F-034. Repeated Inhalation of Aspergillus fumigatus conidia Induces an Allergic Airway Disease that Leads to Pronounced Arterial Remodeling in the Lung

A. B. Shreiner, E. S. White, C. Hogaboam, R. McDonald, B. Fields, P. Christensen, G. B. Huffnagle;
Univ. of Michigan, Ann Arbor, MI.

BACKGROUND: Aspergillus fumigatus is an opportunistic pathogen that is readily cleared from the airway by an intact innate immune system. An adaptive immune response may drive excessive inflammation, and A. fumigatus is implicated in several hypersensitivity diseases. Chronic hypersensitivity responses in the lung can result in debilitating pathophysiology. Therefore, we hypothesized that repeated inhalation of A. fumigatus conidia will result in a hypersensitivity response and immunopathological changes in the lung. METHODS: C57BL/6 mice were treated with 2x106 conidia every 7 days and examined 24 hours after the last treatment. Mice were evaluated after 0, 1, 2, 3, 4 and 8 exposures. In some experiments, one group of mice was treated with anti-CD4 antibody. Contents of the airways were recovered by bronchoalveolar lavage. Cells were analyzed by flow cytometry. Cytokines were measured by ELISA. Whole lung samples were evaluated after histological preparation. RESULTS: A. fumigatus did not accumulate in the lung even after repeated exposure as indicated by staining with Gomori methenamine silver. After 1 and 2 exposures, only the innate response notable for neutrophils and TNFa was detected. By 3 and 4 exposures, mice exhibited hallmark features of allergic airway disease including airway eosinophilia, IL4+ CD4 Th2 cells, serum IgE and goblet cell metaplasia. This hypersensitivity response was dependent on CD4+ cells, but host defense from A. fumigatus was not. Chronic exposure to conidia, measured after 8 exposures, resulted in pronounced remodeling of small muscular arteries in the lung. Smooth muscle hyperplasia in the arterial walls was associated with narrowed or occluded lumens. CONCLUSION: Inhaled A. fumigatus conidia were cleared by innate immune defenses. CD4+ T cells were not required for clearance. Repeated inhalation of conidia induced a hypersensitivity response mediated by CD4 Th2 cells. Chronic allergic airway disease resulted in arterial remodeling and loss of lumen patency. The observed immunopathological response may represent a novel mechanism for the development of pulmonary arterial hypertension, a severe disease that can lead to right-sided heart failure.