Corticosteroid-resistant asthma is associated with classical antimicrobial activation of airway macrophages

doi:10.1016/j.jaci.2008.07.007

Journal of Allergy and Clinical Immunology

Volume 122, Issue 3, September 2008, Pages 550-559.e3

https://doi.org/10.1016/j.jaci.2008.07.007 Get rights and content

Background

The cause of corticosteroid-resistant (CR) asthma is unknown.

Objective

We sought to perform gene microarray analyses by using bronchoalveolar lavage (BAL) cells from well-characterized subjects with CR asthma and subject with corticosteroid-sensitive (CS) asthma to elucidate the differential expression of genes that contribute to the development of corticosteroid resistance.

Methods

The patients were characterized as having CR or CS asthma based on FEV₁ percent predicted improvement after a 1-week course of oral prednisone. Expression of selected gene targets was verified by means of real-time PCR and ELISA.

Results

Microarray analyses demonstrated significantly higher levels (>3-fold increase, P < .05) of transcripts for TNF-α, IL-1α, IL-1β, IL-6, CXCL1, CXCL2, CXCL3, CXCL8 (IL-8), CCL3, CCL4, and CCL20 in BAL cells of subjects with CR asthma. These findings, confirmed by means of RT-PCR in additional BAL samples, were consistent with classical macrophage activation by bacterial products. In contrast, markers of alternatively activated macrophages, arginase I and CCL24, were decreased. Genes associated with activation of the LPS signaling pathway (early growth response 1, dual-specificity phosphatase 2, molecule possessing ankyrin repeats induced by LPS, and TNF-α–induced protein 3) were significantly increased in BAL samples from subjects with CR asthma (P < .05). These patients had significantly higher amounts (1444.0 ± 457.3 pg/mg total protein) of LPS in BAL fluid than seen in subjects with CS asthma (270.5 ± 216.0 pg, P < .05), as detected by using the LAL assay and confirmed by means of gas chromatographic/mass spectrometric analysis. Prolonged exposure to LPS induced functional steroid resistance to dexamethasone in normal human monocytes, as demonstrated by persistently increased IL-6 levels in the presence of dexamethasone.

Conclusions

Classical macrophage activation and induction of LPS signaling pathways along with high endotoxin levels detected in BAL fluid from subjects with CR asthma suggest that LPS exposure might contribute to CR asthma.

Section snippets

Subjects

Patients with a diagnosis of asthma according to American Thoracic Society criteria⁹ were selected for evaluation. Asthmatic subjects had a baseline FEV₁ percent predicted of 55% to 85% of predicted value, a β₂-adrenergic response of 12% or greater of baseline FEV₁ percent predicted, and/or a methacholine PC₂₀ value of 8 mg/mL or less. Asthmatic patients were further subdivided into those with CR or CS asthma based on their response to steroids. The definition was based on change in FEV₁

Patient characteristics

Eighteen asthmatic subjects (10 with CR asthma and 8 with CS asthma) were recruited for this study and underwent bronchoscopy with collection of BAL fluid. Patients were divided into CR and CS groups based on FEV₁ percent predicted responses after a 1-week course of oral prednisone. As shown in Table E1 (available in this article's Online Repository at www.jacionline.org), patients in the CR group did not show any improvement in prebronchodilator FEV₁ percent predicted after exposure to

Discussion

The current study determined gene expression profiles of BAL cells collected from subjects with CR asthma and subjects with CS asthma. As demonstrated by activation of multiple proinflammatory cytokines and chemokines accompanied by activation of LPS signaling pathways, BAL macrophages were remarkably more skewed toward a proinflammatory, antimicrobial, classically activated phenotype in subjects with CR asthma compared with subjects with CS asthma. These data gathered by means of gene

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: Supported by National Institutes of Health grants AI070140 and HL37260, General Clinical Research Center grant MO1 RR00051 from the Division of Research Resources, the Edelstein Family Chair in Pediatric Allergy and Immunology, and the University of Colorado Cancer Center.

: Disclosure of potential conflict of interest: R. J. Martin has received honoraria from Schering-Plough, Genentech/Novartis, Teva, and GlaxoSmithKline and has received grants from Altana (NycoMed) and GlaxoSmithKline. The rest of the authors have declared that they have no conflict of interest.

: Data deposition footnote: The microarray data reported in this article have been deposited in the Gene Expression Omnibus database at www.ncbi.nlm.nih.gov/geo (accession no. GSE7368).

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Asthma and lower airway diseaseCorticosteroid-resistant asthma is associated with classical antimicrobial activation of airway macrophages

Background

Objective

Methods

Results

Conclusions

Section snippets

Subjects

Patient characteristics

Discussion

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

Trends Immunol

J Biol Chem

Blood

FEBS Lett

Gene

Biochem Biophys Res Commun

J Allergy Clin Immunol

J Allergy Clin Immunol

Chest

J Allergy Clin Immunol

J Allergy Clin Immunol

Ann Allergy Asthma Immunol

J Allergy Clin Immunol

Expert panel report: guidelines for the diagnosis and management of asthma update on selected topics—2002

J Allergy Clin Immunol

Steroid-resistant asthma. Cellular mechanisms contributing to inadequate response to glucocorticoid therapy

J Clin Invest

Update on glucocorticoid action and resistance

J Allergy Clin Immunol

Heterogeneity of therapeutic responses in asthma

Br Med Bull

The costs of asthma

Eur Respir J

Association of asthma control with health care utilization: a prospective evaluation

Am J Respir Crit Care Med

Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease (COPD) and asthma. This official statement of the American Thoracic Society was adopted by the ATS Board of Directors, November 1986

Am Rev Respir Dis

Guidelines for fiberoptic bronchoscopy in adults

Am Rev Respir Dis

Cytokine milieu of atopic dermatitis, as compared to psoriasis, skin prevents induction of innate immune response genes

J Immunol

Asthma and lower airway disease
Corticosteroid-resistant asthma is associated with classical antimicrobial activation of airway macrophages