A unifying muco-obstructive paradigm for bronchiectasis

About This Grant

ABSTRACT Bronchiectasis (BE) is a pulmonary disease classically defined by airways dilation/ectasia on CT scans with associated clinic features that include chronic sputum production, intermittent exacerbations, and loss of lung function. BE is associated with a number of monogenetic diseases, e.g., CF, but is most prevalent in an “idiopathic” form known as non-CF bronchiectasis. Indeed, the prevalence of BE in the US has risen to >400,000 adults, making BE the 3rd most prevalent lung disease in the country. The pathogenesis of BE has been classically described by a “Vicious Cycle/vortex” hypothesis that has failed to produce novel insights and, importantly, transformational therapeutics for BE. This application tests the hypothesis that major additions to the “vicious cycle/vortex” model are required to adequately describe BE mechanisms/pathophysiology and develop new therapeutics. Novel additions to the “Vicious Cycle” based on our published and preliminary data paradigm include the recognition that obstructing mucus plugs lead to airway epithelial hypoxia, which induces hypoxic transcriptional responses that include upregulation of mucin production, Na+/fluid absorption, and hyperconcentrated mucus. New data suggest mucus hyperconcentration-dependent osmotic pressures provide the driving forces for airways dilation and add elements of epithelial strain/gene regulatory responses to BE pathogenesis. In parallel, we posit that aspirated oropharyngeal microbiota (AOM) adapted to colonize hypoxic mucus are the early bacterial driver of disease progression. To test these hypotheses, SA1 will study excised human lungs exhibiting BE consequent to a known and relevant obstruction stimulus, i.e., chronic aspiration, to search for molecular features of chronic airway epithelial hypoxia, mucus accumulation and perturbed bronchiectatic airway wall cells as compared to non-bronchiectatic and non-disease control tissue. SA2 will utilize human airway epithelial cultures to study: 1) transmission of pro-ectatic signals from hypoxic airway epithelia to the airway wall using novel human airway explants featuring asymmetric lumen-selective hypoxia; 2) mechanistic aspects of airway epithelial cell hypoxic transcriptional remodeling via HIF1α vs EPAS1-dependent pathways; and 3) the contributions of aspirated AOM to airway epithelial transcriptional responses that, added to hypoxia, may amplify inflammatory/extracellular remodeling processes. SA3 will investigate the concept that hyperconcentrated mucus osmotic pressure provides high and constant driving forces for airway dilation/ectasia. Finally, SA4 will investigate the roles of obstruction, Hif1α- or Epas1-mediated hypoxic responses, AOM challenge, and the absence of secreted mucins (Muc5ac and Muc5b) in the development of chronic aspiration- induced bronchiectasis in a novel mouse model. These studies will provide a more complete and useful “Obstruction paradigm”, novel biomarkers, needed models of BE, and lead to new therapeutic strategies focused on hypoxia signaling interference, reduction of mucus concentration, and AOM eradication.