Abstract
Severe equine asthma is a chronic inflammatory condition of the lower airways similar to adult-onset asthma in humans. Exacerbations are characterized by bronchial and bronchiolar neutrophilic inflammation, mucus hypersecretion and airway constriction. In this study we analyzed the gene expression response of the bronchial epithelium within groups of asthmatic and non-asthmatic animals following exposure to a dusty hay challenge. After challenge we identified 2341 and 120 differentially expressed genes in asthmatic and non-asthmatic horses, respectively. Gene set enrichment analysis of changes in gene expression after challenge identified 587 and 171 significantly enriched gene sets in asthmatic and non-asthmatic horses, respectively. Gene sets in asthmatic animals pertained, but were not limited, to cell cycle, neutrophil migration and chemotaxis, wound healing, hemostasis, coagulation, regulation of body fluid levels, and the hedgehog pathway. Furthermore, transcription factor target enrichment analysis in the asthmatic group showed that transcription factor motifs with the highest enrichment scores for up-regulated genes belonged to the E2F transcription factor family. It is postulated that engagement of hedgehog and E2F pathways in asthmatic horses promotes dysregulated cell proliferation and abnormal epithelial repair. These fundamental lesions may prevent re-establishment of homeostasis and perpetuate inflammation.
Highlights
Severe equine asthma is a naturally occurring lung condition affecting horses that are chronically exposed to airborne environmental dust and microbial components[1]
Transcription factors assessed to date in the equine asthmatic inflammatory response include activator protein-1 (AP-1), cyclic AMP response element binding protein (CREB), CAAT/enhancer binding protein (C/ EBP), GATA-3 and nuclear factor (NF)-κB15–17
Activity of AP-1 in bronchial brushing (BB) cells and NF-κB in bronchoalveolar lavage (BAL) cells positively correlated with active disease, while CREB activity was higher in BB cells of asthmatic than control horses two months after challenge[15,16,17]
Summary
Severe equine asthma (recurrent airway obstruction, heaves) is a naturally occurring lung condition affecting horses that are chronically exposed to airborne environmental dust and microbial components[1]. Data regarding a particular dominant Th set have been equivocal in horses, and a mixed immune response with biological complexity greater than that of the Th1/Th2 paradigm is considered likely[10,11,12,13,14] Other factors such as the heterogeneity of cells and tissues assessed, degree of asthmatic exacerbation in subjects, frequency and timing of Health (APCAH), Faculty of Veterinary and Agricultural Sciences, The University of Melbourne, Victoria, 3010, www.nature.com/scientificreports/. SCGB1A1 production by the bronchial epithelium is one such specialized epithelial function lost in asthmatic horses, and indicates absence of mature club (Clara) cells, which in turn implies limited anti-inflammatory functions of airway secretions[22,23]. Activity of p65 NF-κB homodimer in BAL leukocytes, and production of certain epithelial cytokines, was altered in asthmatic horses[16,24], but changes in the airway epithelium have not been comprehensively analyzed
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