Chronic airway hyperreactivity, goblet cell hyperplasia, and peribronchialfibrosis during allergic airway disease induced by Aspergillus fumigatus

Clinical allergic airway disease is associated with persistent airway hyper reactivity and remodeling, but little is known about the mechanisms leading to these alterations. This paucity of information is related in part to th e absence of chronic models of allergic airway disease, Herein we describe a model of persistent airway hyperreactivity, goblet cell hyperplasia, and subepithelial fibrosis that is initiated by the intratracheal introduction of Aspergillus fumigatus spores or conidia into the airways of mice previou sly sensitized to A, fumigatus. Similar persistent airway alterations were not observed in nonsensitized mice challenged with A. fumigatus conidia alo ne. A. fumigatus-sensitized mice exhibited significantly enhanced airway hy perresponsiveness to a methacholine challenge that was still present at 30 days after the conidia challenge. Eosinophils and lymphocytes were present in bronchoalveolar lavage (BAL) samples from A. fumigatus-sensitized mice a t all times after conidia challenge. Compared with levels measured in A, fu migatus-sensitized mice immediately before conidia, significantly elevated interferon-gamma (IFN-gamma) and transforming growth factor (TGF-beta) leve ls were present in whole lung homogenates up to 7 days after the conidia ch allenge, At day 30 after conidia challenge, significantly elevated levels o f interleukin-4 (IL-4) and IL-13 were present in the A. fumigatus-sensitize d mice. Histological analysis revealed profound goblet cell hyperplasia and airway fibrosis at days 30 after conidia, and the latter finding was confi rmed by hydroxyproline measurements. Thus the introduction of A. fumigatus conidia into A. fumigatus-sensitized mice results in persistent airway hype rresponsiveness, fibrosis, and goblet cell hyperplasia.