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Abstract
Rationale: High levels of ambient environmental particulate matter have been associated with acute exacerbations of asthma. The mechanism(s) by which non-allergic stimuli such as particulate pollutants trigger exacerbations of allergic asthma are unknown, but may involve injury to airway epithelial cells (AEC) via oxidative stress.
Objective: To assess the ability of ambient particulate matter to trigger an exacerbation of experimental chronic asthma, in an established mouse model and to explore the mechanism(s) by which this occurs.
Methods and Results: BALB/c mice were sensitised to ovalbumin and repeatedly challenged with a low mass concentration (~3 mg/m3) of aerosolised ovalbumin for 4 weeks. Animals received a single dose of ambient particulate matter, collected in the geographical centre of Sydney (PM10 i.e. < 10 micron median aerodynamic diameter) via intranasal instillation. Asthmatic inflammation was quantified in terms of cellular recruitment and expression of relevant cytokines in bronchoalveolar lavage (BAL) fluid or airway tissue. Responses were compared to animals administered carbon black as a negative control, or a moderate concentration (~30 mg/m3) of aerosolised ovalbumin, as a positive control for an allergen-induced acute exacerbation. Characteristic features of asthmatic inflammation, including recruitment of eosinophils and neutrophils, developed in animals which received intranasal Sydney PM10.
To identify the mechanisms involved, the effects of ambient particulate matter on mouse AEC were assessed. Ambient particulates induced epithelial injury in vitro, with evidence of oxidative stress, and production of both pro-inflammatory cytokines and Th2 promoting cytokines such as interleukin (IL)-33.
Treatment with dietary antioxidants three times during the final week of chronic challenge, prior to delivery of Sydney PM10, was not effective in abrogating the inflammation induced by particulate matter. However, administration of an IL-33 neutralising monoclonal antibody, prior to exposure to particulates almost completely abrogated the development of acute asthmatic inflammation.
Conclusions: On a background of mild chronic asthma, exposure to environmental particulates can trigger marked allergic inflammation, resembling an acute exacerbation of asthma. IL-33 appears to play an important role in the generation of such an exacerbation and may drive allergic inflammation via cross-talk between the innate and adaptive immune responses.