fluticasone and Pulmonary-Fibrosis

T-helper type 2 (Th2) inflammation, mediated by IL-4, IL-5, and IL-13, is considered the central molecular mechanism underlying asthma, and Th2 cytokines are emerging therapeutic targets. However, clinical studies increasingly suggest that asthma is heterogeneous.. To determine whether this clinical heterogeneity reflects heterogeneity in underlying molecular mechanisms related to Th2 inflammation.. Using microarray and polymerase chain reaction analyses of airway epithelial brushings from 42 patients with mild-to-moderate asthma and 28 healthy control subjects, we classified subjects with asthma based on high or low expression of IL-13-inducible genes. We then validated this classification and investigated its clinical implications through analyses of cytokine expression in bronchial biopsies, markers of inflammation and remodeling, responsiveness to inhaled corticosteroids, and reproducibility on repeat examination.. Gene expression analyses identified two evenly sized and distinct subgroups, "Th2-high" and "Th2-low" asthma (the latter indistinguishable from control subjects). These subgroups differed significantly in expression of IL-5 and IL-13 in bronchial biopsies and in airway hyperresponsiveness, serum IgE, blood and airway eosinophilia, subepithelial fibrosis, and airway mucin gene expression (all P < 0.03). The lung function improvements expected with inhaled corticosteroids were restricted to Th2-high asthma, and Th2 markers were reproducible on repeat evaluation.. Asthma can be divided into at least two distinct molecular phenotypes defined by degree of Th2 inflammation. Th2 cytokines are likely to be a relevant therapeutic target in only a subset of patients with asthma. Furthermore, current models do not adequately explain non-Th2-driven asthma, which represents a significant proportion of patients and responds poorly to current therapies.

Topics: Administration, Inhalation; Adult; Androstadienes; Asthma; Biomarkers; Bronchi; Bronchodilator Agents; Female; Fluticasone; Genetic Heterogeneity; Humans; Inflammation; Macrophages, Alveolar; Male; Mucins; Phenotype; Pulmonary Fibrosis; Respiratory Mucosa; Th2 Cells; Treatment Outcome

Inhaled corticosteroids are the most effective treatment currently available for asthma, but their beneficial effect against airway remodeling is limited. The tyrosine kinase inhibitor nilotinib has inhibitory activity against c-kit and the platelet-derived growth factor receptor. We compared the effects of fluticasone and nilotinib on airway remodeling in a chronic asthma model. We also examined whether co-treatment with nilotinib and fluticasone had any synergistic effect in preventing airway remodeling.. We developed a mouse model of airway remodeling, including smooth muscle thickening, in which ovalbumin (OVA)-sensitized female BALB/c-mice were repeatedly exposed to intranasal OVA administration twice per week for 3 months. Mice were treated with fluticasone and/or nilotinib intranasally during the OVA challenge.. Mice chronically exposed to OVA developed eosinophilic airway inflammation and showed features of airway remodeling, including thickening of the peribronchial smooth muscle layer. Both fluticasone and nilotinib attenuated airway smooth muscle thickening. However, only nilotinib suppressed fibrotic changes, demonstrating inhibition of collagen deposition. Fluticasone reduced pro-inflammatory cells, such as eosinophils, and several cytokines, such as interleukin 4 (IL-4), IL-5, and IL-13, induced by repeated OVA challenges. On the other hand, nilotinib reduced transforming growth factor β1 levels in bronchoalveolar lavage fluid and inhibited fibroblast proliferation significantly.. These results suggest that fluticasone and nilotinib suppressed airway remodeling in this chronic asthma model through anti-inflammatory and anti-fibrotic pathways, respectively.

Topics: Administration, Intranasal; Airway Remodeling; Animals; Anti-Inflammatory Agents; Asthma; Bronchodilator Agents; Cell Line; Cell Proliferation; Chronic Disease; Collagen; Cytokines; Disease Models, Animal; Drug Therapy, Combination; Female; Fluticasone; Inflammation Mediators; Lung; Mice, Inbred BALB C; Muscle, Smooth; Ovalbumin; Protein Kinase Inhibitors; Pulmonary Fibrosis; Pyrimidines; Transforming Growth Factor beta1