Grant: Project Grant

Asthma is the most common chronic inflammatory disease of the respiratory tract worldwide, and 5-10% of patients are severely affected and poorly responsive to current medications. Among those, patients with neutrophilic lung inflammation represent a major health concern has they require high healthcare costs due to the severity of the disease and the poor response to therapy. The severity of asthma is considered to be a consequence of ongoing damage (remodeling) to the lungs. However, currently, the causes, functional consequences, and the possible reversibility of remodeling remain poorly characterized. This is primarily due to ethical considerations limiting lung biopsies in patients, particularly of the peripheral airways, due to their invasiveness. Thus, the study of airway remodeling in animal models of asthma is critical in better understanding the disease and developing effective therapy. The aim of the proposed research program is to investigate the contribution of neutrophilic inflammation to airway remodeling of the central and peripheral asthmatic airways, and their response to therapy with macrolides, a class of antibiotics that has been used to treat neutrophilic asthma, due to their anti-inflammatory properties. Horses, similarly to humans, spontaneously develop a condition (equine asthma) that has most of the clinical, functional, and remodeling features of human asthma. Using this unique animal disease, combined with cell culture, a novel tissue engineered 3D bronchus, and decellularized asthmatic and healthy airways, we will investigate the cells and the signaling pathways contributing to airway remodeling and response to therapy in the asthmatic lung. The proposed research will substantially advance knowledge of the role of neutrophils in asthma, the signaling pathways contributing to the airway remodeling in neutrophilic asthma, and the efficacy of macrolides at controlling airway neutrophilic inflammation and reversing remodeling.