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Response of the Bronchial Epithelium to Challenge in Severe Equine Asthma

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Title: Response of the Bronchial Epithelium to Challenge in Severe Equine Asthma
Author: Tessier, Laurence
Department: Department of Pathobiology
Program: Pathobiology
Advisor: Bienzle, Dorothee
Abstract: Severe equine asthma (recurrent airway obstruction, heaves) is an inflammatory lung disease affecting horses chronically exposed to adverse environments. Genetic predisposition to the disease is reported to be heterogeneous across families, but clinical signs during exacerbation are remarkably similar. In order to identify commonly expressed genes and pathways in horses with asthma, we sequenced RNA from endobronchial biopsies collected from control and affected horses before and after an asthmatic stimulus. Differential expression analysis of the bronchial epithelium yielded 111 genes significantly different between asthmatic and non-asthmatic horses. Gene set and network analyses identified overrepresentation of upregulated genes involved in neutrophil migration and chemotaxis, immune and inflammatory responses, secretion, blood coagulation and apoptosis. Downregulated genes were overrepresented in rhythmic processes, referring to physiological rhythm. Network analysis identified MMP4, MMP1, IL8 and TLR4 as pivotal molecules, suggesting they have key roles in disease. Furthermore, in asthmatic horses, a large number of significantly upregulated genes contained E2F binding motifs, and were associated with cell cycle, neutrophilic response, hedgehog signaling, hemostasis and coagulation. These genes and motifs were not detected at similar frequencies in non-asthmatic horses. RNA-Seq was also used to identify genetic variants potentially linked to disease mechanisms. Single base mutations in parkin co-regulated (PACRG) and rotatin (RTTN) were identified as more prevalent in asthmatic compared to non-asthmatic horses, and confirmed with Sanger sequencing. PACRG and RTTN are essential proteins in motile and primary cilia development and function, befitting further investigation of cilia morphology in asthmatics. As such, cilia and microvilli were evaluated by electron microscopy, and ultrastructural abnormalities consisting of cilia of abnormal shape and size and branching microvilli of heterogeneous length were identified. These changes are hypothesized to be a consequence of chronic inflammation and also to contribute to progressive deterioration of bronchial epithelial function. Abnormal cilia are likely to reduce mucociliary clearance and hedgehog signaling, which in turn links gene expression and variants to physiological abnormalities in the bronchiolar epithelium. In summary, studies in this thesis have revealed multiple unique aspects of the bronchial epithelial response in asthmatic relative to non-asthmatic horses. The epithelial barrier is of paramount importance to modulate the host response to environmental agents, but other components of the lung not examined in this thesis also contribute to development of asthma.
Date: 2018-02-22

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