Bronchial epithelial cell transcriptional responses to inhaled corticosteroids dictate severe asthmatic outcomes.

BACKGROUND: Inhaled corticosteroids (CSs) are the backbone of asthma treatment, improving quality of life, exacerbation rates, and mortality. Although effective for most, a subset of patients with asthma experience CS-resistant disease despite receiving high-dose medication. OBJECTIVE: We sought to investigate the transcriptomic response of bronchial epithelial cells (BECs) to inhaled CSs. METHODS: Independent component analysis was performed on datasets, detailing the transcriptional response of BECs to CS treatment. The expression of these CS-response components was examined in 2 patient cohorts and investigated in relation to clinical parameters. Supervised learning was used to predict BEC CS responses using peripheral blood gene expression. RESULTS: We identified a signature of CS response that was closely correlated with CS use in patients with asthma. Participants could be separated on the basis of CS-response genes into groups with high and low signature expression. Patients with low expression of CS-response genes, particularly those with a severe asthma diagnosis, showed worse lung function and quality of life. These individuals demonstrated enrichment for T-lymphocyte infiltration in endobronchial brushings. Supervised machine learning identified a 7-gene signature from peripheral blood that reliably identified patients with poor CS-response expression in BECs. CONCLUSIONS: Loss of CS transcriptional responses within bronchial epithelium was related to impaired lung function and poor quality of life, particularly in patients with severe asthma. These individuals were identified using minimally invasive blood sampling, suggesting these findings may enable earlier triage to alternative treatments.

Anti-inflammatory actions of aspirin-triggered resolvin D1 (AT-RvD1) in bronchial epithelial cells infected with Cryptococcus neoformans.

BACKGROUND: The interaction of Cryptococcus neoformans with airway epithelial cells is crucial for the establishment of cryptococcosis. Aspirin-triggered-resolvin D1 (AT-RvD1) is a lipid mediator produced during the resolution of inflammation and demonstrates anti-inflammatory and pro-resolution effects in several inflammatory experimental models including in the airways. METHOD: Here, we evaluated the effects of AT-RvD1 (1, 10 or 100 nM) on human bronchial epithelial cells (BEAS-2B) stimulated with C. neoformans (1, 10 or 100 multiplicities of infection; MOI). RESULTS: After 24 h, C. neoformans (all MOI) demonstrated no cytotoxic effects and increased IL-8 production on BEAS-2B cells when compared to controls. In addition, C. neoformans (MOI 100) increased the concentration of IL-6, but not of IL-10. AT-RvD1 (100 nM) significantly reduced the concentration of IL-8 and IL-6 and increased IL-10 production in C. neoformans-stimulated BEAS-2B cells. C. neoformans increased the phosphorylation of NF-κB and ERK1/2, and ALX/FPR2 expression. AT-RvD1 reduced the activation of NF-kB without altering the ERK1/2 and ALX/FPR2 expression. The anti-inflammatory effects of AT-RvD1 were dependent on the ALX/FPR2, once its antagonist (BOC2) reversed its anti-inflammatory effects. No alteration on the fungal burden as well as interactions with BEAS-2B cells was observed by AT-RvD1. CONCLUSION: AT-RvD1 demonstrated significant anti-inflammatory effects in bronchial epithelial cells infected with C. neoformans without affecting the development of C. neoformans infection in the airways. TRIAL REGISTRATION: Not applicable.

AT-RvD1 modulates CCL-2 and CXCL-8 production and NF-κB, STAT-6, SOCS1, and SOCS3 expression on bronchial epithelial cells stimulated with IL-4.

Bronchial epithelial cells represent the first line of defense against microorganisms and allergens in the airways and play an important role in chronic inflammatory processes such as asthma. In an experimental model, both RvD1 and AT-RvD1, lipid mediators of inflammation resolution, ameliorated some of the most important phenotypes of experimental asthma. Here, we extend these results and demonstrate the effect of AT-RvD1 on bronchial epithelial cells (BEAS-2B) stimulated with IL-4. AT-RvD1 (100 nM) decreased both CCL2 and CXCL-8 production, in part by decreasing STAT6 and NF-κB pathways. Furthermore, the effects of AT-RvD1 were ALX/FRP2 receptor dependent, as the antagonist of this receptor (BOC1) reversed the inhibition of these chemokines by AT-RvD1. In addition, AT-RvD1 decreased SOCS1 and increased SOCS3 expression, which play important roles in Th1 and Th17 modulation, respectively. In conclusion, AT-RvD1 demonstrated significant effects on the IL-4-induced activation of bronchial epithelial cells and consequently the potential to modulate neutrophilic and eosinophilic airway inflammation in asthma. Taken together, these findings identify AT-RvD1 as a potential proresolving therapeutic agent for allergic responses in the airways.