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Background  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.    Methodology/Principal Findings  Genome-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 A 2  (PLA 2 ) group X (sPLA 2 -X), an enzyme recently implicated in asthma pathogenesis.    Conclusions/Significance  This study found that TGM2, a mediator that is novel to asthma pathogenesis, is overexpressed in asthmatic airways and functions to increase sPLA 2 -X enzymatic activity. Since PLA 2  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.

Transglutaminase 2, a Novel Regulator of Eicosanoid Production in Asthma Revealed by Genome-Wide Expression Profiling of Distinct Asthma Phenotypes