Alendronate inhalation ameliorates elastase-induced pulmonary emphysema in mice by induction of apoptosis of alveolar macrophages
Alendronate inhalation ameliorates elastase-induced pulmonary emphysema in mice by induction of apoptosis of alveolar macrophages
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DOI：
10.1038/ncomms7332
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发表时间：
2015-03-01
影响因子：
16.6
通讯作者：
Kurabayashi, Masahiko
中科院分区：
文献类型：
--
作者：
Ueno, Manabu;Maeno, Toshitaka;Kurabayashi, Masahiko
肺泡巨噬细胞在肺气肿的发病机制中起着至关重要的作用，目前尚无有效的治疗方法。双膦酸盐被广泛用于治疗破骨细胞介导的骨病。本研究表明，通过雾化吸入含氮双磷酸盐阿仑膦酸盐可改善小鼠弹性酶诱导的肺气肿。吸入，但不口服，阿仑膦酸钠抑制弹性蛋白酶注入后的空域扩大，并通过caspase-3和甲羟戊酸依赖途径诱导支气管肺泡液中巨噬细胞凋亡。细胞分析表明，表征炎症性巨噬细胞的F4/80(+)CD11b（高）CD11c（轻度）群体，以及表征居住肺泡巨噬细胞的F4/80(+)CD11b（轻度）CD11c（高）群体，在雾化吸入后摄取大量双膦酸盐显像剂OsteoSense680。我们进一步表明，阿仑膦酸钠通过抑制核因子κ B信号传导抑制巨噬细胞的迁移和吞噬活性，并减弱肺泡巨噬细胞的炎症反应。鉴于吸入阿仑膦酸钠可有效诱导招募和常驻肺泡巨噬细胞凋亡，我们认为该策略可能具有治疗肺气肿的治疗潜力。
Alveolar macrophages play a crucial role in the pathogenesis of emphysema, for which there is currently no effective treatment. Bisphosphonates are widely used to treat osteoclast-mediated bone diseases. Here we show that delivery of the nitrogen-containing bisphosphonate alendronate via aerosol inhalation ameliorates elastase-induced emphysema in mice. Inhaled, but not orally ingested, alendronate inhibits airspace enlargement after elastase instillation, and induces apoptosis of macrophages in bronchoalveolar fluid via caspase-3- and mevalonate-dependent pathways. Cytometric analysis indicates that the F4/80(+)CD11b(high)CD11c(mild) population characterizing inflammatory macrophages, and the F4/80(+)CD11b(mild)CD11c(high) population defining resident alveolar macrophages take up substantial amounts of the bisphosphonate imaging agent OsteoSense680 after aerosol inhalation. We further show that alendronate inhibits macrophage migratory and phagocytotic activities and blunts the inflammatory response of alveolar macrophages by inhibiting nuclear factor-kappa B signalling. Given that the alendronate inhalation effectively induces apoptosis in both recruited and resident alveolar macrophages, we suggest this strategy may have therapeutic potential for the treatment of emphysema.