Persistent airway eosinophilia after leukotriene (LT) D4 administration in the guinea pig: modulation by the LTD4 receptor antagonist, pranlukast, or an interleukin-5 monoclonal antibody.
Persistent airway eosinophilia after leukotriene (LT) D4 administration in the guinea pig: modulation by the LTD4 receptor antagonist, pranlukast, or an interleukin-5 monoclonal antibody.
复制标题
豚鼠给予白三烯 (LT) D4 后持续气道嗜酸性粒细胞增多：LTD4 受体拮抗剂普仑司特或白细胞介素 5 单克隆抗体的调节。
DOI：
--
复制
发表时间：
1996
影响因子：
24.7
通讯作者：
D. W. Hay
中科院分区：
文献类型：
--
作者：
D C Underwood;R. Osborn;S. J. Newsholme;T J Torphy;D. W. Hay
雾化半胱氨酸白三烯（CysLTs）引起嗜酸性粒细胞迁移到豚鼠肺和哮喘患者的气道。本研究旨在分析白三烯D4 （LTD4）诱导的嗜酸性粒细胞流入清醒豚鼠气道的浓度-反应关系、时间过程以及药理学和组织学特征。将动物暴露于0.3 - 30微克/毫升LTD4的气溶胶中1分钟，在此期间监测特定气道电导（sGaw）。在LTD4激发后4 h至4周的选择时间对豚鼠气道进行支气管肺泡灌洗（BALs）。LTD4在所有测试浓度下均产生最大的sGaw下降（减少70%至90%），并且在刺激24小时后评估BALs中嗜酸性粒细胞水平的浓度相关增加。组织学证实支气管上皮及上皮下嗜酸性粒细胞增多。明显的嗜酸性维持了4周。LTD4受体拮抗剂pranlukast (ONO-1078, SB 205312) （20 mg/kg，灌胃）预处理24 h时可显著抑制支气管收缩和嗜酸性粒细胞增多，而环加氧酶抑制剂甲氯芬酸（5 mg/kg，灌胃）对这两个参数均无影响。组织学观察与BAL结果一致。大鼠抗小鼠白素-5 （IL-5）、TRFK-5抗体（10-300 μ g，腹腔注射）预处理，在24 h或3周BAL中测量，对ltd4诱导的嗜酸性粒细胞产生剂量相关的抑制作用，但对急性支气管收缩没有影响。这些结果表明，LTD4诱导豚鼠气道嗜酸性粒细胞内流，这种内流在单次暴露后持续长达4周，并首次提供了IL-5可能在LTD4诱导的气道炎症中起作用的证据。这和其他先前报道的LTD4的促炎作用可能对其在哮喘病理生理中的整体影响作用有重要贡献，并且可能是CysLT受体拮抗剂（如pranlukast）在这种疾病中的治疗益处的基础。
Aerosolized cysteinyl leukotrienes (CysLTs) elicit migration of eosinophils into guinea pig lungs and the airways of patients with asthma. The present studies were designed to analyze the concentration-response relationship, time course, and pharmacologic and histologic characteristics of leukotriene D4 (LTD4)-induced eosinophil influx into the airways of conscious guinea pigs. Animals were exposed to aerosols of 0.3 to 30 microg/ml LTD4 for 1 min, during which specific airway conductance (sGaw) was monitored. Bronchoalveolar lavages (BALs) of guinea pig airways were conducted at selected times from 4 h to 4 wk after LTD4 challenge. LTD4 produced maximal decreases in sGaw (70 to 90% reduction) at all concentrations tested and concentration-related increases in eosinophil levels in BALs, assessed 24 h after challenge. Increased numbers of eosinophils in the bronchial epithelium and subepithelium were confirmed histologically. Significant eosinophilia was maintained for up to 4 wk postchallenge. Pretreatment with the LTD4 receptor antagonist, pranlukast (ONO-1078, SB 205312) (20 mg/kg, intragastrically), significantly inhibited both the bronchoconstriction and the eosinophilia at 24 h, whereas the cyclooxygenase inhibitor, meclofenamic acid (5 mg/kg, intragastrically), had no effect on either parameter. Histologic observations were consistent with BAL results. Pretreatment with the rat anti-mouse antibody to interleukin-5 (IL-5), TRFK-5 (10-300 microg, intraperitoneally), produced dose-related inhibition of LTD4-induced eosinophilia, measured in 24 h or 3 wk BAL, but did not affect the acute bronchoconstriction. These results indicate that LTD4 elicits airway eosinophil influx in guinea pigs which persists as long as 4 wk after a single exposure, and provide the first evidence that IL-5 may have a role in LTD4-induced airways inflammation. This and other previously reported proinflammatory effects of LTD4 may contribute significantly to its overall influential role in the pathophysiology of asthma, and may underlie the therapeutic benefit of CysLT receptor antagonists, such as pranlukast, in this disorder.