Alendronate inhalation ameliorates elastase-induced pulmonary emphysema in mice by induction of apoptosis of alveolar macrophages

Manabu Ueno, Toshitaka Maeno, Satoshi Nishimura, Fusa Ogata, Hiroaki Masubuchi, Kenichiro Hara, Kouichi Yamaguchi, Fumiaki Aoki, Tatsuo Suga, Ryozo Nagai and Masahiko Kurabayashi ()
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Manabu Ueno: Gunma University Graduate School of Medicine
Toshitaka Maeno: Gunma University Graduate School of Medicine
Satoshi Nishimura: Translational Systems Biology and Medicine Initiative, Graduate School of Medicine, The University of Tokyo
Fusa Ogata: Translational Systems Biology and Medicine Initiative, Graduate School of Medicine, The University of Tokyo
Hiroaki Masubuchi: Gunma University Graduate School of Medicine
Kenichiro Hara: Gunma University Graduate School of Medicine
Kouichi Yamaguchi: Gunma University Graduate School of Medicine
Fumiaki Aoki: Gunma University Graduate School of Medicine
Tatsuo Suga: Gunma University Graduate School of Medicine
Ryozo Nagai: Jichi Medical University
Masahiko Kurabayashi: Gunma University Graduate School of Medicine

Nature Communications, 2015, vol. 6, issue 1, 1-13

Abstract: Abstract 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+CD11bhighCD11cmild population characterizing inflammatory macrophages, and the F4/80+CD11bmildCD11chigh 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-κB 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.

Date: 2015
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DOI: 10.1038/ncomms7332

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