Although corticosteroids are very efficient in managing asthma and other inflammatory diseases, a small percentage of patients affected by “severe asthma” fail to respond even to high doses of oral glucocorticoids. It is therefore important to try to understand the potential mechanisms behind this insensitivity to corticosteroid therapy in order to be able to effectively control asthma in this patient subset. We have decided to focus on one particular channel called K[subscript Ca]3.1, a calcium-activated potassium channel. First, emerging evidence in the literature to date has strongly supported a significant role for K[subscript Ca]3.1 channel in the pathophysiology of asthma. K[subscript Ca]3.1 channel is expressed by several inflammatory and structural airway cells including mast cells and human bronchial smooth muscle (HBSM). Therefore these channels might serve as new targets for the treatment of lung diseases. Here we established a cellular model of corticosteroid insensitivity consisting of primary HBSM cells exposed to two cytokines TNF-α and IFN-γ. Under these conditions, HBSMC exhibit a marked production of different pro-asthmatic chemokines like CCL5, CX3CL1, CCL11 and CXCL10 that are completely resistant to corticosteroid treatment. In this model, we found that although K[subscript Ca]3.1 channel expression did not change between healthy control, asthmatic and COPD subjects, K[subscript Ca]3.1 channel blockers (ICA-17043 and TRAM-34) were able to inhibit the production of corticosteroid-resistant chemokines either directly via the suppression of gene expression or indirectly via the restoration of the anti-inflammatory action of fluticasone. We also found that K[subscript Ca]3.1 channel blockers restored cell sensitivity to corticosteroid in cytokine-treated HBSMC by re-establishing the transactivation function of fluticasone via the prevention of dephosphorylation of Glucocorticoid Receptors (GRα) at Ser[superscript 211] and induction of anti-inflammatory genes such as Glucocorticoid-induced leucine zipper (GILZ). The likely mechanism of this restoration of corticosteroid sensitivity by K[subscript Ca]3.1 channel blockers is via the inhibition of protein phosphatase 5 (PP5) expression found to be up-regulated in steroid resistant conditions.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:631496 |
| Date | January 2014 |
| Creators | Chachi, Latifa |
| Contributors | Amrani, Yassine |
| Publisher | University of Leicester |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://hdl.handle.net/2381/29242 |
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