Published ahead of print on May 12, 2008, doi:10.1165/rcmb.2008-0028OC
© 2008 American Thoracic Society DOI: 10.1165/rcmb.2008-0028OC Steroid-Resistant Neutrophilic Inflammation in a Mouse Model of an Acute Exacerbation of Asthma1 Airway Disease Section, National Heart and Lung Institute, Imperial College, London, United Kingdom; 2 Department of Pathology, School of Medical Sciences, and 4 Department of Respiratory Medicine, Prince of Wales Clinical School, University of New South Wales, Sydney, Australia; 3 Discipline of Immunology and Microbiology, Faculty of Health, University of Newcastle, Newcastle, Australia; and 5 Division of Molecular Bioscience, John Curtin School of Medical Research, Australian National University, Canberra, Australia Correspondence and requests for reprints should be addressed to Rakesh K. Kumar, PhD, MD, Department of Pathology, School of Medical Sciences, University of New South Wales, Sydney, Australia 2052. E-mail: R.Kumar{at}unsw.edu.au
Neutrophilic inflammation in acute exacerbations of asthma tends to be resistant to treatment with glucocorticoids. This may be related to decreased activity and expression of histone deacetylase-2 (HDAC2), which down-regulates expression of proinflammatory genes via recruitment to the glucocorticoid receptor complex. We assessed airway inflammation and response to steroid treatment in a novel mouse model of an acute exacerbation of chronic asthma. Systemically sensitized mice received low-level challenge with aerosolized ovalbumin for 4 weeks, followed by a single moderate-level challenge to induce enhanced inflammation in distal airways. We assessed the effects of pre-treatment with dexamethasone on the accumulation of inflammatory cells in the airways, airway responsiveness to methacholine, expression and enzymatic activity of nuclear proteins including histone acetyl transferase (HAT) and HDAC2, and levels of transcripts for neutrophil chemoattractant and survival cytokines. Dexamethasone suppressed inflammation associated with eosinophil and T-lymphocyte recruitment, but did not prevent neutrophil accumulation or development of airway hyperresponsiveness. Increased activity of HAT was suppressed by steroid treatment, but the marked diminution of HDAC2 activity and increased activity of nuclear factor-
Key Words: airway inflammation • cytokines • dexamethasone • histone deacetylase-2
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B were not reversed. Correspondingly, elevated expression of mRNA for TNF-
, granulocyte-macrophage colony-stimulating factor, IL-8, and p21waf were also not suppressed by dexamethasone. Levels of lipid peroxidation and protein nitration products were elevated in the acute exacerbation model. We conclude that impaired nuclear recruitment of HDAC2 could be an important mechanism of steroid resistance of the neutrophilic inflammation in exacerbations of asthma. Oxidative stress may contribute to decreased HDAC2 activity. 
