The Harry M. Zweig Memorial Fund for Equine Research


Airway Epithelial Cell Contributions to the Immunopathogenesis of Heaves—Preliminary Investigations

Dr. Dorothy M. Ainsworth

Heaves or recurrent airway disease is a debilitating respiratory disease of middle aged and older horses that are fed hay and stabled indoors. Horses that are afflicted with heaves have a chronic cough, accentuated breathing effort (heave), nasal discharge, and exercise intolerance. Physiologically, the disorder is characterized by excess mucus production in the lower respiratory tract, a reversible narrowing of the small airways and hyper-reactive airways. In many respects, the disorder resembles asthma in humans in that it is precipitated by inhalation of environmental dusts and molds. In horses, the condition is life-long but the frequency and severity of the episodes can be reduced by environmental alterations. Nevertheless, many horse owners are unable or unwilling to comply with husbandry recommendations causing the horses to suffer recurrences of the disease (Aviza et al., 2001). Furthermore, for the performance horse that is frequently transported in a van filled with hay bags, stabled in a show barn with poor ventilation, and ridden in an arena that is dusty, the current management and therapeutic recommendations are either not efficacious or are not able to be implemented.

For the past three years, our laboratory has focused on understanding the mechanisms involved in causing this disorder (Ainsworth et al., 2002). We are currently examining the role of the pulmonary immune cells (lymphocytes and macrophages) in the precipitation of heaves. We suspected that the immune cells of heaves-affected horses over react to normally-inhaled dusts and molds. As a result, these immune cells produce excess quantities of mediators that signal inflammatory cells (neutrophils) to migrate into and accumulate within the lung, contributing to the production of excessive airway secretions. Our preliminary work supports the hypothesis that heaves is not a typical allergic reaction like one that occurs with bee stings. Instead, heaves is more representative of an inflammatory reaction that develops with certain bacterial or fungal infections! Our findings are particularly relevant to the horse owner as programs to "hyposensitize" a heaves-affected horse by multiple injections of "allergens" are scientifically unfounded.

Since heaves does not seem to represent a simple allergic reaction, our next question is whether lung cells, other than the immune cells, are playing a role in the development of the inflammatory reaction. Recent studies in human asthmatics have suggested that the bronchial epithelium plays a key role in initiating and propagating asthma by two mechanisms. First, cytokines or protein molecules, secreted by the epithelial cells in response to inhaled allergens, signal inflammatory cells to migrate from the vasculature into the lung. Second, cytokines cause remodeling of the lung parenchyma by increasing the thickness of the airway smooth muscle and by causing airway epithelial cells to increase in number. The net effect is to reduce the effective airway diameter and to increase the work of breathing.

To date, the role of the epithelial cell in the development of heaves in the horse has not been thoroughly examined and serves as the focus of this grant. We propose to determine if the bronchial epithelium of heaves-affected horses produces excessive amounts of cytokines that would signal inflammatory cells to migrate into and remain within the respiratory tract. We would specifically measure the amounts of interleukin-6, interleukin-8 and GM-CSF when horses are asymptomatic and when they are acutely and chronically affected with heaves. Control horses would be examined simultaneously.

Our second objective in this proposal is to develop cell culture techniques that would enable us to optimize growth of epithelial cells obtained from the airways of heaves-affected and healthy horses. This technique would be used in future studies to examine the interactions of the epithelial cells ex vivo with pulmonary immune cells and with particulate matter found in the hay and straw.

Understanding the pathophysiological mechanisms of this disorder, at the cellular and molecular levels, is the first step in designing and implementing more physiological approaches to the management and prevention of the disease.

References:

Aviza GM, DM Ainsworth, SW Eicker, MA Santiago, TJ Divers and GA Perkins. Outcome of horses diagnosed with and treated for heaves. Eq. Vet. Educ. 13: 243-246, 2001.

Ainsworth DM, JA Appleton, DF Antczak, MA Santiago, G Aviza. IgG antibody responses to an inhaled antigen in horses with "heaves" (recurrent airway obstruction). Vet Immunol Immunopathol 84:169-180, 2002.