Exposure to cockroach allergen is a strong risk factor for developing asthma. Asthma has been associated with allergen-induced airway epithelial damage and heightened oxidant stress. In this study, we investigated cockroach allergen-induced oxidative stress in airway epithelium and its underlying mechanisms. We found that cockroach extract (CRE) could induce reactive oxygen species (ROS) production, particularly mitochondrial-derived ROS, in human bronchial epithelial cells. We then used the RT Profiler PCR array and identified that cyclooxygenase-2 (COX-2) was the most significantly upregulated gene related to CRE-induced oxidative stress. miR-155, predicted to target COX-2, was increased in CRE-treated human bronchial epithelial cells, and was showed to regulate COX-2 expression. Moreover, miR-155 can bind COX-2, induce COX-2 reporter activity, and maintain mRNA stability. Furthermore, CRE-treated miR-155 mice showed reduced levels of ROS and COX-2 expression in lung tissues and PGE in bronchoalveolar lavage fluid compared with wild-type mice. These miR-155 mice also showed reduced lung inflammation and Th2/Th17 cytokines. In contrast, when miR-155 mice were transfected with adeno-associated virus carrying miR-155, the phenotypic changes in CRE-treated miR-155 mice were remarkably reversed, including ROS, COX-2 expression, lung inflammation, and Th2/Th17 cytokines. Importantly, plasma miR-155 levels were elevated in severe asthmatics when compared with nonasthmatics or mild-to-moderate asthmatics. These increased plasma miR-155 levels were also observed in asthmatics with cockroach allergy compared with those without cockroach allergy. Collectively, these findings suggest that COX-2 is a major gene related to cockroach allergen-induced oxidative stress and highlight a novel role of miR-155 in regulating the ROS-COX-2 axis in asthma.
BackgroundMicroRNAs (miRNAs) are emerging as central regulators of inflammation, but their role in asthma and airway epithelial cells is not well studied. Glucocorticoids are the cornerstone of therapy in asthma and other inflammatory disease, yet their mechanisms of action are not completely elucidated, and it is not clear whether miRNAs modulate their effects.ObjectiveWe aimed to identify miRNAs that regulate cytokine and chemokine expression in airway epithelial cells and whether these miRNAs are subject to the effects of glucocorticoids.Methods and resultsMicroRNAomic analyses of immortalized, normal human bronchial epithelial cells identified 7 miRNAs that were altered by inflammatory cytokine treatment and 22 that were regulated by glucocorticoids (n = 3 for each treatment condition). MiR-146a emerged as a central candidate, whose expression was induced by TNF-α and repressed by glucocorticoids. Its role as a candidate in asthmatic inflammation was supported by expression profiling in human asthmatics, which showed that plasma miR-146a expression was elevated in asthma and associated with measures related to worse asthma outcomes, including elevated blood eosinophil counts, higher asthma control questionnaire scores, and need for higher doses of inhaled glucocorticoids. However, transfection of miR-146a in A549 cells treated with TNF-α +/- glucocorticoids produced an anti-inflammatory effect and increased efficacy of glucocorticoids.ConclusionsWe propose a model whereby miR-146a is induced by inflammatory conditions as a feedback mechanism to limit inflammation. Exogenous administration of miR-146a augmented the effects of glucocorticoids and could be a novel therapeutic strategy to enhance efficacy of these medications.
Transmission success for helminths with free-living stages depends on the ability of eggs and larvae to develop and survive once in the environment. While environmental conditions are often suggested to influence egg phenology and hatching rate, immunity against parasite eggs might also play a role. We examined this hypothesis using the gastrointestinal helminths Trichostrongylus retortaeformis and Graphidium strigosum, two common infections of the European rabbit. Changes in egg hatching rate and volume were examined in relation to specific antibodies in the serum and bound to eggshells, using eggs shed in host faeces over a 15-week period. Hatching rate was consistently higher for T. retortaeformis than G. strigosum and no changes were observed between weeks. Egg volume increased for G. strigosum but decreased for T. retortaeformis. We did find evidence of egg-specific antibody responses and fewer antibodies were bound to eggs of T. retortaeformis compared to G. strigosum. Little to no association was found between antibodies and hatchability, or volume, for both helminths. We suggest that host antibodies play a relatively minor role in the egg hatching rate of these gastrointestinal helminths.
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