An inhalation model of airway allergic response to inhalation of environmentalAspergillus fumigatusconidia in sensitized BALB/c mice

Abstract

Fungal exposure may elicit a number of pulmonary diseases in man, including allergic asthma. Fungal sensitization is linked to asthma severity, although the basis for this increased pathology remains ambiguous. To recapitulate environmental fungal allergen exposure in a human, a nose-only inhalation delivery of Aspergillus fumigatus conidia was employed in mice previously sensitized to Aspergillus antigen extract. BALB/c mice were immunized with subcutaneous and intraperitoneal injections of soluble A. fumigatus extract in alum, followed by 3 intranasal inoculations of the same fungal antigens dissolved in saline to elicit global sensitization in a manner similar to other published models. The animals were then challenged with a 10-min inhaled dose of live conidia blown directly from the surface of a mature A. fumigatus culture. After a single challenge with inhaled A. fumigatus conidia, allergic pulmonary inflammation and airway hyperresponsiveness were significantly increased above that of either naïve animals or animals that had been sensitized to A. fumigatus antigens but not challenged with conidia. The architecture of the lung was changed by inhalation of conidia with epithelial thickness, goblet cell metaplasia, and peribronchial collagen deposition significantly increased when compared to controls. Additionally, α-smooth muscle actin staining of histological sections showed visual evidence of increased peribronchial smooth muscle mass after fungal challenge. In summary, the inhalation of live A. fumigatus spores to the sensitized airways of BALB/c mice advances the study of the pulmonary response to fungus by providing a more natural route of exposure and, for the first time, demonstrates the consistent development of fibrosis and smooth muscle changes accompanying exposure to inhaled fungal spores in a mouse model.

B lymphocytes regulate airway granulocytic inflammation and cytokine production in a murine model of fungal allergic asthma

“…17 For each sample, at least 50 discrete points were measured at 50-mm intervals along the largest lateral bronchiolar branch visible on the histological section (the second or third lateral branch). A perpendicular line was drawn from the basement membrane through the full thickness of the collagen layer located immediately below.…”

“…One week after the final dose, the animals were challenged by being exposed to a nasal aerosol of live A. fumigatus conidia as the first inhalational challenge (IH1). 17 For the inhalational challenge (IH), each anesthetized mouse was placed supine with its nose in an inoculation port to inhale the live fungal conidia for 10 min. This challenge was performed once at week 8 (IH2) and repeated at week 10 (IH3).…”

“…15,16 To recapitulate many of the acute and chronic features of clinical fungal asthma, we developed an Aspergillus fumigatus experimental model in which sensitization of mice with fungal extracts is followed by allergy challenge with inhaled Aspergillus conidia. 17 The model results in IgE production, leukocytic pulmonary inflammation, and pronounced peribronchial fibrosis, all of which are exaggerated upon subsequent repeated exposure to inhaled conidia. 10,14,17,18 Recruitment of eosinophils and B cells is a particularly interesting component of the inflammatory response following fungal challenge, as the roles of these cells in the context of pulmonary responses to fungi have not been investigated.…”

“…17 The model results in IgE production, leukocytic pulmonary inflammation, and pronounced peribronchial fibrosis, all of which are exaggerated upon subsequent repeated exposure to inhaled conidia. 10,14,17,18 Recruitment of eosinophils and B cells is a particularly interesting component of the inflammatory response following fungal challenge, as the roles of these cells in the context of pulmonary responses to fungi have not been investigated.…”

“…Using an A. fumigatus murine inhalation model to mimic human fungal asthma, 14,17 we compared the effects of repeated A. fumigatus inhalation in BALB/c wild-type controls and J H 2/2 animals. The absence of JH gene did not alter the pulmonary pathology that results from inhalation of A. fumigatus in allergic animals; airway hyperresponsiveness (AHR), pulmonary inflammation, epithelial changes and collagen deposition in J H 2/2 mice were equivalent to those in wild-type controls.…”