Asthma, a clinical syndrome affecting over 7 million children in the U.S., is characterized by acute inflammatory exacerbations punctuating a persistent disease. Airway obstruction due to allergic inflammation is largely reversible;however, the cycle of damage and repair that typifies airway wall """"""""remodeling"""""""" in chronic allergic asthma is not. Sensitivity to fungus has been linked to severe asthma that is particularly difficul to treat. Because of their ubiquitous nature, fungal spores are nearly impossible to avoid. The proposed research will use our newly developed in vivo model of fungal asthma to evaluate the effect of cyclic B cell recruitment on the peribronchial environment. Our preliminary data show a previously unrecognized contribution of B cells to an airway wall remodeling phenotype in allergic fungal asthma. Failure to understand these processes will perpetuate the physical and financial burden of this life-long disease. The objective of this proposal is to show that changes in pulmonary hyaluronic acid (HA) influence the movement and the function of activated B lymphocytes in the allergic lung and that fibrosis and smooth muscle mass is, in turn, impacted by these cells'function. Our preliminary ex vivo data show that low molecular mass (LMM) HA activates not only B cell movement but also pro-fibrotic/pro-allergy cytokine production by B cells. We hypothesize that airway wall remodeling is facilitated by sequential interactions between recruited cells, hyaluronic acid, and structural cells in the extracellular matrix of the peribronchial space, helping to facilitate the irreversible airway obstruction of chronic wound repair in allergic asthma. We propose the following specific aims to test our central hypothesis: 1. To determine the extent to which eosinophil egress initiates a LMM HA-dependent recruitment and pro-remodeling modulation of activated B cells. Using in vivo animal modeling, immuno-histochemical analysis, and laser microdissection techniques, we will test our working hypothesis that eosinophil egress to the airway lumen is a prerequisite to B cell recruitment which then function to support airway wall remodeling. 2. To characterize the recruitment mechanism and functional phenotype of activated B cells in response to LMM HA in the allergen-challenged lung. Using ex vivo and in vitro strategies, we will test our working hypothesis that LMM HA signals through CD44 for chemotaxis of activated B cells, but that when treated with LMM HA B cells produce a metabolically distinct cellular program that enables a pro-fibrotic and pro-smooth muscle through non-CD44 pathways.
The significance of the proposed research is allied with clinical practice, where therapeutic strategies for chronic asthma are urgently needed to arrest or prevent long-term airway dysfunction, particularly in the rapidly expanding population of asthmatic children. The proposed research will define the molecular mechanisms that control cellular responses to hyaluronic acid in the allergic lung after fungal exposure.
