Increased activities of cysteine cathepsins in mouse models of asthma (151.23)

Abstract

Abstract Asthma is a severe disorder characterized by chronic inflammation of the airways and increased responsiveness to nonspecific stimuli. During an asthma attack, a number of immune cells are recruited to the lung. In addition to cytokines, these cells secrete a number of proteolytic enzymes or proteases to mediate the inflammation and airway remodeling associated with asthma. Cysteine cathepsins (CCs), a family of lysosomal proteases, have been found to be present in asthma patients, but little is known about their role in asthma pathology. In our study, we have used small molecule activity-based probes that specifically target CCs to investigate the in vivo profiles of CCs in two mouse models of asthma. The two models differ in their mechanism of initiating allergic inflammation by sensitization either in presence of the adjuvant alum (mast cell independent, Alum+) or in its absence (mast cell dependent, Alum-). In the Alum- model, we have found that the activities of CCs, especially Cathepsin S, were elevated in asthmatic lungs. Using immunostaining and flow cytometry, we have discovered that macrophage is a major cell type that produces elevated CCs in asthmatic lungs, while in the fluids of bronchoalveolar lavage, both macrophage and eosinophils are the main cell types that are associated with CC activities. We are now profiling CC activities in Alum+ model. These studies will allow us to gain a complete understanding of CC activities during asthmatic responses.