ABSTRACT
Steroid resistance in asthma has been associated with neutrophilic inflammation and severe manifestations of the disease. Macrolide add-on therapy can improve the quality of life and the exacerbation rate in refractory cases, possibly with greater effectiveness in neutrophilic phenotypes. The mechanisms leading to these beneficial effects are incompletely understood and whether macrolides potentiate the modulation of bronchial remodeling induced by inhaled corticosteroids (ICS) is unknown. The objective of this study was to determine if adding azithromycin to ICS leads to further improvement of lung function, airway inflammation and bronchial remodeling in severe asthma. The combination of azithromycin (10 mg/kg q48h PO) and inhaled fluticasone (2500 µg q12h) was compared to the sole administration of fluticasone for five months in a randomized blind trial where the lung function, airway inflammation and bronchial remodeling (histomorphometry of central and peripheral airways and endobronchial ultrasound) of horses with severe neutrophilic asthma were assessed. Although the proportional reduction of airway neutrophilia was significantly larger in the group receiving azithromycin, the lung function and the peripheral and central airway smooth muscle mass decreased similarly in both groups. Despite a better control of airway neutrophilia, azithromycin did not potentiate the other clinical effects of fluticasone.
Subject(s)
Airway Remodeling/drug effects , Anti-Bacterial Agents/therapeutic use , Asthma/veterinary , Azithromycin/therapeutic use , Horse Diseases/drug therapy , Administration, Inhalation , Animals , Anti-Bacterial Agents/pharmacology , Asthma/drug therapy , Asthma/immunology , Azithromycin/pharmacology , Bronchodilator Agents/administration & dosage , Drug Therapy, Combination , Female , Fluticasone/administration & dosage , Horse Diseases/immunology , Horses , Male , NeutrophilsABSTRACT
Severe equine asthma is characterized by airway hyperresponsiveness, neutrophilic inflammation and structural alterations of the lower airways. In asthmatic horses with neutrophilic inflammation, there is insensitivity to corticosteroids characterized by the persistence of neutrophils within the airways with therapy. We hypothesized that hypoxia or oxidative stress in the microenvironment of the lung contributes to this insensitivity of neutrophils to corticosteroids in asthmatic horses. Blood neutrophils isolated from horses with severe asthma (N = 8) and from healthy controls (N = 8) were incubated under different cell culture conditions simulating hypoxia and oxidative stress and, in the presence, or absence of dexamethasone. The pro-inflammatory gene and protein expression of neutrophils were studied. In both groups, pyocyanin-induced oxidative stress increased the mRNA expression of IL-8, IL-1ß, and TNF-α. While IL-1ß and TNF-α were downregulated by dexamethasone under these conditions, IL-8 was not. Simulated hypoxic conditions did not enhance pro-inflammatory gene expression in neutrophils from either group of horses. In conclusion, oxidative stress but not hypoxia may contribute to corticosteroid insensitivity via a selective gene regulation pathway. Equine neutrophil responses were similar in both heathy and asthmatic horses, indicating that it is not specific to asthmatic inflammation.
Subject(s)
Asthma/veterinary , Dexamethasone/pharmacology , Glucocorticoids/pharmacology , Horse Diseases/drug therapy , Neutrophils/drug effects , Animals , Asthma/drug therapy , Asthma/immunology , Cells, Cultured , Chemokines/biosynthesis , Chemokines/genetics , Female , Gene Expression Regulation/drug effects , Horse Diseases/immunology , Horses , Hypoxia/immunology , Hypoxia/metabolism , Hypoxia/veterinary , Inflammation Mediators/metabolism , Interleukin-17/pharmacology , Lipopolysaccharides/pharmacology , Male , Metabolic Networks and Pathways/drug effects , Neutrophils/metabolism , Oxidative Stress/genetics , Oxidative Stress/immunology , Pyocyanine/pharmacologyABSTRACT
Reproductive traits in livestock species are genetically controlled by the action of single genes with a major effect, commonly known as fecundity genes. One of the genes involved in controlling prolificacy is BMPR1B (FecB), a dominant autosomal gene located in chromosome 6 responsible for the fecundity and twinning rate in sheep and goat species. Markhoz goat is a valuable Iranian genetic resource endangered by extinction. Increasing the genetic variability and reproductive performances of Markhoz goat could preserve and enhance its economic value. This study was carried out to detect possible polymorphisms in BMPR1B gene in a sample of 100 Markhoz goats from Iran. DNA samples were screened by PCR-RFLP to assess the presence of the previously reported FecB mutation. Finally, the amplicons from seven goats out of the 100 samples were sequenced. The results showed that all the analyzed individuals did not carry the previously reported FecB mutant allele. However, our findings revealed two novel possible mutations in exon 8 of BMPR1B gene (775A > G and 777G > A) that need further investigations.
