Studies of molecular pathways associated with blood neutrophil corticosteroid insensitivity in equine asthma
Equine asthma is characterized by bronchial hyperactivity, neutrophilic inflammation, and structural alterations of the airways. Asthmatic patients with neutrophilic inflammation, are insensitive to corticosteroids. The hypothesis of this study is that hypoxia and/or oxidative stress in the microenvironment of the asthmatic lungs may contribute to this insensitivity of neutrophils to corticosteroids. Horses are unique animal models naturally affected by neutrophilic asthma and share several pathophysiological features with humans. Viability, apoptosis, IL-1, TNF- and IL-8 gene expression were measured in neutrophils isolated from peripheral blood of severe asthmatic horses (N = 8) and healthy horses (N = 8) in culture conditions stimulating hypoxia and oxidative stress, in the presence or absence of corticosteroids (Dexamethasone (Dex)). IL-1 and TNF- but not IL-8 were downregulated in the presence of Dex under pyocyanin-induced oxidative stress conditions. Also, in IL-17 and LPS stimulated equine neutrophils, pro-inflammatory gene expression did not decrease after Dex administration. In hypoxemic conditions induced by CoCl2, gene expression of TNF- was significantly reduced by Dex, this was also true in conditions without hypoxia. In conclusion, oxidative stress, but not hypoxia, leads to insensitivity to corticosteroids, which presents a selective gene regulatory pathway (that of IL-8). Both groups of horses demonstrated a similar response indicating a reaction to dexamethasone and not related to asthmatic inflammation.
Asthma Corticosteroid Equine Hypoxia Neutrophil Oxidative stress