title: Development of asthmatic inflammation in mice following early-life exposure to ambient environmental particulates and chronic allergen challenge.
abstract: Childhood exposure to environmental particulates increases the risk of development of asthma. The underlying mechanisms might include oxidant injury to airway epithelial cells (AEC). We investigated the ability of ambient environmental particulates to contribute to sensitization via the airways, and thus to the pathogenesis of childhood asthma. To do so, we devised a novel model in which weanling BALB/c mice were exposed to both ambient particulate pollutants and ovalbumin for sensitization via the respiratory tract, followed by chronic inhalational challenge with a low mass concentration of the antigen. We also examined whether these particulates caused oxidant injury and activation of AEC in vitro. Furthermore, we assessed the potential benefit of minimizing oxidative stress to AEC through the period of sensitization and challenge by dietary intervention. We found that characteristic features of asthmatic inflammation developed only in animals that received particulates at the same time as respiratory sensitization, and were then chronically challenged with allergen. However, these animals did not develop airway hyper-responsiveness. 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 IL-33. Treatment of AEC with an antioxidant in vitro inhibited the pro-inflammatory cytokine response to these particulates. Ambient particulates also induced pro-inflammatory cytokine expression following administration to weanling mice. However, early-life dietary supplementation with antioxidants did not prevent the development of an asthmatic inflammatory response in animals that were exposed to particulates, sensitized and challenged. We conclude that injury to airway epithelium by ambient environmental particulates in early life is capable of promoting the development of an asthmatic inflammatory response in sensitized and antigen-challenged mice. These findings are likely to be relevant to the induction of childhood asthma.
authors.affiliation: Inflammation and Infection Research Centre, School of Medical Sciences, University of New South Wales, Sydney, 2052, Australia.
authors.forename: Cristan
authors.initials: C
authors.lastname: Herbert
authors.forename: Jessica S
authors.initials: JS
authors.lastname: Siegle
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Shadie
authors.forename: Stina
authors.initials: S
authors.lastname: Nikolaysen
authors.forename: Linda
authors.initials: L
authors.lastname: Garthwaite
authors.forename: Nicole G
authors.initials: NG
authors.lastname: Hansbro
authors.forename: Paul S
authors.initials: PS
authors.lastname: Foster
authors.forename: Rakesh K
authors.initials: RK
authors.lastname: Kumar
mesh_terms: D000485:Allergens / Q000276:immunology*; D000818:Animals; D000831:Animals, Newborn; D000975:Antioxidants / Q000494:pharmacology; D001249:Asthma / Q000150:complications / Q000276:immunology* / Q000473:pathology* / Q000503:physiopathology; D016535:Bronchial Hyperreactivity / Q000150:complications / Q000276:immunology / Q000503:physiopathology; D001992:Bronchoalveolar Lavage Fluid; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004781:Environmental Exposure; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D007114:Immunization; D016210:Methacholine Chloride / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D018384:Oxidative Stress / Q000187:drug effects; D052638:Particulate Matter / Q000009:adverse effects / Q000276:immunology*; D011014:Pneumonia / Q000150:complications / Q000276:immunology* / Q000473:pathology* / Q000503:physiopathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014886:Weaning
chemical_list: D000485:Allergens; D000975:Antioxidants; D016207:Cytokines; D052638:Particulate Matter; D012333:RNA, Messenger; D016210:Methacholine Chloride