了其中一种机制。P物质诱导花生四烯酸级联反应，产生白藜芦醇和白三烯。在这项研究中，我们考虑花生四烯酸代谢产物是否参与P物质诱导的瘙痒相关反应。磷脂酶A（2）抑制剂花生酰三氟甲基酮抑制P物质诱导的小鼠瘙痒相关反应。用糖皮质激素倍他米松和地塞米松预处理也抑制了小鼠和人类中P物质诱导的瘙痒相关反应。5-脂氧合酶抑制剂齐留通，而不是环氧合酶抑制剂吲哚美辛和双氯芬酸，抑制P物质诱导的瘙痒相关反应。白三烯B-4受体拮抗剂5-[2-（2-羧乙基）-3-{6-甲基-IH-吡唑-4-基}-2-甲基-IH-吡唑（4-甲氧基苯基）-5E-己烯基}氧基苯氧基]戊酸产生抑制作用，而普仑司特（白三烯C-4/D-4/E-4受体拮抗剂）和5（Z）-7-[1 S，2S，3S，5 R-3-（5-氨基-2-甲基-2-氧代-2（traps-b-styren）sulfonamido-6，6-dimethylbicyclo（3，1，1）hept-2-yl]-5-heptenoic acid（EP，受体拮抗剂）无作用。此外，当在注射P物质的皮肤和施用P物质的小鼠角质形成细胞中测量白三烯B-4和前列腺素E-2的产生时，两种产物的水平均增加。由于白三烯B-4而不是前列腺素E-2也诱导小鼠瘙痒相关反应，这些结果表明，白三烯B-4和角质形成细胞，产生白三烯B-4的皮肤细胞，在P物质诱导的小鼠瘙痒-抓挠反应中起重要作用。白三烯B_4受体拮抗剂和5-脂氧合酶抑制剂可能成为新的抗炎药物。
Intradermal injection of substance P elicits an itch sensation in human subjects and an itch-associated response in mice. The substance P-induced itch-associated response in mice is not inhibited by antihistamine. Therefore, the mechanisms of substance P-induced itch-associated response are unclear. In this study, we demonstrated one of the mechanisms. Substance P induces an arachidonate cascade to produce prostaglandins and leukotriene. In this study we considered whether arachidonate metabolites are involved in the substance P-induced itch-associated response. A phospholipase A(2) inhibitor arachidoryl-trifluoromethyl ketone inhibited the substance P-induced itch-associated response in mice. Pretreatment with the glucocorticoids betamethasone and dexamethasone also produced inhibition of the substance P-induced itch-associated response in mice as well as humans. The 5-lipoxygenase inhibitor zileuton, but not the cyclooxygenase inhibitors indomethacin and diclofenac, suppressed substance P-induced itch-associated response. The leukotriene B-4 receptor antagonist 5-[2-(2-carboxyethyl)-3-{6-(4-methoxyphenyl)-5E-hexenyl}oxyphenoxy]valeric acid produced inhibition, whereas pranlukast (leukotriene C-4/D-4/E-4 receptor antagonist) and 5(Z)-7-[1S,2S, 3S,5R-3-(traps-b-styren)sulfonamido-6,6-dimethylbicyclo(3,1,1)hept-2-yl]-5-heptenoic acid (EP, receptor antagonist) were without effect. Furthermore, when the production of leukotriene B-4 and prostaglandin E-2 was measured in skin injected with substance P and in mouse keratinocytes applied with substance P, the level of both products increased. As leukotriene B-4, but not prostaglandin E-2, also induces the itch-associated response in mice, these results suggest that leukotriene B-4 and keratinocytes, cutaneous cells which produced leukotriene B-4, play an important role in substance P-induced itch-scratch response in mice. Leukotriene B4 receptor antagonist and 5-lipoxygenase inhibitor may be novel antipruritic drugs.