Abstract
BackgroundThe current paradigm describing asthma pathogenesis recognizes the central role of abnormal epithelial function in the generation and maintenance of the disease. However, the mechanisms responsible for the initiation of airway remodeling, which contributes to decreased lung function, remain elusive. Therefore, we aimed to determine the role of altered pulmonary gene expression in disease inception and identify proremodeling mediators.MethodsUsing an adenoviral vector, we generated mice overexpressing smad2, a TGF-β and activin A signaling molecule, in the lung. Animals were exposed to intranasal ovalbumin (OVA) without systemic sensitization.ResultsControl mice exposed to inhaled OVA showed no evidence of pulmonary inflammation, indices of remodeling, or airway hyper-reactivity. In contrast, local smad2 overexpression provoked airway hyper-reactivity in OVA-treated mice, concomitant with increased airway smooth muscle mass and peribronchial collagen deposition. Pulmonary eosinophilic inflammation was not evident, and there was no change in serum IgE or IgG1 levels. The profound remodeling changes were not mediated by classical pro-inflammatory Th2 cytokines. However, uric acid and interleukin-1β levels in the lung were increased. Epithelial-derived endothelin-1 and fibroblast growth factor were also augmented in smad2-expressing mice. Blocking endothelin-1 prevented these phenotypic changes.ConclusionsInnate epithelial-derived mediators are sufficient to drive airway hyper-reactivity and remodeling in response to environmental insults in the absence of overt Th2-type inflammation in a model of noneosinophilic, noninflammed types of asthma. Targeting potential asthma therapies to epithelial cell function and modulation of locally released mediators may represent an effective avenue for therapeutic design.
Highlights
The current paradigm describing asthma pathogenesis recognizes the central role of abnormal epithelial function in the generation and maintenance of the disease
AdS mice exposed to OVA showed significantly increased airway resistance and decreased compliance in response to methacholine when compared with PBS-treated mice or the adenoviral vector (AdC) OVA group (Fig. 1A,B)
There were no significant differences in the total number of leukocytes or eosinophils recovered from the lung (Fig. 1D,E) or bronchoalveolar lavage (BAL) fluid in mice exposed to intranasal OVA compared with PBS
Summary
The current paradigm describing asthma pathogenesis recognizes the central role of abnormal epithelial function in the generation and maintenance of the disease. The mechanisms responsible for the initiation of airway remodeling, which contributes to decreased lung function, remain elusive. Results: Control mice exposed to inhaled OVA showed no evidence of pulmonary inflammation, indices of remodeling, or airway hyper-reactivity. Local smad overexpression provoked airway hyper-reactivity in OVA-treated mice, concomitant with increased airway smooth muscle mass and peribronchial collagen deposition. Epithelial-derived endothelin-1 and fibroblast growth factor were augmented in smad2-expressing mice. Conclusions: Innate epithelial-derived mediators are sufficient to drive airway hyper-reactivity and remodeling in response to environmental insults in the absence of overt Th2-type inflammation in a model of noneosinophilic, noninflammed types of asthma. Targeting potential asthma therapies to epithelial cell function and modulation of locally released mediators may represent an effective avenue for therapeutic design
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