The role of CRAC channel in asthma. (December 2015)

• Record Type: Journal Article
• Authors: Kaur, Manminder; Birrell, Mark A.; Dekkak, Bilel; Reynolds, Sophie; Wong, Sissie; De Alba, Jorge; Raemdonck, Kristof; Hall, Simon; Simpson, Karen; Begg, Malcolm; Belvisi, Maria G.; Singh, Dave
• Is Part Of: Pulmonary pharmacology & therapeutics. Volume 35(2015:Dec.)
• Page Start: 67
• Page End: 74
• Publication Date: 2015-12
• Subjects: Asthma -- Lymphocytes -- CRAC channel -- Orai channels NF-AT; ACQ asthma control questionnaire -- BAL bronchoalveolar lavage -- CRAC calcium released activated channel -- Dex dexamethasone -- ELISA enzyme linked immunosorbent assay -- FEV forced expiratory volume -- GR glucocorticoid receptor -- GSK-4601A ITK inhibitor -- HNS healthy never smoker -- ICS Inhaled corticosteroids -- IL interleukin -- ITK inducible tyrosine kinase -- Lck lymphocyte specific tyrosine kinase -- MA mild asthma -- NFAT nuclear factor activated by T cells -- SA severe asthma -- SOCE store operated calcium entry -- Synta 66 iCRAC inhibitor -- Th T helper; Respiratory organs -- Diseases -- Chemotherapy -- Periodicals; 615.7205
• DOI: 10.1016/j.pupt.2015.09.002
• Languages: English
• ISSNs: 1094-5539

Abstract

Abstract: Asthma is increasing globally and current treatments only manage a proportion of patients. There is an urgent need to develop new therapies. Lymphocytes are thought to play a central role in the pathophysiology of asthma through the production of inflammatory mediators. This is thought to be via the transcription factor NFAT which in turn can be activated through Ca 2+ release-activated Ca 2+ (CRAC) channels. The aim of this work was to investigate the role of CRAC in clinical and pre-clinical models of allergic asthma. Initial data demonstrated that the NFAT pathway is increased in stimulated lymphocytes from asthmatics. To confirm a role for the channel we showed that a selective inhibitor, Synta 66, blocked mediator production from lymphocytes. Synta 66 inhibited CD2/3/28 induced IL-2, IL-7, IL-13 & IFNΥ in a concentration-dependent manner in healthy and severe asthma donors, with over 60% inhibition observed for all cytokines. NFAT pathway was also increased in a pre-clinical asthma model. In this model we have demonstrated that CRAC played a central role in the airway inflammation and late asthmatic response (LAR). In conclusion, our data provides evidence that suggests targeting CRAC channels could be of therapeutic benefit for asthma sufferers.