A unifying muco-obstructive paradigm for bronchiectasis
openNHLBI - National Heart Lung and Blood Institute
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.
Up to $777K
health research