The role of CRAC channel in asthma.
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.
University of Manchester, Institute of Inflammation and Repair, University Hospital of South Manchester Foundation Trust, Southmoor Road, Manchester, M23 9LT, UK. Electronic address: manminder.kaur@manchester.ac.uk.
Manminder
M
Kaur
Respiratory Pharmacology Group, Pharmacology and Toxicology Section, NHLI, Sir Alexander Fleming Building (SAF), South Kensington Campus, Exhibition Road, Imperial College London, London SW7 2AZ, UK; MRC-Asthma UK Centre in Allergic Mechanisms of Asthma, GSK Medicines Research Centre, Stevenage, UK.
Mark A
MA
Birrell
Respiratory Pharmacology Group, Pharmacology and Toxicology Section, NHLI, Sir Alexander Fleming Building (SAF), South Kensington Campus, Exhibition Road, Imperial College London, London SW7 2AZ, UK.
Bilel
B
Dekkak
University of Manchester, Institute of Inflammation and Repair, University Hospital of South Manchester Foundation Trust, Southmoor Road, Manchester, M23 9LT, UK.
Sophie
S
Reynolds
Respiratory Pharmacology Group, Pharmacology and Toxicology Section, NHLI, Sir Alexander Fleming Building (SAF), South Kensington Campus, Exhibition Road, Imperial College London, London SW7 2AZ, UK.
Sissie
S
Wong
Respiratory Pharmacology Group, Pharmacology and Toxicology Section, NHLI, Sir Alexander Fleming Building (SAF), South Kensington Campus, Exhibition Road, Imperial College London, London SW7 2AZ, UK.
Jorge
J
De Alba
Respiratory Pharmacology Group, Pharmacology and Toxicology Section, NHLI, Sir Alexander Fleming Building (SAF), South Kensington Campus, Exhibition Road, Imperial College London, London SW7 2AZ, UK.
Kristof
K
Raemdonck
Refractory Respiratory Inflammation DPU, Respiratory TAU, GSK Medicines Research Centre, Stevenage, UK.
Simon
S
Hall
Refractory Respiratory Inflammation DPU, Respiratory TAU, GSK Medicines Research Centre, Stevenage, UK.
Karen
K
Simpson
Refractory Respiratory Inflammation DPU, Respiratory TAU, GSK Medicines Research Centre, Stevenage, UK.
Malcolm
M
Begg
Respiratory Pharmacology Group, Pharmacology and Toxicology Section, NHLI, Sir Alexander Fleming Building (SAF), South Kensington Campus, Exhibition Road, Imperial College London, London SW7 2AZ, UK; MRC-Asthma UK Centre in Allergic Mechanisms of Asthma, GSK Medicines Research Centre, Stevenage, UK.
Maria G
MG
Belvisi
University of Manchester, Institute of Inflammation and Repair, University Hospital of South Manchester Foundation Trust, Southmoor Road, Manchester, M23 9LT, UK.
Dave
D
Singh
D000328:Adult; D000485:Allergens / Q000633:toxicity; D000818:Animals; D001249:Asthma / Q000378:metabolism* / Q000473:pathology; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D015220:Calcium Channels / Q000187:drug effects / Q000378:metabolism*; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D008168:Lung / Q000473:pathology; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D050778:NFATC Transcription Factors / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D051381:Rats
D000485:Allergens; D015220:Calcium Channels; D016207:Cytokines; D050778:NFATC Transcription Factors
Asthma; CRAC channel; Lymphocytes; Orai channels NF-AT