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. A genetic susceptibility to these diseases is suggested by the observation that many horses are housed without apparent problems in environments that can provoke airway obstruction in a RAO susceptible horse. Evidence in support of such a genetic component does exist

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.

 

 

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.

 

Many apparently normal horses develop low levels of airway inflammation when housed in the environment that causes a massive influx of neutrophils into the airways on RAO susceptible animal [41,42]. The reasons for the up-regulation of the inflammatory response following a dust challenge and the persistence of inflammation when RAO susceptible horses are returned to pasture are under active investigation. There is evidence for depletion of endogenous antioxidants in the airways of RAO susceptible animals [43,44] and for prolonged activation of NFkB, a transcription factor that initiates the production of many pro-inflammatory cytokines [22]. Activation of NFkB may be due to a positive feedback loop involving the persistent production of TNFa and IL-1b by neutrophils [45]. Inflammation also persists because apoptosis of neutrophils is delayed [46].

Because of the diffuse obstruction of the peripheral airways, horses with RAO have a mismatching of ventilation and blood flow that leads to inefficient gas exchange and hypoxemia [47]. In order to compensate for the poor gas exchange, RAO-affected horses increase their minute ventilation by increasing respiratory rate [47,48]. Tidal volume does not change. Inhaling the same tidal volume in less time requires that the horse with RAO develop a higher mean airflow rates in the face of airway obstruction [47-49]. This is why, the horse adopts the breathing pattern characteristic of heaves.

==Signalment==

==Signalment==