Alexander M. Shadie

Differential injurious effects of ambient and traffic-derived particulate matter on airway epithelial cells

Exposure to airborne particulate matter (PM) may promote development of childhood asthma and trigger acute exacerbations of existing asthma via injury to airway epithelial cells (AEC).

Ambient particulate matter induces an exacerbation of airway inflammation in experimental asthma: role of interleukin-33

High levels of ambient environmental particulate matter (PM10 i.e. < 10 μm median aerodynamic diameter) have been linked to acute exacerbations of asthma. We examined the effects of delivering a single dose of Sydney PM10 by intranasal instillation to BALB/c mice that had been sensitized to ovalbumin and challenged repeatedly with a low (≈3 mg/m3) mass concentration of aerosolized ovalbumin for 4 weeks. Responses were compared to animals administered carbon black as a negative control, or a moderate (≈30 mg/m3) concentration of ovalbumin to simulate an allergen‐induced acute exacerbation of airway inflammation. Delivery of PM10 to mice, in which experimental mild chronic asthma had previously been established, elicited characteristic features of enhanced allergic inflammation of the airways, including eosinophil and neutrophil recruitment, similar to that in the allergen‐induced exacerbation. In parallel, there was increased expression of mRNA for interleukin (IL)‐33 in airway tissues and an increased concentration of IL‐33 in bronchoalveolar lavage fluid. Administration of a monoclonal neutralizing anti‐mouse IL‐33 antibody prior to delivery of particulates significantly suppressed the inflammatory response induced by Sydney PM10, as well as the levels of associated proinflammatory cytokines in lavage fluid. We conclude that IL‐33 plays a key role in driving airway inflammation in this novel experimental model of an acute exacerbation of chronic allergic asthma induced by exposure to PM10.

Interleukin-33 Drives Activation of Alveolar Macrophages and Airway Inflammation in a Mouse Model of Acute Exacerbation of Chronic Asthma

We investigated the role of interleukin-33 (IL-33) in airway inflammation in an experimental model of an acute exacerbation of chronic asthma, which reproduces many of the features of the human disease. Systemically sensitized female BALB/c mice were challenged with a low mass concentration of aerosolized ovalbumin for 4 weeks to induce chronic asthmatic inflammation and then received a single moderate-level challenge to trigger acute airway inflammation simulating an asthmatic exacerbation. The inflammatory response and expression of cytokines and activation markers by alveolar macrophages (AM) were assessed, as was the effect of pretreatment with a neutralizing antibody to IL-33. Compared to chronically challenged mice, AM from an acute exacerbation exhibited significantly enhanced expression of markers of alternative activation, together with enhanced expression of proinflammatory cytokines and of cell surface proteins associated with antigen presentation. In parallel, there was markedly increased expression of both mRNA and immunoreactivity for IL-33 in the airways. Neutralization of IL-33 significantly decreased both airway inflammation and the expression of proinflammatory cytokines by AM. Collectively, these data indicate that in this model of an acute exacerbation of chronic asthma, IL-33 drives activation of AM and has an important role in the pathogenesis of airway inflammation.

Development of asthmatic inflammation in mice following early-life exposure to ambient environmental particulates and chronic allergen challenge

SUMMARY 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.

Interleukin-17 Signalling in a Murine Model of Mild Chronic Asthma

Background: The role of Th17 cell-derived cytokines in the pathogenesis of airway inflammation and remodelling in mild asthma remains unclear. We investigated this in a mouse model which reproduces most of the features of the human disease. Methods: Systemically sensitised BALB/c mice were challenged via the airways with a low mass concentration of ovalbumin aerosol for 8 weeks to induce lesions of mild chronic asthma. Changes were compared with those in animals deficient in signalling via the interleukin (IL)-17 receptor A (IL-17R). Low-passage airway epithelial cells (AEC) and fibroblasts were cultured with IL-17A, or with media from Th17-polarised cells, to assess activation. Results: In CD4+ T cells from chronically challenged mice, expression of mRNA for Th17 cytokines IL-17A, IL-17F, IL-21 and IL-22 was significantly increased. Both recombinant IL-17A and media from Th17 cells significantly stimulated the production of various pro-inflammatory and pro-remodelling cytokines by AEC and fibroblasts. In the mouse model, abrogation of IL-17R signalling had no effect on the development of airway inflammation or on most changes of remodelling. However, numbers of mucus-producing cells and expression of mRNA for Gob-5 were attenuated in the absence of IL-17R signalling. Conclusions: Although IL-17A and Th17 cells stimulate cytokine production by structural cells of the airways, and Th17 cells are induced in our model of mild chronic asthma, signalling via IL-17R did not contribute significantly to the development of airway inflammation and most changes of remodelling in this model. However, in mild asthma, IL-17A appears to have a role in the goblet cell response in the airways.

Anti-Inflammatory and Anti-Remodelling Effects of ISU201, a Modified Form of the Extracellular Domain of Human BST2, in Experimental Models of Asthma: Association with Inhibition of Histone Acetylation

There are few alternatives to glucocorticosteroids for treatment of asthma. We assessed the activity of a novel protein drug designated ISU201, the extracellular domain of the human cell surface protein BST2, stabilised by fusion with the Fc region of IgG, in mouse models of mild chronic asthma and an acute exacerbation of asthma. The ability of ISU201 to suppress airway inflammation and remodelling was compared with that of dexamethasone. Female BALB/c mice were systemically sensitised with ovalbumin, then received controlled low-level challenge with aerosolised ovalbumin for 6 weeks, which induced lesions of mild chronic asthma, and were treated with drugs during the final 2 weeks. Alternatively, sensitised mice received 4 weeks of chronic low-level challenge and were treated 24 and 2 hours before a final single moderate-level challenge, which triggered acute airway inflammation simulating an asthmatic exacerbation. Inflammation and remodelling were quantified, as was the expression of pro-inflammatory cytokines in bronchoalveolar lavage fluid and tissues. To identify cellular targets of ISU201, we assessed the effects of the drug on activated lymphocytes, macrophages and airway epithelial cells. In the model of mild chronic asthma, ISU201 was as effective as dexamethasone in suppressing airway inflammation and most changes of remodelling. In the model of an allergen-induced acute exacerbation of chronic asthma, ISU201 was also an effective anti-inflammatory agent, although it was less active than dexamethasone. The drug acted on multiple cellular targets, suppressing production of pro-inflammatory cytokines by lymphocytes and macrophages. ISU201 significantly reduced acetylation of histone H4 in airway epithelial cells, suggesting at least one potential mechanism of action. We conclude that in these models of asthma, ISU201 is a broad-spectrum inhibitor of both airway inflammation and remodelling. Thus, unlike drugs which target specific mediators, it could potentially be an alternative or an adjunct to glucocorticoids for the treatment of asthma.

Associate Editor Hirohisa Saito

Prof. Hirohisa Saito, Deputy Director of the National Research Institute for Child Health and Development, serves as a board member of the Japanese Society of Allergology (JSA), Editor in Chief of Allergology International (official journal of the JSA) and Associate Editor of the Journal of Allergy and Clinical Immunology . He graduated from Jikei University School of Medicine in 1977 and started his career as a Pediatrician. After receiving his PhD, he taught immunology, especially mast cell biology, at the Johns Hopkins University, under the supervision of Prof. Teruko Ishizaka, from 1986 until 1988. In 1996, after serving as a clinical allergy specialist, he was appointed as Director of the Department of Allergy and Immunology, National Children’s Medical Research Center. In 2002, his Institute was unified and renamed as National Research Institute for Child Health and Development. Since 2003, he has been Professor of Pediatrics at Jikei University, Toho University and Juntendo University. He was concurrently serving as Leader of the Allergy Transcriptome Unit at the Research Center for Allergy and Immunology, RIKEN, from 2002 until 2006. In 2010, he was promoted to Deputy Director of the Research Institute for Child Health and Development. In 2013, he was elected President of the Japanese Society of Allergology. Published online: September 5, 2013

Associate Editor Andreas Radbruch

A biologist by education, Andreas Radbruch did his PhD at the Genetics Institute of the Cologne University with Klaus Rajewsky. He later became Associate Professor there and was a visiting scientist with Max Cooper and John Kearney at the University of Alabama, Birmingham. In 1996, Andreas Radbruch became Director of the German Rheumatism Research Center in Berlin, a Leibniz Institute, and in 1998, Professor of Rheumatology at the Charité Medical Center and Humboldt University of Berlin. Andreas Radbruch has been President of the German Society for Rheumatology, the German Society for Immunology and is incoming President of the International Society for Advancement of Cytometry (ISAC). He serves on a number of advisory and editorial boards and is a fellow of many academic organizations. He is Editorial Chair of the European Journal of Immunology . Most recently, he was awarded the Carol Nachman Prize and an advanced research grant of the European Research Council. Andreas Radbruch has authored more than 250 original publications on immunological memory, antibody class switching, T and B lymphocyte differentiation, cytometry and cell sorting. His research group described the organization of memory plasma cells and memory T helper (Th) lymphocytes in bone marrow and identified memory plasma cells secreting pathogenic antibodies as novel target in chronic immune-mediated diseases. Andreas Radbruch demonstrated, by targeted mutagenesis, that antibody class switch recombination in activated B lymphocytes is targeted to distinct switch regions by transcription. His group contributed significantly to our current understanding of Th1 and Th2 cytokine memory, its imprinting and plasticity and, more recently, has identified critical molecular adaptations of Th effector memory cells to chronic inflammation. Radbruchs group developed the MACS technology and the cytometric secretion assay. Published online: September 5, 2013