Airway hyperresponsiveness is associated with airway remodeling but not inflammation in aging Cav1-/- mice

Background: Airway inflammation and airway remodeling are the key contributors to airway hyperresponsiveness (AHR), a characteristic feature of asthma. Both processes are regulated by Transforming Growth Factor (TGF)-beta. Caveolin 1 (Cav1) is a membrane bound protein that binds to a variety of receptor and signaling proteins, including the TGF-beta receptors. We hypothesized that caveolin-1 deficiency promotes structural alterations of the airways that develop with age will predispose to an increased response to allergen challenge. Methods: AHR was measured in Cav1-deficient and wild-type (WT) mice 1 to 12 months of age to examine the role of Cav1 in AHR and the relative contribution of inflammation and airway remodeling. AHR was then measured in Cav1(-/-) and WT mice after an ovalbumin-allergen challenge performed at either 2 months of age, when remodeling in Cav1(-/-) and WT mice was equivalent, and at 6 months of age, when the Cav1(-/-) mice had established airway remodeling. Results: Cav1(-/-) mice developed increased thickness of the subepithelial layer and a correspondingly increased AHR as they aged. In addition, allergen-challenged Cav1(-/-) mice had an increase in AHR greater than WT mice that was largely independent of inflammation. Cav1(-/-) mice challenged at 6 months of age have decreased AHR compared to those challenged at 2 months with correspondingly decreased BAL IL-4 and IL-5 levels, inflammatory cell counts and percentage of eosinophils. In addition, in response to OVA challenge, the number of goblet cells and alpha-SMA positive cells in the airways were reduced with age in response to OVA challenge in contrast to an increased collagen deposition further enhanced in absence of Cav1. Conclusion: A lack of Cav1 contributed to the thickness of the subepithelial layer in mice as they aged resulting in an increase in AHR independent of inflammation, demonstrating the important contribution of airway structural changes to AHR. In addition, age in the Cav1(-/-) mice is a contributing factor to airway remodeling in the response to allergen challenge.