title: A biophysical basis for mucus solids concentration as a candidate biomarker for airways disease.
abstract: In human airways diseases, including cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD), host defense is compromised and airways inflammation and infection often result. Mucus clearance and trapping of inhaled pathogens constitute key elements of host defense. Clearance rates are governed by mucus viscous and elastic moduli at physiological driving frequencies, whereas transport of trapped pathogens in mucus layers is governed by diffusivity. There is a clear need for simple and effective clinical biomarkers of airways disease that correlate with these properties. We tested the hypothesis that mucus solids concentration, indexed as weight percent solids (wt%), is such a biomarker. Passive microbead rheology was employed to determine both diffusive and viscoelastic properties of mucus harvested from human bronchial epithelial (HBE) cultures. Guided by sputum from healthy (1.5-2.5 wt%) and diseased (COPD, CF; 5 wt%) subjects, mucus samples were generated in vitro to mimic in vivo physiology, including intermediate range wt% to represent disease progression. Analyses of microbead datasets showed mucus diffusive properties and viscoelastic moduli scale robustly with wt%. Importantly, prominent changes in both biophysical properties arose at ∼4 wt%, consistent with a gel transition (from a more viscous-dominated solution to a more elastic-dominated gel). These findings have significant implications for: (1) penetration of cilia into the mucus layer and effectiveness of mucus transport; and (2) diffusion vs. immobilization of micro-scale particles relevant to mucus barrier properties. These data provide compelling evidence for mucus solids concentration as a baseline clinical biomarker of mucus barrier and clearance functions.
authors.affiliation: Cystic Fibrosis Pulmonary Research and Treatment Center, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America ; Department of Physics and Astronomy, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors.forename: David B
authors.initials: DB
authors.lastname: Hill
authors.affiliation: Departments of Mathematics and Biomedical Engineering, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors.forename: Paula A
authors.initials: PA
authors.lastname: Vasquez
authors.affiliation: Departments of Mathematics and Biomedical Engineering, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors.forename: John
authors.initials: J
authors.lastname: Mellnik
authors.affiliation: Department of Mathematics, University of Florida, Gainesville, Florida, United States of America.
authors.forename: Scott A
authors.initials: SA
authors.lastname: McKinley
authors.affiliation: Cystic Fibrosis Pulmonary Research and Treatment Center, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors.forename: Aaron
authors.initials: A
authors.lastname: Vose
authors.affiliation: Cystic Fibrosis Pulmonary Research and Treatment Center, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors.forename: Frank
authors.initials: F
authors.lastname: Mu
authors.affiliation: Cystic Fibrosis Pulmonary Research and Treatment Center, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America ; Department of Medicine, Division of Pulmonary and Critical Care, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors.forename: Ashley G
authors.initials: AG
authors.lastname: Henderson
authors.affiliation: Cystic Fibrosis Pulmonary Research and Treatment Center, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors.forename: Scott H
authors.initials: SH
authors.lastname: Donaldson
authors.affiliation: Center for Environmental Medicine Asthma and Lung Biology, Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors.forename: Neil E
authors.initials: NE
authors.lastname: Alexis
authors.affiliation: Cystic Fibrosis Pulmonary Research and Treatment Center, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors.forename: Richard C
authors.initials: RC
authors.lastname: Boucher
authors.affiliation: Departments of Mathematics and Biomedical Engineering, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors.forename: M Gregory
authors.initials: MG
authors.lastname: Forest
mesh_terms: D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000378:metabolism*; D003550:Cystic Fibrosis / Q000175:diagnosis* / Q000378:metabolism; D004058:Diffusion; D018450:Disease Progression; D004548:Elasticity; D005583:Fourier Analysis; D005782:Gels; D006801:Humans; D008875:Middle Aged; D015233:Models, Statistical; D009093:Mucus / Q000502:physiology*; D029424:Pulmonary Disease, Chronic Obstructive / Q000175:diagnosis* / Q000378:metabolism; D015203:Reproducibility of Results; D012137:Respiratory System / Q000503:physiopathology; D012212:Rheology; D013183:Sputum; D014783:Viscosity; D055815:Young Adult
chemical_list: D015415:Biomarkers; D005782:Gels