Approximately 50 million people suffer from asthma and allergies of which 5 millions are under the age of 18 years. It is our central working HYPOTHESIS that JAK3 plays a central role in the pathophysiology of allergic asthma and JAK3 inhibitors may be useful to prevent asthmatic responses in vivo by inhibiting the mast cell mediator release and recruitment of eosinophils in airways. To test this hypothesis we will study the effect of the JAK3 inhibitor JANEX-1 using a well-characterized mouse model of allergic asthma. Specifically, we will examine the effect of JANEX-1 on the magnitude and outcome of antigen-induced asthmatic reactions in a well-characterized mouse model of allergic asthma. In the allergic asthma model, JANEX-1 treated mice will be examined for their antigen-induced early (airway obstruction) as well as late phase asthmatic response, bronchial hyper-responsiveness and airway inflammation. We will examine if: (i) chronic pretreatment (intra-peritoneal as well as oral) of mice with JAK3 inhibitor can prevent antigen-induced bronchial hyper-responsiveness and eosinophil recruitment. We will also examine if ongoing asthmatic reaction can be abrogated by intravenous treatment with JAK3 inhibitors. Further, since aerosolized drugs provide best treatment strategy for asthma, we will also examine the effect of aerosolized JAK3 inhibitors on allergic asthma in mice. To assess the inflammatory response, release of inflammatory mediators (e.g. IL-5, histamine, EPO, leukotriene C4) and influx of inflammatory cells viz. (basophils, eosinophils, neutrophils) will also be estimated in bronchoalveolar lavage fluids. Lung tissue obtained from JANEX-1 treated and untreated mice will be examined for cellular infiltration and pathological changes. The completion of the proposed studies may provide the foundation for novel preventive and therapeutic measures against allergic asthma.
