Genome-wide profiling identifies epithelial cell genes associated with asthma and with treatment response to corticosteroids

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 104; no. 40; pp. 15858 - 15863
• Main Authors: Woodruff, Prescott G, Boushey, Homer A, Dolganov, Gregory M, Barker, Chris S, Yang, Yee Hwa, Donnelly, Samantha, Ellwanger, Almut, Sidhu, Sukhvinder S, Dao-Pick, Trang P, Pantoja, Carlos, Erle, David J, Yamamoto, Keith R, Fahy, John V
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 02.10.2007; National Acad Sciences
• Series: From the Cover
• Subjects: Administration, Inhalation; adrenal cortex hormones; Adrenal Cortex Hormones - administration & dosage; Adrenal Cortex Hormones - therapeutic use; Airway management; Allergies; Asthma; Asthma - drug therapy; Asthma - genetics; Asthma - pathology; Biological Sciences; Bronchoscopy; CD4-positive T-lymphocytes; Cell Adhesion Molecules - genetics; Cells; Chloride Channels - genetics; Clinical trials; Corticoids; Corticosteroids; Cystic fibrosis; Cytokines; Disease control; Epithelial cells; Epithelial Cells - pathology; Epithelial Cells - physiology; fibrosis; Gene expression; Gene Expression Profiling; gene expression regulation; genes; Genome, Human; Humans; hyperplasia; Hypersensitivity; inflammation; Inflammation - genetics; Inflammation - physiopathology; interleukin-13; Lungs; metaplasia; microarray technology; Oligonucleotide Array Sequence Analysis; ovalbumin; Placebos; randomized clinical trials; Reference Values; RNA; serine; Serpins - genetics; Smoking - pathology; smooth muscle; Steroids
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0707413104

Airway inflammation and epithelial remodeling are two key features of asthma. IL-13 and other cytokines produced during T helper type 2 cell-driven allergic inflammation contribute to airway epithelial goblet cell metaplasia and may alter epithelial-mesenchymal signaling, leading to increased subepithelial fibrosis or hyperplasia of smooth muscle. The beneficial effects of corticosteroids in asthma could relate to their ability to directly or indirectly decrease epithelial cell activation by inflammatory cells and cytokines. To identify markers of epithelial cell dysfunction and the effects of corticosteroids on epithelial cells in asthma, we studied airway epithelial cells collected from asthmatic subjects enrolled in a randomized controlled trial of inhaled corticosteroids, from healthy subjects and from smokers (disease control). By using gene expression microarrays, we found that chloride channel, calcium-activated, family member 1 (CLCA1), periostin, and serine peptidase inhibitor, clade B (ovalbumin), member 2 (serpinB2) were up-regulated in asthma but not in smokers. Corticosteroid treatment down-regulated expression of these three genes and markedly up-regulated expression of FK506-binding protein 51 (FKBP51). Whereas high baseline expression of CLCA1, periostin, and serpinB2 was associated with a good clinical response to corticosteroids, high expression of FKBP51 was associated with a poor response. By using airway epithelial cells in culture, we found that IL-13 increased expression of CLCA1, periostin, and serpinB2, an effect that was suppressed by corticosteroids. Corticosteroids also induced expression of FKBP51. Taken together, our findings show that airway epithelial cells in asthma have a distinct activation profile and identify direct and cell-autonomous effects of corticosteroid treatment on airway epithelial cells that relate to treatment responses and can now be the focus of specific mechanistic studies.