Eosinophils are rare white blood cells in healthy individuals;however, they accumulate in larger numbers in a spectrum of disorders ranging from allergic diseases and asthma, parasitic infections, and cancer. A pathogenic role for eosinophils has been established in many of these disorders. Our long-term goal is to understand the mechanisms of eosinophilia with the ultimate aim of changing the outcome of eosinophil-mediated diseases. Our recent studies have focused on eosinophil viability. Notably, we have demonstrated that eosinophils respond to acidic pH by alterations in viability/cell death pathway. Importantly, the microenvironment of allergic airway in patients with asthma is acidic. In this grant application we propose to focus on mouse models of allergic airway inflammation, in which airway pH has not been measured. We believe it is critical to establish and validate novel methods that will measure the airway pH in allergen-challenged mice, as mouse models will enable important mechanistic studies, establishment of causality and therapeutic proof-of- principle for studies in the role of airway pH in eosinophilic inflammation. The central hypothesis of this application is that airway pH has a role in pathophysiology of eosinophilic airway inflammation. Our preliminary data suggest that acidic pH affects eosinophil viability. Our preliminary data also demonstrates that acidic pH leads to increased cAMP accumulation in eosinophils in a TDAG8- dependent manner. In the first aim, we will test the hypothesis that acidic pH inhibits eosinophil apoptosis and that this is mediated by TDAG8 and cAMP. Previous studies have shown that airway pH is acidic during exacerbations of asthma in patients. However, similar measurements have not been performed in allergen-challenged mice. Furthermore, the effect of modulating airway pH on outcomes of allergic airway inflammation has not been determined. Thus, the second aim will test the hypothesis that the milieu of allergic airway inflammation is acidic and affects survival of eosinophils in the bronchoalveolar space. While we focus on the effect of pH on eosinophils, development of methods for measurement of airway pH in allergic airway inflammation will enable future studies aimed at determining the effect of pH on other asthma-related phenotypes, such as ciliary beating, mucus viscosity, cough reflex, and bronchoconstriction. Experiments in this application will dissect critical properties of proton-mediated effects in eosinophils. It is hoped that our studies will provide critical preliminary data for future translational and clinical studies aimed at eosinophilic airway inflammation and asthma.
While eosinophils are a rare type of white blood cells in healthy individuals, they accumulate in large numbers in a spectrum of eosinophil-mediated diseases, including asthma, leading to significant morbidity and mortality. This grant application will research the role of acidic environment, that is present in the airways of patients with asthma, on eosinophil viability and function, and ultimately disease outcomes.
|Kano, Gen; Almanan, Maha; Bochner, Bruce S et al. (2013) Mechanism of Siglec-8-mediated cell death in IL-5-activated eosinophils: role for reactive oxygen species-enhanced MEK/ERK activation. J Allergy Clin Immunol 132:437-45|