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

Firestone Institute for Respiratory Health, Department of Medicine and Center for Gene Therapeutics, Department of Pathology, McMaster University, Hamilton, Ontario, Canada

Address correspondence to: Mark D. Inman, M.D., Ph.D., Firestone Institute for Respiratory Health, St. Joseph's Healthcare, 50 Charlton Avenue East, Hamilton, Ontario L8N 4A6 Canada. E-mail: inmanma{at}mcmaster.ca

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.

Abbreviations: airway hyperresponsiveness, AHR • bronchoalveolar lavage, BAL • extracellular matrix, ECM • hematoxylin and eosin, H&E • interleukin, IL • intranasal, IN • intraperitoneal, IP • methacholine, MCh • ovalbumin, OVA • periodic acid Schiff, PAS • total respiratory system resistance, R_RS • T helper type 2, Th2 • -smooth muscle actin, -SMA

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