Dysfunction and Remodeling of the Mouse Airway Persist after Resolution of Acute Allergen-Induced Airway Inflammation

Abstract

The mechanisms underlying airway hyperresponsiveness remain unclear, although airway inflammation and remodeling are likely important contributing factors. We hypothesized that airway physiology would differ between mice subjected to brief or chronic allergen exposure, and that these differences would be associated with characteristic inflammatory markers and indices of airway remodeling. BALB/c mice were sensitized to ovalbumin and studied at several time points following brief or chronic allergen challenge protocols. By measuring airway responses to methacholine, we demonstrated increases in maximal inducible bronchoconstriction that persisted for 8 wk following either brief or chronic allergen challenge; we also observed increases in airway reactivity, although it was only in chronically challenged mice that these changes persisted beyond the resolution of allergen-induced inflammation. Using airway morphometry, we further demonstrated that increases in maximal bronchoconstriction were associated with increases in airway contractile tissue in both models, and that chronic, but not brief, allergen challenge resulted in subepithelial fibrosis. Our observations that different aspects of sustained airway dysfunction and remodeling persist beyond the resolution of acute inflammatory events support the concept that remodeling occurs as a consequence of allergic airway inflammation, and that these structural changes contribute independently to the persistence of airway hyperresponsiveness.

CD4+ cells are required for chronic eosinophilic lung inflammation but not airway remodeling

“…Perhaps, after initiation of the remodeling process, which collectively requires CD4 T cells, other CD4ϩ cells, and eosinophilic inflammation, a number of growth factors and cytokines, including TGF-␤1 and VEGF, produced by CD4-negative cell types such as macrophages or activated epithelial cells, are sufficient for maintenance of remodeling as implied from other reports (25,31). Although our data support an uncoupling of inflammation and remodeling similar to prior observations (13,20,27,31), the mechanisms that lead to such a divergence have yet to be fully elucidated.…”

Inhibition of Glycogen Synthase Kinase-3β Is Sufficient for Airway Smooth Muscle Hypertrophy

“…Ovalbumin Sensitization/Challenge Model and Isolation of Murine Airway Smooth Muscle Cells-BALB/c mice (Charles River Laboratories, Wilmington, MA) were sensitized and challenged to endotoxin-free ovalbumin (Pierce), as previously described (30). On day 0, mice were anesthetized and injected intraperitoneally with 200 l of a suspension of 25% (w/v) alum (Pierce) in either PBS or ovalbumin (5 mg/ml).…”

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

“…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).…”