Mechanisms of Eosinophilic Inflammation in Human Asthma

DESCRIPTION (provided by applicant): Bronchial asthma is characterized by episodic exacerbations of airflow limitation, bronchial hyperreactivity and airway inflammation. Eosinophilic infiltration in the airways is common in asthma even in mild, stable, or newly diagnosed asthma. Studies suggest a strong correlation between airway eosinophilia and disease severity in human asthma. Our Program Project will elucidate the immunologic and cellular mechanisms responsible for persistent eosinophilic airway inflammation and the subsequent development of physiologic and pathologic abnormalities in the airways of patients with asthma; at present these mechanisms are poorly understood. The combined resources of this Asthma and Allergic Diseases Research Center (AADRC) provide a unique opportunity to conduct a coordinated set of interdisciplinary research projects focused on understanding the mechanisms of eosinophilic inflammation in human asthma. The first project will investigate post-receptor signaling pathways that control eosinophil degranulation and granule protein toxicity with a specific focus on calcium mobilization and protein kinase C (PKC) activation. The project uses biochemical, pharmacological, and electrophysiological approaches to elucidate the mechanisms of actin rearrangement and granule acidification, which are critical events in the degranulation process of human eosinophils. The second project will investigate how the eosinophil?s release of granule proteins leads to airway narrowing and bronchial hyperreactivity in patients with asthma. The project addresses the mechanisms by which eosinophil major basic protein (MBP) alters contractile responses of human airway smooth muscle by examining two cellular targets for MBP in the airways: epithelia cells and smooth muscle cells. The third project will investigate why eosinophilic airway inflammation persists in patients who do not have immunoglobulin E (IgE) antibodies to exogenous antigens, namely "intrinsic" asthma. It tests the hypothesis that enhanced immune responses to fungi in human airways and subsequent production of eosinophil-active cytokines, such as interleukin (IL)-5 and interferon (IFN)-gamma, are involved. The project also examines how eosinophil degranulation in the airways leads to exacerbation of asthma in patients. The Administrative Core will provide administrative services and support for the collaborative efforts among the projects. Finally, the Eosinophil Granule Protein Core is an essential resource that provides unique reagents and technical service to analyze eosinophilic inflammation. Altogether, these projects may elaborate the pathogenic and pathophysiologic mechanisms of human bronchial asthma and may improve the diagnosis and therapeutic interventions in the management of patients suffering form asthma.