Alendronate Attenuates Eosinophilic Airway

Bisphosphonates (BPs) have been widely used to treat osteoporosis. They act by inhibiting farnesyl diphosphate synthase in the mevalonate pathway. This resembles the action of statins, whose immune-modulating effect has recently been highlighted. In contrast , the effect of BPs on immune responses has not been elucidated well. In this study, we examined the effect of alendronate (ALN), a nitrogen-containing BP, on allergic airway inflammation in a mouse model. BALB/c mice were sensitized twice with OVA and challenged three times with nebulized OVA to induce eosinophilic airway inflammation. ALN was administered by an intragastric tube before each inhalation. ALN strongly suppressed airway eosinophilia and Th2, as well as Th17 cytokine production in the lung. ALN also attenuated eotaxin-2 production in the lung. Immunohistochemistry demonstrated that the major cell source of eotaxin-2 was peribronchial/perivascular macrophages, and flow cytometrical studies confirmed that ALN decreased eotaxin-2 expression in these macrophages. Furthermore, ALN attenuated eotaxin-2 production from mouse pleural macrophages and human monocyte/ macrophage-like THP-1 cells in vitro. These results suggest that ALN suppressed Ag-induced airway responses in the mouse model. The suppression of eotaxin-2 production from macrophages appears to be one of ALN's immunomodulatory effects, whereas the mechanism by which ALN suppressed Th2 and Th17 responses could not be fully elucidated in this study. Although a clinical study should be conducted, ALN could be a novel therapeutic option for asthma. B isphosphonates (BPs) are widely used for the treatment of osteoporosis in the elderly and for other bone diseases such as bone cancer. Second-generation " nitrogen-containing BPs (N-BPs), such as alendronate (ALN) and risedronate, inhibit farnesyl pyrophosphate synthase in the mevalonate pathway. The mechanism of their action is similar to that of statins, the inhibition of HMG-CoA reductase. The immune-modulating effect of statins has recently been elucidated (1). The suppressive effects of statins have been reported in many animal models of immune-mediated disorders (2–6). For example , several studies have been conducted using simvastatin (7, 8) or pravastatin (9) in models of allergic airway inflammation. We also showed that pravastatin suppressed allergic airway inflammation partly by suppressing the Ag-presenting capacity of dendritic cells (10). Based on their similar mechanism of action to statins, N-BPs may affect allergic airway inflammation; however, this possibility has not yet been examined. N-BPs are mainly distributed in the bones. Few reports have examined the tissue distribution of BPs in the respiratory system. Hisaka and coworkers (11) reported that …