Advisor

Swiderski, Cyprianna E.

Committee Member

Burgess, Shane C.

Committee Member

Perkins, Andy D.

Other Advisors or Committee Members

Nanduri, Bindu||McCarthy, Fiona M.

Date of Degree

1-1-2015

Document Type

Dissertation - Open Access

Degree Name

Doctor of Philosophy

College

College of Veterinary Medicine

Abstract

Asthma is a chronic respiratory disease characterized by reversible airway obstruction, persistent airway hyperresponsiveness, chronic airway inflammation, and chronic airway remodeling. Most adult asthmatics have neutrophilic airway inflammation that correlates to increasing disease severity, and fail to respond to corticosteroid therapies that mitigate other asthma endotypes. Accordingly, there is a need to investigate the molecular mechanisms responsible for neutrophilic asthma. Pasture heaves, a respiratory disease affecting horses housed on pasture in conditions of high heat and humidity, shares the aforementioned characteristics of human asthma, including neutrophilic inflammation. The cause is undetermined, but genetic propensities for reactivity to seasonally inhaled, pasture-associated, aeroallergens are presumed. Complexities of diseases like asthma and pasture heaves, that include temporal interactions between environmental and genetic factors, lend themselves to exploration using -omics technologies. An emergent paradigm in disease pathogenesis views disease as the result of imbalances in a biological system of thousands of proteins that maintain eukaryotic homeostasis. Consistent with this paradigm, this dissertation describes systematic efforts to identify groups of proteins in the bronchoalveolar lavage fluids of horses with pasture heaves that are altered in a manner that influences neutrophilic airway inflammation, and are similarly changed in human asthma. This is the first use of -omics technologies to investigate pasture heaves. This was accomplished first by improving functional annotation of the equine genome by providing functional annotation for an equine oligoarray, thereby facilitating future functional modeling of equine gene products. Next, through comparative modeling of protein functions in normal bronchoalveolar lavage fluid (BALF) proteomes from horse, human, and mouse, we demonstrated conservation of protein functions in lung fluids across these species. Finally, comparative modeling of pasture heaves-affected and non-diseased BALF proteomes demonstrated that proteins in diseased BALF favor airway neutrophilic inflammation by increasing neutrophil migration, chemotaxis, adhesion, detachment, transmigration, and degranulation, while reducing activation, cell spreading, infiltration, phagocytosis, respiratory burst, apoptosis, and clearance. Collectively, these molecular events contribute to airway neutrophilic inflammation in pasture heaves, and are conserved in human asthma. This method further validates pasture heaves as a robust model for human neutrophilic asthma, and highlights proteins of potential clinical and therapeutic relevance.

URI

https://hdl.handle.net/11668/18166

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