Aging, brain-derived neurotrophic factor, and allergen-induced pulmonary responses in mice

Asthma in the elderly is being recognized as more severe, resistant to standard therapies, and having greater morbidity. Therefore, it becomes important to understand the impact of aging-associated airway structure and functional changes toward pathogenesis of asthma in the elderly. Here, airway smooth muscle plays important roles in airway hyperreactivity and structural remodeling. The role of smooth muscle in asthma can be modulated by growth factors [including neurotrophins such as brain-derived neurotrophic factor (BDNF)] and proinflammatory senescence factors. In this study, we investigated aging effects on airway hyperreactivity, structural remodeling, inflammation, and senescence in a mouse model of allergic asthma. C57BL/6J wild-type mice or smooth muscle-specific BDNF knockout mice at 4, 18, and 24 mo of age were intranasally exposed to mixed allergens (MAs, ovalbumin, Aspergillus, Alternaria, and house dust mite) over 4 wk. Assessing lung function by flexiVent, we found that compared with 4-mo-old mice, 18- and 24-mo-old C57BL/6J mice showed decreased airway resistance and increased airway compliance after PBS or MA treatment. Deletion of smooth muscle BDNF blunted airway hyperreactivity in aged mice. Lung histology analysis revealed that aging increased bronchial airway thickness and decreased lung inflammation. Multiplex assays showed that aging largely reduced allergen-induced lung expression of proinflammatory chemokines and cytokines. By immunohistochemistry staining, we found that aging increased bronchial airway expression of senescence markers, including p21, phospho-p53, and phospho-γH2A.X. Our data suggest that aging-associated increase of airway senescence in the context of allergen exposure may contribute to asthma pathology in the elderly.NEW & NOTEWORTHY The pathogenesis of asthma in elderly is not well understood. Using a mouse model of asthma, we show that aging results in decreased lung function and less responsiveness to allergen exposure, impacted by locally produced brain-derived neurotrophic factor. Aging also decreases allergen-induced inflammation but increases airway remodeling and senescence. Our results suggest that senescence pathways may contribute to asthma pathogenesis in elderly.