卵清蛋白致敏的豚鼠中吸入孟鲁司特抑制半胱氨酰白三烯诱导的支气管收缩：治疗哮喘的一种潜在新药
2009/10/15
口服半胱氨酸白三烯（LT）受体拮抗剂，如孟鲁司特，可用于降低气道炎症及恶化。然而，尚未对吸入LT受体拮抗剂治疗进行研究。本实验在动物哮喘模型中研究吸入孟鲁司特对气道高反应性的影响，后者通过半胱氨酰白三烯诱导的支气管收缩来检测。
在卵清蛋白（OVA）致敏的Hartley雄性豚鼠中通过吸入LTC4和LTD4 （0.2 mg/ml 每个药物）或三个剂量静脉给予LTC4和LTD4T（0.3, 1, 3mg /kg）诱发支气管收缩反应。通过检测气道开放峰值压力（Pao）变化来评价气道反应。通过比较试验动物治疗前、吸入孟鲁司特10mg/ml 15分钟、吸入生理盐水10mg/ml15分钟的支气管收缩反应评价孟鲁司特的疗效。为评价吸入孟鲁司特可能造成的组织损伤，对肺进行组织学检查。
豚鼠中通过OVA致敏使得吸入LTC4和LTD4诱导的支气管收缩反应增强。在致敏动物中，Pao峰值明显增加，平均为18.5+/-2.1 cmH2O（LTC4）和25.0+/-1.6 cmH2O（LTD4）。采用吸入孟鲁司特预处理能抑制静脉和吸入LTC4和LTD4诱导的Pao峰值增加（所有P<0.01 vs. 生理盐水作为对照）。而且吸入孟鲁司特拮抗LTD4诱导的支气管收缩反应的作用能至少持续24h。组织学检查显示，吸入孟鲁司特不会对肺组织产生损伤作用。
吸入孟鲁司特作为一种半胱氨酰白三烯受体拮抗剂，能有效抑制半胱氨酰白三烯诱导的急性支气管收缩，可能成为治疗哮喘的一个新药。
（林江涛 审校）
Muraki M, et al.
Int Immunopharmacol. 2009 Aug 22. [Epub ahead of print]
Inhaled montelukast inhibits cysteinyl-leukotriene-induced bronchoconstriction in ovalbumin-sensitized guinea-pigs: The potential as a new asthma medication.
Muraki M, Imbe S, Sato R, Ikeda Y, Yamagata S, Iwanaga T, Tohda Y.
Department of Respiratory Medicine and Allergology, Kinki University School of Medicine.
Oral cysteinyl-leukotriene (LT) receptor antagonists such as montelukast are used for reducing airway inflammation and exacerbations. However, inhaled therapy using LT receptor antagonists has not been studied. In the present study, the effect of inhaled montelukast was investigated on airway hyperresponsiveness measured by cysteinyl-LT induced bronchoconstriction in an animal model of asthma. Bronchoconstriction responses were induced by inhaled LTC4 and LTD4 (0.2microg/ml each) or three doses of intravenous LTC4 and LTD4 (0.3, 1, 3microg/kg) in ovalbumin (OVA)-sensitized Hartley male guinea-pigs. The response was measured by the change in peak pressure of airway opening (Pao). The effect of montelukast was evaluated by the comparison of bronchoconstriction responses between the groups of animals pre-treated with 15-min inhalation of 10mg/ml montelukast and saline. To evaluate the tissue injury which might be caused by montelukast inhalation, lung tissues were examined for the histology. The broncoconstriction responses induced by inhaled LTC4 and LTD4 were enhanced by OVA sensitization in the guinea-pigs. In sensitized animals, the significant increases in peak Pao were 18.5+/-2.1cmH(2)O by LTC4 and 25.0+/-1.6cmH(2)O by LTD4 on average. Prior treatment of inhaled montelukast potently suppressed the peak Pao increases induced by both inhaled and intravenous LTC4 and LTD4 (all P<0.01 vs. saline control). Moreover, the suppression of inhaled montelukast against LTD4-induced bronchoconstriction was observed for at least up to 24h. According to the histological examination, montelukast inhalation produced no injury to the lung tissue. Inhaled montelukast, a cysteinyl-LT receptor antagonist, was effective in inhibiting cysteinyl-LT-induced acute bronchoconstriction, and may have the potential for clinical use as a new asthma drug.
