Abstract
BackgroundA frequent manifestation of asthma, exercise-induced bronchoconstriction (EIB), occurs in 30–50% of asthmatics and is characterized by increased release of inflammatory eicosanoids. The objective of this study was to identify genes differentially expressed in EIB and to understand the function of these genes in the biology of asthma.Methodology/Principal FindingsGenome-wide expression profiling of airway leukocytes and epithelial cells obtained by induced sputum was conducted in two groups of subjects with asthma with and without EIB (n = 7 per group), at baseline and following exercise challenge. Based on the results of the gene expression study, additional comparisons were made with a normal control group (n = 10). Localization studies were conducted on epithelial brushings and biopsies from an additional group of asthmatics with EIB (n = 3). Genes related to epithelial repair and mast cell infiltration including β-tryptase and carboxypeptidase A3 were upregulated by exercise challenge in the asthma group with EIB. A gene novel to asthma pathogenesis, transglutaminase 2 (TGM2), was the most differentially expressed at baseline between the groups. In vivo studies confirmed the increased expression of TGM2 in airway cells and airway lining fluid, and demonstrate that TGM2 is avidly expressed in the asthmatic airway epithelium. In vitro studies using recombinant human enzymes reveal that TGM2 augments the enzymatic activity of secreted phospholipase A2 (PLA2) group X (sPLA2-X), an enzyme recently implicated in asthma pathogenesis.Conclusions/SignificanceThis study found that TGM2, a mediator that is novel to asthma pathogenesis, is overexpressed in asthmatic airways and functions to increase sPLA2-X enzymatic activity. Since PLA2 serves as the first rate-limiting step leading to eicosanoid formation, these results suggest that TGM2 may be a key initiator of the airway inflammatory cascade in asthma.
Highlights
Asthma is the most common chronic disease among young adults, the molecular basis of asthma, especially related to non-allergic stimuli remains poorly understood
We have previously demonstrated that there is a distinct pattern of airway inflammation in asthmatics with exercise-induced bronchoconstriction (EIB) that is notable for increased concentrations of inflammatory eicosanoids such as cysteinyl leukotriene (CysLT)s and disrupted lower airway epithelial cells in induced sputum [8]
Little is known about the immunological basis of indirect airway hyperresponsiveness (AHR), an aspect of asthma that is manifested by the presence of airway narrowing triggered by exercise, hypertonic aerosols, cold air and adenosine [7]
Summary
Asthma is the most common chronic disease among young adults, the molecular basis of asthma, especially related to non-allergic stimuli remains poorly understood. Crosssectional studies demonstrate that EIB occurs in a distinct group of subjects with asthma, representing about 30–50% of all asthmatics [2,3,4,5,6]. We have previously demonstrated that there is a distinct pattern of airway inflammation in asthmatics with EIB that is notable for increased concentrations of inflammatory eicosanoids such as cysteinyl leukotriene (CysLT)s and disrupted lower airway epithelial cells in induced sputum [8]. We and others have shown that these eicosanoids along with cellular products from mast cells and eosinophils have a pivotal role in the pathogenesis of EIB, causing airway narrowing and mucin release [10,11]. A frequent manifestation of asthma, exercise-induced bronchoconstriction (EIB), occurs in 30–50% of asthmatics and is characterized by increased release of inflammatory eicosanoids. The objective of this study was to identify genes differentially expressed in EIB and to understand the function of these genes in the biology of asthma
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