Despite the development of new therapies, cystic fibrosis (CF) remains a life-shortening disease. Early interventions aimed at correcting the initial host defense defects and preventing/reducing infection and mucus accumulation could dramatically improve the course of CF lung disease. It is widely known that mutations in the gene encoding the HCO3- and Cl--conducting channel CFTR cause CF; in spite of this knowledge, lack of an animal model that replicates human CF has obscured the origins of disease. CF pigs provided us with the unprecedented opportunity to investigate the CF lung at very early time points. At birth, CF pigs lack airway disease, but within weeks of birth CF pigs spontaneously develop hallmark features of CF lung disease including airway inflammation, infection, mucus accumulation, and remodeling. We previously found that CF pigs have at least two host defense defects on the day that they are born: a) reduced activity of airway surface liquid antimicrobials; and b) defective mucociliary transport (MCT) following cholinergic stimulation, which elicits copious mucus secretion from submucosal glands. Recent mechanistic investigations revealed that CF submucosal glands secrete strands of mucus that sometimes do not break free after emerging onto the airway surface. Instead, they remain attached to the gland ducts, hindering MCT. These findings directly link impaired MCT to loss of anion transport, indicating that defective MCT is a primary abnormality. Our central hypothesis is that loss of CFTR causes MCT defects that contribute to early CF airway disease. Thus, there is a critical need to better understand the underlying mechanism for MCT defects, whether these defects are impacted by disease progression, and how they might be corrected. In a new direction for this project, we focus our studies on the mucus strands that fail to detach from the CF submucosal gland duct and concentrate our efforts towards determining if this defect is correctable. We will investigate the following Specific Aims: (1) Which factors impact mucus strand formation, breakage, and clearance? Our working hypothesis is that altering the chemical environment into which mucus strands are formed and released will impact strand breakage and clearance. (2) In CF airways, does inducing release of mucus strands from submucosal gland ducts restore MCT? We postulate that releasing stuck mucus strands will reverse MCT defects, thereby enhancing MCT in CF. (3) How does early CF disease progression and viral infection impact MCT? CF pigs have host defense defects present at birth and within weeks of age develop airway disease. Here we will discover how early infection, inflammation, and mucus accumulation affect MCT in CF pigs. By focusing on the pathogenesis of early CF airway disease, we hope to accelerate discovery of new therapeutic interventions and identify endpoints for early CF.
Cystic fibrosis is a common life-shortening genetic disease that causes progressive lung failure due to recurrent infections and airway obstruction. These studies will use a cystic fibrosis animal model to investigate mucociliary transport in hopes of developing better therapies for cystic fibrosis lung disease.
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