Changes

==Pathogenesis==

==Pathogenesis==

Organic dusts contain a variety of components that can initiate lung inflammation. These include specific allergens, endotoxin, components of molds such as beta-glucan, and small particulates. Elevated levels of specific IgE in bronchoalveolar lavage fluid (BALF) [8] favor the hypothesis that RAO is initiated by an allergic response to thermophilic molds and actinomycetes such as Faeni rectivirgula. A similar increase in specific IgE could not be documented in horses with SPAOD [9]. More recent studies examining the cytokine responses in both RAO and SPAOD lean toward a TH2 (allergic) immune response [10]. However, it has proved impossible to induce the heaves syndrome simply by administration of molds to susceptible horses [11-13]. Hay and stable dust contains endotoxin [7] and it is known from work in other species that administration of endotoxin into the airways can also induce many of the changes typical of RAO such as neutrophilic inflammation and mucus hypersecretion [14]. Small particles and fibers landing on the surface of the epithelium also can initiate the release of pro-inflammatory cytokines such as IL-8 [15,16]. Because organic dusts contain such a mixture of materials, RAO and SPAOD probably are initiated by several of these factors acting in concert.

When a horse with a history of RAO is moved from pasture to a stable, the hay it is fed and the straw it is bedded on harbour organic dusts. These dusts contain components which are capable of causing inflammation of the lungs, such as specific allergens, endotoxin, moulds and small particulate matter¹. Although small particles and endotoxin are known to cause pulmonary inflammation, there is evidence to suggest that there is an allergic component to recurrent airway obstruction. For example, bronchoalveolar lavage fluid in RAO has been shown to have increased levels of IgE specific for various moulds^haliwell,  and the cytokine response appaears to be skewed towards Th2^lavoi: both of these facts are suggestive of an allergic mechanism.

Pathophysiology

Pathophysiology

When a horse with a history of RAO is moved from pasture to a stable where it is fed hay, airway inflammation develops [18,19]. Under the influence of IL-8 [20,21] perhaps leukotriene B4, and ICAM-1 [22], neutrophils accumulate in the lung and invade the airway lumen within six to eight hours [23]. Concurrently, airway obstruction develops. This obstruction is a result of bronchospasm, mucus accumulation, and inflammatory changes in the wall of the airway [1]. Inflammatory mediators acting on cholinergic nerves and airway smooth muscle are responsible for bronchospasm [24-27]. Mucus accumulation is due to augmented mucus production and increased mucus viscoelasticity which impairs mucus clearance [28]. Changes in glycosylation of mucus may contribute to its reduced clearability [29]. Inflammatory changes in the airway wall occur both acutely (edema) and chronically (airway wall remodeling). Airway wall remodeling, including mucus metaplasia, smooth muscle hypertrophy, peribronchial fibrosis, and peribronchial inflammation, is responsible for the chronic, intractable development of airway obstruction in RAO [30,31]. This remodeling likely is a result of the repeated bouts of airway inflammation and the accompanying release of proteases [32,33] and other mediators that occur in the RAO-susceptible animal.

W where it is fed hay, airway inflammation develops [18,19]. Under the influence of IL-8 [20,21] perhaps leukotriene B4, and ICAM-1 [22], neutrophils accumulate in the lung and invade the airway lumen within six to eight hours [23]. Concurrently, airway obstruction develops. This obstruction is a result of bronchospasm, mucus accumulation, and inflammatory changes in the wall of the airway [1]. Inflammatory mediators acting on cholinergic nerves and airway smooth muscle are responsible for bronchospasm [24-27]. Mucus accumulation is due to augmented mucus production and increased mucus viscoelasticity which impairs mucus clearance [28]. Changes in glycosylation of mucus may contribute to its reduced clearability [29]. Inflammatory changes in the airway wall occur both acutely (edema) and chronically (airway wall remodeling). Airway wall remodeling, including mucus metaplasia, smooth muscle hypertrophy, peribronchial fibrosis, and peribronchial inflammation, is responsible for the chronic, intractable development of airway obstruction in RAO [30,31]. This remodeling likely is a result of the repeated bouts of airway inflammation and the accompanying release of proteases [32,33] and other mediators that occur in the RAO-susceptible animal.

One of the characteristic features of horses with RAO is increased non-specific airway hyperresponsiveness [34,35]. This means that airways of RAO-affected horses narrow in an exaggerated fashion in response to a wide variety of stimuli including neurotransmitters [36], inflammatory mediators such as histamine [34,35,37], and non-specific stimuli such as citric acid [36]. The airway hyperresponsiveness is most pronounced during acute exacerbations of RAO when inflammation is most severe and hyperresponsiveness wanes when animals are out at pasture [34,36] and inflammation is less severe. Even quite brief exposure of a RAO-susceptible horse to a stable environment can induce hyperresponsiveness that persists for several days [38]. The causes of the hyperresponsiveness include airway wall thickening, smooth muscle hypertrophy, a reduction in some of the inhibitory mechanisms that limit smooth muscle contraction [39,40] and actions of inflammatory mediators on cholinergic nerves and smooth muscle to facilitate smooth muscle contraction [25,26]. Clinically, airway hyperresponsiveness is important because it means that RAO-susceptible horses are prone to develop bronchospasm in response to levels of stimuli that would not affect a normal horse. Reducing the level of airway inflammation best controls hyperresponsiveness.

One of the characteristic features of horses with RAO is increased non-specific airway hyperresponsiveness [34,35]. This means that airways of RAO-affected horses narrow in an exaggerated fashion in response to a wide variety of stimuli including neurotransmitters [36], inflammatory mediators such as histamine [34,35,37], and non-specific stimuli such as citric acid [36]. The airway hyperresponsiveness is most pronounced during acute exacerbations of RAO when inflammation is most severe and hyperresponsiveness wanes when animals are out at pasture [34,36] and inflammation is less severe. Even quite brief exposure of a RAO-susceptible horse to a stable environment can induce hyperresponsiveness that persists for several days [38]. The causes of the hyperresponsiveness include airway wall thickening, smooth muscle hypertrophy, a reduction in some of the inhibitory mechanisms that limit smooth muscle contraction [39,40] and actions of inflammatory mediators on cholinergic nerves and smooth muscle to facilitate smooth muscle contraction [25,26]. Clinically, airway hyperresponsiveness is important because it means that RAO-susceptible horses are prone to develop bronchospasm in response to levels of stimuli that would not affect a normal horse. Reducing the level of airway inflammation best controls hyperresponsiveness.