Novel acute hypersensitivity pneumonitis model induced by airway mycosis and high dose lipopolysaccharide

Xinyan Huang,Yubiao Guo,Lizhen Song,Yun Zhang,John M. Knight,Farrah Kheradmand,Yuying Zeng,David B. Corry,Linda K. Green,Yifan Wu,Katherine Polsky

doi:10.1186/s12931-021-01850-5

Abstract

BackgroundInhalation of fungal spores is a strong risk factor for severe asthma and experimentally leads to development of airway mycosis and asthma-like disease in mice. However, in addition to fungal spores, humans are simultaneously exposed to other inflammatory agents such as lipopolysaccharide (LPS), with uncertain relevance to disease expression. To determine how high dose inhalation of LPS influences the expression of allergic airway disease induced by the allergenic mold Aspergillus niger (A. niger).MethodsC57BL/6J mice were intranasally challenged with the viable spores of A. niger with and without 1 μg of LPS over two weeks. Changes in airway hyperreactivity, airway and lung inflammatory cell recruitment, antigen-specific immunoglobulins, and histopathology were determined.ResultsIn comparison to mice challenged only with A. niger, addition of LPS (1 μg) to A. niger abrogated airway hyperresponsiveness and strongly attenuated airway eosinophilia, PAS+ goblet cells and TH2 responses while enhancing TH1 and TH17 cell recruitment to lung. Addition of LPS resulted in more severe, diffuse lung inflammation with scattered, loosely-formed parenchymal granulomas, but failed to alter fungus-induced IgE and IgG antibodies.ConclusionsIn contrast to the strongly allergic lung phenotype induced by fungal spores alone, addition of a relatively high dose of LPS abrogates asthma-like features, replacing them with a phenotype more consistent with acute hypersensitivity pneumonitis (HP). These findings extend the already established link between airway mycosis and asthma to HP and describe a robust model for further dissecting the pathophysiology of HP.

Highlights

Inhalation of fungal spores is a strong risk factor for severe asthma and experimentally leads to development of airway mycosis and asthma-like disease in mice
We examined the effect of high dose of LPS (1 μg) on airway mycosis-induced allergic airway disease in mice; in a parallel manuscript, we explore the effect of lower doses (10–100 ng) of LPS in the same model (Zeng et al submitted)
High dose LPS attenuates key features of airway mycosis‐induced allergic airway disease Low doses of LPS have previously been shown to elicit allergic airway disease in mice, but less is known about the effect of higher LPS doses

Summary

Introduction

Inhalation of fungal spores is a strong risk factor for severe asthma and experimentally leads to development of airway mycosis and asthma-like disease in mice. To determine how high dose inhalation of LPS influences the expression of allergic airway disease induced by the allergenic mold Aspergillus niger (A. niger). Asthma, including both allergic and non-allergic forms, is one of the most common chronic disorders affecting both children and adults. Other environmental exposures, including lipopolysaccharide (LPS), appear to critically influence the expression of asthma. Exposure to some farm environments has been linked to higher asthma prevalence [12] and experimentally, LPS has been shown to promote the expression of allergic airway disease, a model of asthma, in mice [13]

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