In Vitro Evaluation of a Novel Drug on Airway Epithelial Cells Obtained From Participants With Severe Asthma

Asthma and COPD are chronic inflammatory diseases of the airway although the precise cells and mediators involved are distinct. Both diseases are characterised by airway hyperresponsiveness (AHR) in response to exogenous stimuli such as allergens in asthma or environmental pollutants. There is currently no cure for asthma and new drugs or combinations of drugs are needed that will be of benefit to patients particularly those with more severe disease. Activation of JAK/STAT pathways may participate in the pathogenesis of asthma. STAT1 and STAT6 expression is elevated in animal models of asthma and in the lower airways of some but not all patients. STAT6 is activated by key cytokines involved in asthma such as IL-13 in primary human bronchial epithelial cells. In addition, baseline phospho-STAT1 and phospho-STAT6 levels are increased in systemic T cells from steroid naïve asthmatics and the Th2 cytokines IL-4, IL-13 and TSLP activate STAT1 and STAT6 in a number of airway cells. In animal models of allergen-induced AHR, airway inflammation including CXCL9 and CXCL10 involves STAT1. In addition, STAT6 knockout mice have no response to IL-4, do not develop Th2 cells in response to IL-4, and fail to produce IgE, bronchial hyperresponsiveness or BAL eosinophilia after allergen sensitization. The expression of CCL11, CCL17 and CCL22 also involves STAT6 in these models. Importantly, STAT1 is a critical signalling molecule involved in the production of type I IFNs (α/β), IFN-γ and for resistance to viral respiratory infections. JAK/STATs inhibitors have proved effective in clinical trials for rheumatoid arthritis and inflammatory bowel disease. Therefore, we propose to use the primary airway epithelial cell culture model grown at air:liquid interface (ALI culture) to evaluate the efficacy of a novel JAK/STAT inhibitor, VR588, against CP-690550 and fluticasone proprionate (FP) in suppressing inflammatory readouts induced by IL-13 and by TNF/IFN.