title: Alendronate inhalation ameliorates elastase-induced pulmonary emphysema in mice by induction of apoptosis of alveolar macrophages.
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(+)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-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.
authors.affiliation: Department of Medicine and Biological Science, Gunma University Graduate School of Medicine, 3-39-15 Showa-machi, Maebashi 371-8511, Japan.
authors.forename: Manabu
authors.initials: M
authors.lastname: Ueno
authors.affiliation: Department of Medicine and Biological Science, Gunma University Graduate School of Medicine, 3-39-15 Showa-machi, Maebashi 371-8511, Japan.
authors.forename: Toshitaka
authors.initials: T
authors.lastname: Maeno
authors.affiliation: 1] Department of Cardiovascular Medicine, Translational Systems Biology and Medicine Initiative, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan [2] Jichi Medical University, Tochigi 329-0498, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Nishimura
authors.affiliation: 1] Department of Cardiovascular Medicine, Translational Systems Biology and Medicine Initiative, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan [2] Jichi Medical University, Tochigi 329-0498, Japan.
authors.forename: Fusa
authors.initials: F
authors.lastname: Ogata
authors.affiliation: Department of Medicine and Biological Science, Gunma University Graduate School of Medicine, 3-39-15 Showa-machi, Maebashi 371-8511, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Masubuchi
authors.affiliation: Department of Medicine and Biological Science, Gunma University Graduate School of Medicine, 3-39-15 Showa-machi, Maebashi 371-8511, Japan.
authors.forename: Kenichiro
authors.initials: K
authors.lastname: Hara
authors.affiliation: Department of Medicine and Biological Science, Gunma University Graduate School of Medicine, 3-39-15 Showa-machi, Maebashi 371-8511, Japan.
authors.forename: Kouichi
authors.initials: K
authors.lastname: Yamaguchi
authors.affiliation: Department of Medicine and Biological Science, Gunma University Graduate School of Medicine, 3-39-15 Showa-machi, Maebashi 371-8511, Japan.
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Aoki
authors.affiliation: Department of Medicine and Biological Science, Gunma University Graduate School of Medicine, 3-39-15 Showa-machi, Maebashi 371-8511, Japan.
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Suga
authors.affiliation: Jichi Medical University, Tochigi 329-0498, Japan.
authors.forename: Ryozo
authors.initials: R
authors.lastname: Nagai
authors.affiliation: Department of Medicine and Biological Science, Gunma University Graduate School of Medicine, 3-39-15 Showa-machi, Maebashi 371-8511, Japan.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Kurabayashi
mesh_terms: D000280:Administration, Inhalation; D000336:Aerosols; D019386:Alendronate / Q000494:pharmacology*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D000943:Antigens, Differentiation / Q000235:genetics / Q000276:immunology; D017209:Apoptosis / Q000187:drug effects; D050071:Bone Density Conservation Agents / Q000494:pharmacology*; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D039481:CD11b Antigen / Q000235:genetics / Q000276:immunology; D039521:CD11c Antigen / Q000235:genetics / Q000276:immunology; D053148:Caspase 3 / Q000235:genetics / Q000276:immunology; D002465:Cell Movement / Q000187:drug effects; D003287:Contrast Media / Q000378:metabolism; D058492:Drug Repositioning; D015870:Gene Expression; D008168:Lung / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D016676:Macrophages, Alveolar / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D008297:Male; D008798:Mevalonic Acid / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology; D010196:Pancreatic Elastase; D010587:Phagocytosis / Q000187:drug effects; D011656:Pulmonary Emphysema / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D015398:Signal Transduction
chemical_list: D000336:Aerosols; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000943:Antigens, Differentiation; D050071:Bone Density Conservation Agents; D039481:CD11b Antigen; D039521:CD11c Antigen; D003287:Contrast Media; D016328:NF-kappa B; C036763:monocyte-macrophage differentiation antigen; D010196:Pancreatic Elastase; C505409:Casp3 protein, mouse; D053148:Caspase 3; D008798:Mevalonic Acid; D019386:Alendronate