Involvement of LTB4 in zymosan-induced joint nociception in mice:: participation of neutrophils and PGE2
Involvement of LTB4 in zymosan-induced joint nociception in mice:: participation of neutrophils and PGE2
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DOI：
10.1189/jlb.0207123
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发表时间：
2008-01-01
影响因子：
5.5
通讯作者：
Ferreira, Sergio H.
中科院分区：
文献类型：
--
作者：
Guerrero, Ana T. G.;Verri, Waldiceu A., Jr.;Ferreira, Sergio H.
白细胞三烯B-4（LTB 4）介导不同的炎症事件，例如中性粒细胞迁移和疼痛。本研究探讨了LTB 4介导的关节炎症诱导的高伤害性感受的机制。观察到酵母多糖诱导的关节高伤害性感受和中性粒细胞迁移通过MK 886（1-9 mg/kg; LT合成抑制剂）预处理以及在5-脂氧合酶缺陷小鼠（5LO（-/-））中或通过LTB 4受体的选择性拮抗剂（CP 105696; 3 mg/kg）呈剂量依赖性降低。组织学分析显示，在5LO（-/-）小鼠中酵母多糖诱导的关节炎性损伤减少。LTB 4的痛觉过敏作用进一步通过证明LTB 4的关节注射诱导剂量（8.3、25和75 ng）依赖性关节痛觉过敏而得到证实。此外，酵母多糖诱导关节LTB 4产生增加。研究LTB 4介导酵母多糖诱导的高伤害性感受的潜在机制，LTB 4诱导的高伤害性感受被吲哚美辛（5 mg/kg）、MK 886（3 mg/kg）、塞来昔布（10 mg/kg）、抗神经肽抗体（100 μ g，两次剂量）和岩藻依聚糖（20 mg/kg）处理以及在5LO（-/-）小鼠中降低。褐藻糖胶或抗神经元抗体预处理可减少酵母多糖诱导的关节LTB_4的产生，也可减少LTB_4诱导的PGE_2的产生。因此，除了加强内源性LTB 4作为炎症关节高伤害性感受的重要介质的作用外，这些结果还表明LTB 4诱导的关节高伤害性感受的机制取决于前列腺素和中性粒细胞的募集。此外，结果还清楚地表明，LTB 4诱导的高伤害性感受依赖于内源性LT的额外释放。结论，靶向LTB 4合成/作用可能构成抑制关节炎性高伤害性感受的有用治疗方法。
Leukotriene B-4 (LTB4) mediates different inflammatory events such as neutrophil migration and pain. The present study addressed the mechanisms of LTB4-mediated joint inflammation-induced hypernociception. It was observed that zymosan-induced articular hypernociception and neutrophil migration were reduced dose-dependently by the pretreatment with MK886 (1-9 mg/kg; LT synthesis inhibitor) as well as in 5-lypoxygenase-deficient mice (5LO(-/-)) or by the selective antagonist of the LTB4 receptor (CP105696; 3 mg/kg). Histological analysis showed reduced zymosan-induced articular inflammatory damage in 5LO(-/-) mice. The hypernociceptive role of LTB4 was confirmed further by the demonstration that joint injection of LTB4 induces a dose (8.3, 25, and 75 ng)-dependent articular hypernociception. Furthermore, zymosan induced an increase in joint LTB4 production. Investigating the mechanism underlying LTB4 mediation of zymosan-induced hypernociception, LTB4-induced hypernociception was reduced by indomethacin (5 mg/kg), MK886 (3 mg/kg), celecoxib (10 mg/kg), antineutrophil antibody (100 mu g, two doses), and fucoidan (20 mg/kg) treatments as well as in 5LO(-/-) mice. The production of LTB4 induced by zymosan in the joint was reduced by the pretreatment with fucoidan or antineutrophil antibody as well as the production of PGE(2) induced by LTB4. Therefore, besides reinforcing the role of endogenous LTB4 as an important mediator of inflamed joint hypernociception, these results also suggested that the mechanism of LTB4-induced articular hypernociception depends on prostanoid and neutrophil recruitment. Furthermore, the results also demonstrated clearly that LTB4-induced hypernociception depends on the additional release of endogenous LTs. Concluding, targeting LTB4 synthesis/action might constitute useful therapeutic approaches to inhibit articular inflammatory hypernociception.