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The effects of therapeutically administered anti-inflammatory compounds in a chronic mouse smoking model Chronic mouse smoking models have been developed to investigate the potential anti-inflammatory efficacy of candidate compounds for the treatment of chronic obstructive pulmonary disease; however, in almost all studies, the compounds tested have been dosed prophylactically. The aims of this study were to develop a chronic smoking model and to assess the effects of reference anti-inflammatory compounds using a therapeutic dosing regimen to reflect the clinical situation more accurately. To develop this model we exposed female C57BL/6 mice (18-20g) to mainstream cigarette smoke (CS) generated from 1R3F research cigarettes once a day, five days a week as previously described (Stevenson et al.2005) for 1 week and up to 6 months. To test the anti-inflammatory compounds, mice were exposed to CS for 12 weeks before dosing. The doses chosen for each compound were demonstrated to be efficacious in other murine models of lung inflammation. Budesonide was given once daily by intranasal (i.n.) administration under short-acting anaesthesia. Roflumilast (once daily) and fluvastatin (twice daily) were given by oral administration (p.o.). Compound or vehicle was administered 1 hour prior to CS exposure (and 5 hours after in the case of fluvastatin) for two weeks. In all studies, mice were culled 24 hours after the last exposure and BAL inflammatory cells were counted. We found that the inflammatory response to CS initially peaked after 1 week (primarily neutrophils), then began to resolve; however, after 1 month of exposures, the response of neutrophils, macrophages and lymphocytes all progressively increased over time and at 6 months there was an increase in the mean linear intercept of the alveoli (p < 0.05). The results (reported as mean ± SEM) from the compound studies are in Table 1.
These results demonstrate that the therapeutic efficacy of compounds do not always replicate their effects when dosed prophylactically (i.e. steroid and roflumilast) (Leclerc et al., 2006). In addition, this model appears to accurately reflect the clinical efficacy of these compounds (e.g. steroid) (Barnes et al., 2007). As such, we propose that this 14 week therapeutic model is an exacting test of a compound's ability to attenuate an established chronic inflammation in the lung induced by CS that is believed to eventually lead to structural changes to the lung. |
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