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Animal Models |
From the Department of Pathology *
and the Division of
Pulmonary and Critical Care,
Department of
Internal Medicine, University of Michigan Medical School, Ann
Arbor, Michigan
Clinical allergic airway disease is associated with persistent
airway hyperreactivity and remodeling, but little is known
about the mechanisms leading to these alterations. This paucity of
information is related in part to the 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 previously sensitized to A.
fumigatus. Similar persistent airway alterations were not
observed in nonsensitized mice challenged with A.
fumigatus conidia alone. A. fumigatus-sensitized
mice exhibited significantly enhanced airway hyperresponsiveness 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 at all times after conidia challenge.
Compared with levels measured in A. fumigatus-sensitized
mice immediately before conidia, significantly elevated
interferon-
(IFN-) and transforming growth factor (TGF-ß)
levels were present in whole lung homogenates up to 7 days after the
conidia challenge. At day 30 after conidia challenge,
significantly elevated levels of interleukin-4 (IL-4) and IL-13 were
present in the A. fumigatus-sensitized mice.
Histological analysis revealed profound goblet cell hyperplasia and
airway fibrosis at days 30 after conidia, and the latter
finding was confirmed by hydroxyproline measurements. Thus the
introduction of A. fumigatus conidia into A.
fumigatus-sensitized mice results in persistent airway
hyperresponsiveness, fibrosis, and goblet cell
hyperplasia.
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