Friday, May 9, 2025
5/9/2025
Identifying mechanisms and reversibility of eosinophil-induced airway hyperinnervation in asthma - Asthma is characterized by excessive bronchoconstriction and a heightened sensitivity to inhaled irritants. Airway nerves control these responses. Recently, we found that eosinophils, which are a defining feature of airway inflammation in a majority of asthmatics, increased sensory nerve density in humans with asthma and in mice. Increased innervation produced exaggerated neuronally-mediated reflex bronchoconstriction. These data show that eosinophil-induced nerve remodeling has a key role in the development of excessive bronchoconstriction in asthma. The central hypothesis of this proposal is that eosinophils increase airway nerve density in asthma by releasing granule proteins that induce neurotrophins, which in turn promote nerve growth and potentiate nerve-mediated reflex bronchoconstriction. We will test this hypothesis in three aims that will 1) determine the role of eosinophil granule proteins EPX and MBP in sensory and parasympathetic nerve remodeling, neurotrophin expression and nerve-mediated reflex bronchoconstriction 2) test which neurotrophins mediate eosinophil-induced nerve remodeling and reflex bronchoconstriction and 3) determine whether airway hyperinnervation is reversed in humans with asthma by measuring airway nerves in bronchoscopic airway biopsies before and after initiation of the anti-IL5 antibody mepolizumab. Effects of eosinophil depletion will also be tested in mice with established hyperinnervation. The ultimate goals of this study are to discover new asthma mechanisms and to identify drug targets that will prevent and/or reverse effects of nerve dysfunction in asthma.
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