BACKGROUND: Ciclesonide, an inhaled corticosteroid administered as inactive compound with almost no binding affinity for the glucocorticoid receptor, is clinically effective in asthma being converted by airway epithelial cells into its active metabolite desisobutyryl-(des)-ciclesonide. AIM: To evaluate whether ciclesonide could directly modulate in vitro bronchial fibroblast functions being converted into des-ciclesonide by these pluripotent cells involved in the regulation of airway inflammation and remodelling. METHODS: Ciclesonide (0.09-9.0 microM) was added to a human adult lung fibroblast cell line (CCL-202), seeded in medium in the presence of the following cytokines and growth factors: (a) basic fibroblast growth factor (bFGF) for cell proliferation, measured by tritiated thymidine ([3H]TdR) incorporation; (b) tumour necrosis factor (TNF)-alpha, to stimulate intercellular adhesion molecule (ICAM)-1 expression and monocyte chemoattractant protein-1 (MCP-1) and eotaxin release, evaluated by flow cytometry and ELISA, respectively; (c) transforming growth factor (TGF)-beta1, for induction of alpha smooth muscle actin (alpha-SMA) protein expression and modification of the organization of alpha-SMA stress fibres, evaluated by Western blot analysis and fluorescence microscopy. RESULTS: The presence of ciclesonide in cell cultures induced a significant downregulation of: (a) bFGF-induced fibroblast proliferation and TNF-alpha-induced ICAM-1 expression, at the 0.3-9.0 microM concentrations (p<0.05); (b) TNF-alpha-induced MCP-1 release, at all the concentrations tested (p<0.05); (c) TNF-alpha-induced eotaxin release, at the three highest concentrations (0.9-9.0 microM) (p<0.05); (d) TGF-beta1-induced of alpha-SMA protein expression at the 0.3-3.0 microM concentrations, associated with a reduction in the organization of alpha-SMA stress fibres. CONCLUSIONS: These data show at cellular level an effective anti-inflammatory activity of ciclesonide on human lung fibroblasts and support the hypothesis that also these cells, in addition to airway epithelial cells, may be involved in converting the parental compound into its active metabolite in the airways.
BACKGROUND:Ciclesonide, an inhaled corticosteroid administered as inactive compound with almost no binding affinity for the glucocorticoid receptor, is clinically effective in asthma being converted by airway epithelial cells into its active metabolite desisobutyryl-(des)-ciclesonide. AIM: To evaluate whether ciclesonide could directly modulate in vitro bronchial fibroblast functions being converted into des-ciclesonide by these pluripotent cells involved in the regulation of airway inflammation and remodelling. METHODS:Ciclesonide (0.09-9.0 microM) was added to a human adult lung fibroblast cell line (CCL-202), seeded in medium in the presence of the following cytokines and growth factors: (a) basic fibroblast growth factor (bFGF) for cell proliferation, measured by tritiated thymidine ([3H]TdR) incorporation; (b) tumour necrosis factor (TNF)-alpha, to stimulate intercellular adhesion molecule (ICAM)-1 expression and monocyte chemoattractant protein-1 (MCP-1) and eotaxin release, evaluated by flow cytometry and ELISA, respectively; (c) transforming growth factor (TGF)-beta1, for induction of alpha smooth muscle actin (alpha-SMA) protein expression and modification of the organization of alpha-SMA stress fibres, evaluated by Western blot analysis and fluorescence microscopy. RESULTS: The presence of ciclesonide in cell cultures induced a significant downregulation of: (a) bFGF-induced fibroblast proliferation and TNF-alpha-induced ICAM-1 expression, at the 0.3-9.0 microM concentrations (p<0.05); (b) TNF-alpha-induced MCP-1 release, at all the concentrations tested (p<0.05); (c) TNF-alpha-induced eotaxin release, at the three highest concentrations (0.9-9.0 microM) (p<0.05); (d) TGF-beta1-induced of alpha-SMA protein expression at the 0.3-3.0 microM concentrations, associated with a reduction in the organization of alpha-SMA stress fibres. CONCLUSIONS: These data show at cellular level an effective anti-inflammatory activity of ciclesonide on human lung fibroblasts and support the hypothesis that also these cells, in addition to airway epithelial cells, may be involved in converting the parental compound into its active metabolite in the airways.
Authors: Marta Michalik; Katarzyna Wójcik-Pszczoła; Milena Paw; Dawid Wnuk; Paulina Koczurkiewicz; Marek Sanak; Elżbieta Pękala; Zbigniew Madeja Journal: Cell Mol Life Sci Date: 2018-08-12 Impact factor: 9.261