Cytokines and aeroallergens in the pathogenesis of summer-pasture associated obstructive pulmonary disease: effects on endothelin production, neutrophil activation and chemotaxis

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Summer pasture-associated obstructive pulmonary disease (SPAOPD), a naturally occurring airway disease of horses, is characterized by clinical exacerbation associated with exposure to pasture environment during the summer. Aeroallergens are believed to trigger exacerbation of SPAOPD, cytokines are likely associated with the anamnestic response to aeroallergens, and endothelin (ET)-1 is a potential mediator of airway obstruction. The goal of this dissertation was to describe and explore the interaction of aeroallergens triggering inflammation and T lymphocytes cytokine profile with the recruitment and activation of neutrophils and synthesis of ET-1 by mononuclear leukocytes and airway epithelial cells. The temporal pattern of clinical exacerbation was associated with hot and humid conditions and with increases in grass pollen and mold spore counts. Circulating concentrations of ET-1 were increased during clinical exacerbation of SPAOPD compared with remission and controls. Gene expression of ET-1 and cytokines, interleukin (IL)-8 and IL-4, but not interferon (IFN)-γ, tended to be greater in lungs of SPAOPD-affected than non-affected horses. The immunoreactive ET-1 distribution tended to be greater in airway tissues of affected horses. The putative aeroallergens, grass pollen & mold spores, and ET-1 induced neutrophil activation and chemotaxis in vitro. Putative aeroallergens induced IL-4 and IFN-γ expression and up-regulation of ET-1 release in mononuclear leukocytes. Cultures of airway epithelial cells were established under air-liquid interface and microgravity conditions and evaluated for differentiation. Cytokines IL-4 and tumor necrosis factor (TNF)-α induced up-regulation and directional (basolateral) release of ET-1 by differentiated airway epithelial cells, grown under air-liquid interface.