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

Abstract

BackgroundAirway 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)-β. Caveolin 1 (Cav1) is a membrane bound protein that binds to a variety of receptor and signaling proteins, including the TGF-β 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.MethodsAHR 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.ResultsCav1-/- 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 α-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.ConclusionA 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.

Transforming Growth Factor β1 Function in Airway Remodeling and Hyperresponsiveness. The Missing Link?

“…It is suggested that frequent asthma exacerbations evoke an airway injury-repair cycle that promotes sustained AHR by altering the structure and function of ASM cells (13,14). In addition, recent literature suggests an uncoupling of airway inflammation and AHR in asthma (9,11,15,16). Understandably, the link between injury-repair responses and AHR remains unclear.…”

“…The mechanisms by which each exacerbates the other, or whether a direct connection exists between the two, remain highly debated. Although it is suggested that airway inflammation precedes the development of both pathologies (9,10), airway structural alterations may also independently modify AHR (11,12). It is suggested that frequent asthma exacerbations evoke an airway injury-repair cycle that promotes sustained AHR by altering the structure and function of ASM cells (13,14).…”

Myocardial Tissue Caveolae

“…These studies revealed that loss of Cav impairs diverse cellular signaling processes, thus subsequently genetically modified animals develop mainly organ disorders such as cardiac hypertrophy and pulmonary remodeling. These effects are prominent as the mice aged, also suggesting the cumulative effect of malfunction by caveolae (69,94,122). Endothelial reintroduction of Cav-1 largely rescued cardiac abnormality found in the Cav-1-deficient mice, and indicated the cell-specific importance of Cav function.…”

Bronchoconstriction and Airway Biology

“…37 Multiple in vitro studies have demonstrated that infl ammation and remodeling can be dissociated and studied separately in models of disease. 38,39 Tschumperlin et al 10 showed that EGFR activation in response to bronchoconstriction can be achieved in naïve animals not previously exposed to allergen; similarly, using naive guinea pig precision cut lung slices, Oenema et al 4 demonstrated that bronchoconstriction induced by methacholine and histamine was suffi cient to enhance the expression of smooth muscle-specifi c marker proteins in the large and small airways. Th is involved a mechanism similar to that reported by Tatler et al, 26 including the release of bioactive TGF-b .…”