Cysteinyl-leukotriene 1 receptor antagonist attenuates bleomycin-induced pulmonary fibrosis in mice
Cysteinyl-leukotriene 1 receptor antagonist attenuates bleomycin-induced pulmonary fibrosis in mice
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DOI：
10.1016/j.lfs.2007.02.038
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发表时间：
2007-04-24
期刊：
影响因子：
6.1
通讯作者：
Nagai, Atsushi
中科院分区：
文献类型：
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作者：
Izumo, Takehiro;Kondo, Mitsuko;Nagai, Atsushi
白三烯是源自花生四烯酸代谢的 5-脂氧合酶途径的炎症脂质介质，最近的证据表明它们在肺纤维化中发挥重要作用。孟鲁司特是一种半胱氨酰白三烯 1 受体拮抗剂，在小鼠哮喘模型中被发现可以减少气道重塑，包括上皮下纤维化，但孟鲁司特对肺纤维化的治疗作用仍不清楚。在这项研究中，我们研究了孟鲁司特是否能够预防博莱霉素诱导的小鼠肺纤维化。第 1 天，C57BL/6 小鼠在 2 小时后以及每周第 1-5 天进行单次气管内注射博来霉素 (2.5 mg/kg) 和孟鲁司特 (1.0 mg/kg) 或单独的载体，持续两周。孟鲁司特组第 7 天和第 14 天支气管肺泡灌洗液 (BALF) 中的细胞总数减少，第 14 天细胞炎症和纤维化减弱，Ashcroft 评分和肺羟脯氨酸含量显着降低表明。尽管 BALF 中的半胱氨酰白三烯水平没有显着差异，但在孟鲁司特组中，第 14 天，通过 ELISA 检测到的 BALF 中转化生长因子 β (TGF β) 水平以及通过免疫组织化学检测到的肺组织中 TGF β 表达有所降低。这项研究的结果表明，孟鲁司特可抑制小鼠炎症过程和博来霉素诱导的肺纤维化的发展，这些作用可能与 TGFβ 表达的减少有关。他们还建议孟鲁司特可能作为间质性肺纤维化患者的新疗法。 (C) 2007 Elsevier Inc. 保留所有权利。
Leukotrienes are lipid mediators of inflammation derived from the 5-lipoxygenase pathway of arachidonic acid metabolism, and recent evidence suggests that they play an important role in pulmonary fibrosis. Montelukast is a cysteinyl-leukotriene 1 receptor antagonist that has been found to reduce airway remodeling, including subepithelial fibrosis, in a murine model of asthma, but the therapeutic effect of montelukast on pulmonary fibrosis remains unclear. In this study, we investigated whether montelukast is capable of preventing bleomycin-induced pulmonary fibrosis in mice. On day 1, C57BL/6 mice were given a single intratracheal injection of bleomycin (2.5 mg/kg), and montelukast (1.0 mg/kg) or vehicle alone subcutaneously 2 h later and on days 1-5 of each week for two weeks. The total number of cells in bronchoalveolar lavage fluid (BALF) was reduced in the montelukast group on day 7 and on day 14, and cellular inflammation and fibrosis were attenuated on day 14 as indicated by significant decrease in the Ashcroft score and lung hydroxyproline content. Although cysteinyl-leukotriene level in BALF was not significantly different, transforming growth factor beta (TGF beta) level in BALF by ELISA and TGF beta expression in lung tissue by immunohistochemistry was reduced on day 14 in the montelukast group. The results of this study show that montelukast inhibits the inflammatory process and development of bleomycin-induced pulmonary fibrosis in mice and that these effects may be associated with a decrease in TGF beta expression. They also suggest that montelukast may serve as a new therapy for patients with interstitial pulmonary fibrosis. (C) 2007 Elsevier Inc. All rights reserved.