E significantly correlated with the percentage of lymphocytes. Both were also correlated with the peribronchial space and the number of nucleated cells within the peribronchial space. Finally, only normalized PBA was significantly correlated with Gracillin supplier remodeling parameters such as bronchial wall area, smooth muscle area and peribronchial fibrosis. The higher the normalized PBA, the higher the bronchial smooth muscle remodeling was.DiscussionTaken together, these results demonstrate that, using a flexible model of murine asthma, normalized PBA extracted from microCT examinations in living mice, can predict the presence of airway remodeling. The peribronchial attenuation value normalized by the total lung attenuation value was increased in mice exhibiting remodeling, was unchanged in mice exhibiting inflammation only, and was the best micro-CT parameter correlated with remodeling markers. In this study, we paid a special attention to build flexible challenge protocols based upon different endpoints which reproduced 3 features of human asthma (i.e. inflammation only, inflammation and remodeling, and remodeling only), although the latter remains theoretical, since inflammatory cells are still present in fixed airways obstruction [20]. Particularly, eosinophilic inflammation was observed in groups A and B only, while themain markers of remodeling, i.e. increased bronchial smooth muscle size and peribronchial fibrosis, were observed in groups B (day 75) and C (Day 110) only. The use of Penh to assess BHR in mice deserves a specific comment. Indeed, Penh does not represent the airway resistance per se [21] and it may vary according to the respiratory rate and/or experimental conditions [22]. For instance, Penh is not accurate in C57BL6 mice [23]. However, in our study, both Penh and LR ratios were similarly increased in OVA-sensitized mice as compared to control mice, which is in agreement with earlier studies performed in Balb/C mice [23]. Moreover, invasive plethysmography cannot be performed longitudinally. BHR is one of the characteristics of asthma but the exact contribution of inflammation or remodeling remains undetermined [24]. In our study, BHR assessed by the Penh ratio was only observed in mice exhibiting inflammation either alone or with remodeling. In small animals, even if clear model-dependent differences have been shown [25], Penh ratio has been shown to be mainly related to eosinophilic inflammation in Balb/C mice [26], which is consistent with our results. So far, to the best of our knowledge, there was no reported in vivo method able to assess bronchial remodeling noninvasively. By contrast, airway inflammation can be assessed through exhaled nitric oxide or induced sputum [27,28]. In the present study, we Gracillin site demonstrated that micro-CT can quantify remodeling noninvasively in sensitized mice. However, PBA and normalized PBA were also correlated with some parameters of bronchial inflammation. These results can be partly explained by the close relationship between inflammation and remodeling [29,30], which is likely to entail potential cross-correlations. Our 3 endpoints protocol allowed us to demonstrate the absence of any significant difference in micro-CT parameters between sensitized and control mice from group A, thereby suggesting that the sole inflammation has no influence on PBA or normalized PBA. In the absence of normalization by the lung attenuation value, PBA appeared to be less specific to remodeling and only increased in.E significantly correlated with the percentage of lymphocytes. Both were also correlated with the peribronchial space and the number of nucleated cells within the peribronchial space. Finally, only normalized PBA was significantly correlated with remodeling parameters such as bronchial wall area, smooth muscle area and peribronchial fibrosis. The higher the normalized PBA, the higher the bronchial smooth muscle remodeling was.DiscussionTaken together, these results demonstrate that, using a flexible model of murine asthma, normalized PBA extracted from microCT examinations in living mice, can predict the presence of airway remodeling. The peribronchial attenuation value normalized by the total lung attenuation value was increased in mice exhibiting remodeling, was unchanged in mice exhibiting inflammation only, and was the best micro-CT parameter correlated with remodeling markers. In this study, we paid a special attention to build flexible challenge protocols based upon different endpoints which reproduced 3 features of human asthma (i.e. inflammation only, inflammation and remodeling, and remodeling only), although the latter remains theoretical, since inflammatory cells are still present in fixed airways obstruction [20]. Particularly, eosinophilic inflammation was observed in groups A and B only, while themain markers of remodeling, i.e. increased bronchial smooth muscle size and peribronchial fibrosis, were observed in groups B (day 75) and C (Day 110) only. The use of Penh to assess BHR in mice deserves a specific comment. Indeed, Penh does not represent the airway resistance per se [21] and it may vary according to the respiratory rate and/or experimental conditions [22]. For instance, Penh is not accurate in C57BL6 mice [23]. However, in our study, both Penh and LR ratios were similarly increased in OVA-sensitized mice as compared to control mice, which is in agreement with earlier studies performed in Balb/C mice [23]. Moreover, invasive plethysmography cannot be performed longitudinally. BHR is one of the characteristics of asthma but the exact contribution of inflammation or remodeling remains undetermined [24]. In our study, BHR assessed by the Penh ratio was only observed in mice exhibiting inflammation either alone or with remodeling. In small animals, even if clear model-dependent differences have been shown [25], Penh ratio has been shown to be mainly related to eosinophilic inflammation in Balb/C mice [26], which is consistent with our results. So far, to the best of our knowledge, there was no reported in vivo method able to assess bronchial remodeling noninvasively. By contrast, airway inflammation can be assessed through exhaled nitric oxide or induced sputum [27,28]. In the present study, we demonstrated that micro-CT can quantify remodeling noninvasively in sensitized mice. However, PBA and normalized PBA were also correlated with some parameters of bronchial inflammation. These results can be partly explained by the close relationship between inflammation and remodeling [29,30], which is likely to entail potential cross-correlations. Our 3 endpoints protocol allowed us to demonstrate the absence of any significant difference in micro-CT parameters between sensitized and control mice from group A, thereby suggesting that the sole inflammation has no influence on PBA or normalized PBA. In the absence of normalization by the lung attenuation value, PBA appeared to be less specific to remodeling and only increased in.
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