Targeting pathological hyaluronan matrices

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Asthma is a chronic inflammatory disease in which the genetic background and the immune system interact with environmental factors to elicit overt manifestations of the disease. As a consequence of the chronic inflammation, lung morphology may become altered even in milder forms of the disease. Extracellular matrix (ECM) components such as hyaluronan (HA) and proteoglycans are deposited in the submucosa, and it is thought that the accumulation of these molecules compromises the biomechanical properties of the airway tissue. In the lung, ECM has traditionally been considered to be Inert scaffolding, having only a mechanical role in supporting and maintaining tissue structure. However, recent findings indicate that the role of ECM molecules is much broader than previously thought. These molecules play a role in cell-cell interactions, cellmatrix interactions, cell proliferation, cell locomotion and inflammation. Investigators are also increasingly aware that hyaluronan exhibits a variety of molecular size-dependent biologic functions. Specifically, the large polymers and very small oligomers are anti-inflammatory and anti-angiogenic, while intermediate-sized hyaluronan fragments take on pro-inflammatory and pro-anglogenic properties. Our preliminary studies support a role for HA In the pathogenesis of asthma and In inflammatory cell recruitment. Our studies also suggest a role for HA not only as a biomarker for disease activity but also as a potential therapeutic agent to modulate ainA/ay Inflammation. Thus, we hypothesize that HA is a central mediator in the organization of inflammation and remodeling in the asthmatic airway and that HA will be a biomarker for disease activity, and low molecular weight (MW) HA will inhibit inflammation and be a useful therapeutic agent in the treatment of asthma. To test this hypothesis we propose the following specific alms. Aim 1 Investigates the utility of HA as a biomarker of inflammation In the asthmatic ainway and determine correlation with disease activity, or severity. Aim 2 investigates the utility of HA as a therapeutic in the asthmatic ainway. Aim 3 Investigates the mechanisms of HA production by the airway smooth muscle cells (SMCs) and determines the functional consequences of lymphocytes binding to the HA. Together with Projects 1, 2, and 4, Project 3 plans mechanistic aims that have clear translational potential to clinical asthma care. The synergistic research and expert TPPG cores provide substantial benefit to Project 3 and assure success of the overall goals to translate fundamental discoveries into improvements for asthma patients.