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 osteoclastmediated 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 þ CD11b high CD11c mild population characterizing inflammatory macrophages, and the F4/80 þ 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-kB 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.

Elimination of p19ARF‐expressing cells protects against pulmonary emphysema in mice

“…As alveolar fibroblasts are the major p19 ARF ‐expressing cells in the lung (Figure 1f; Hashimoto et al, 2016), these cells likely affected the expression of MMP‐12 and TIMP‐2 cell nonautonomously through SASP. Consistent with previous findings (Limjunyawong et al, 2015; Ueno et al, 2015), the expression of these genes was mostly diminished after 3 weeks, and DT also had a minor effect on these genes at this time point (Figures 5b and S5b). Collectively, these results suggest that the presence of p19 ARF ‐expressing cells in lung tissues facilitates the accumulation of inflammatory cells during the early phase of a PPE challenge, which promotes the development of emphysema‐associated pathologies.…”

“…Although a significant change was observed in lung morphology and function 3 weeks after the administration of PPE (Figures 2 and 3), no significant difference was found in the number or composition of inflammatory cells in BALF among PPE‐ and/or DT‐treated samples at this time point (Figure S3). This result was expected because a single shot of PPE only has temporal effects on BALF cells in the C57BL/6J strain (Limjunyawong, Craig, Lagassé, Scott, & Mitzner, 2015; Ueno et al, 2015). Therefore, we analyzed BALF cells at an earlier time point after the administration of PPE.…”

“…In the PPE‐induced emphysema model, elastin fragments produced by PPE increase macrophage numbers, which secrete elastolytic enzymes such as MMPs (Houghton et al, 2006; Hunninghake et al, 1981). This inflammation is an essential step in the development of PPE‐induced emphysema, and the suppression of alveolar inflammation has been shown to be sufficient at preventing PPE‐induced alveolar collapse (Shapiro et al, 2003; Ueno et al, 2015). In addition, the inactivation of MMP‐12 or neutrophil elastase confers resistance to cigarette smoke‐induced emphysema in mice (Hautamaki et al, 1997; Shapiro et al, 2003).…”

“…Macrophages are predominant inflammatory cells in lung tissues, and their number increases in emphysema (Rodriguez, White, Senior, & Levine, 1977). Matrix metalloproteinase (MMP)‐12, also known as macrophage elastase, is required for the development of cigarette smoke‐induced emphysema in mice (Hautamaki, Kobayashi, Senior, & Shapiro, 1997), and the inhibition of macrophage recruitment or induction of apoptosis in alveolar macrophages was found to suppress alveolar collapse in an elastase‐induced emphysema model (Houghton et al, 2006; Ueno et al, 2015). Neutrophils are also known to contribute to the pathology of emphysema, and the inactivation of neutrophil elastase was shown to confer resistance in a mouse emphysema model (Shapiro et al, 2003).…”

Targeting the phospholipase A2 receptor ameliorates premature aging phenotypes

“…Our results point out that bisphosphonate strongly impacts senescent phenotype reinforcing a potential functional link between bone fragility during aging and increase cellular senescence. It has also been reported that bisphosphonates can impact bone‐independent marks of aging like emphysema (Ueno et al, 2015), emphysema being thought to be regulated by cellular senescence (Taraseviciene‐Stewart, & Voelkel, 2008), further suggesting that FDPS/bisphosphonates can regulate cellular senescence and aging beyond their well‐known bone effects.…”