The Importance of the p38 MAP Kinase Signaling Pa

National Jewish Health, Denver CO

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Abstract

DESCRIPTION (provided by applicant): Asthma is a polyetiologic disease with a complex pathogenesis. Atopy predisposes patients to developing asthma, and a Th2-type immune response plays a dominant role in the pathogenesis of asthma. However, natural asthma exacerbations are frequently triggered by upper respiratory infections, and physical, environmental and emotional stress. Some of the foregoing asthma triggers are likely to stimulate a non-Th2 type immune response and thereby, cause asthma exacerbation. The exact mechanism of asthma exacerbation induced with these diverse triggers is unknown. The main objective of this proposal is to identify a common signaling mechanism that links allergens (Th2 trigger), viral (Th1 trigger) and bacterial (innate trigger) infections-induced asthma exacerbations. Our central hypothesis is that the p38-MK2 signaling pathway links the innate and Th1 immunity to allergic inflammation and thereby, plays an important role in asthma exacerbation. In order to test this hypothesis we will study the role of the p38 MAP kinase and its downstream effector MK2 in induced asthma in a mouse model of multiple allergic sensitivity and chronic exposure. The activation and the role of p38 and MK2 will be examined following challenge of sensitized animals with allergens, virus and bacterial peptidoglycans (TLR2 ligand). The importance of p38 will be examined by pharmacological inhibition as well as by overexpression of a dominant negative mutant. We will examine MK2 knockout mice to establish its biological relevance in asthma. Finally, we will examine the activation of p38 and MK2 in biopsy samples from patients with increasing asthma severity and from control subjects. Our preliminary results suggest that both p38 and MK2 play an essential role in airway inflammation, mucus production, airway hyperreactivity and airway remodeling. Therapeutic interventions targeting the p38-MK2 pathway are likely to prevent asthma exacerbations induced with diverse triggers.