Ligand-Receptor Segregation and Airway Remodeling

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DESCRIPTION (provided by applicant): Asthma is a heterogeneous disease of the airways characterized by chronic inflammation, airway remodeling, goblet cell metaplasia/hyperplasia, increased mucus secretion and bronchial hyperresponsiveness. The airway epithelium functions primarily as a barrier, preventing access of inhaled particulate matter, viruses, and pollutants to the lung. The polarized nature of an epithelium is such that the tight junctions function to separate the apical membrane and its components from the basolateral membrane and its components. The importance of this barrier is highlighted by the novel observation provided by our preliminary data that explains how human airway epithelia can constitutively express both a mitogenic ligand (heregulin-alpha) and its receptors (erbB) while simultaneously maintaining a low rate of cellular proliferation. Immunolocalization of erbB receptors and heregulin-alpha suggests that heregulin-alpha localizes to the apical compartment and erbB receptors localize to the basolateral membrane. Epithelial injury results in activation of the receptors. This paradigm serves as a powerful system able to be activated the instant epithelial integrity is compromised. Thus, our overarching hypothesis is that alteration of airway epithelial integrity allows basolateral access of heregulin-alpha and other factors present in asthmatic airway surface liquid (ASL) and that this may play an important role in the pathogenesis of asthma. We propose to investigate three specific aims: 1. Do airway epithelia segregate ligand from receptor? 2. Is the airway epithelia barrier disrupted to allow ligand: receptor interaction by non-mechanical injuries? We will investigate two main hypotheses. 3. Is airway epithelial remodeling in asthma a consequence of altered ligand: receptor segregation? Our preliminary data suggests that disruption of the airway epithelial barrier results in a heregulin-alpha-mediated epithelial hyperplasia and hypertrophy, two hallmarks of airway remodeling in asthma. We hypothesize that in the asthmatic airways, alterations in the epithelial barrier play a central role in airway epithelial remodeling.