Journal Article

A Biophysical Basis for Mucus Solids Concentration as a Candidate Biomarker for Airways Disease

McKinley, Scott A., Forest, M. Gregory, Boucher, Richard C., Vasquez, Paula A., Mellnik, John, Alexis, Neil E., Henderson, Ashley G., Hill, David B., Vose, Aaron, Mu, Frank, Donaldson, Scott H.

2014

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Adult / Aged / Analysis / Bioindicators / Biology / Biomarkers / Biomarkers - metabolism / Biomedical engineering / Chronic obstructive lung disease / Chronic obstructive pulmonary disease / Cilia / Cystic fibrosis / Cystic Fibrosis - diagnosis / Cystic Fibrosis - metabolism / Departments / Development and progression / Diffusion / Diffusion barriers / Diffusion layers / Disease / Disease Progression / Effectiveness / Efficiency / Elasticity / Engineering / Fourier Analysis / Gels / Health aspects / Humans / Immobilization / Lung diseases / Mathematics / Medicine / Middle Aged / Models, Statistical / Modulus of elasticity / Mucus / Mucus - physiology / Nanoparticles / Obstructive lung disease / Pathogenesis / Pathogens / Physics / Physiological aspects / Physiology / Properties (attributes) / Pulmonary Disease, Chronic Obstructive - diagnosis / Pulmonary Disease, Chronic Obstructive - metabolism / Reproducibility of Results / Respiratory System - physiopathology / Rheological properties / Rheology / Solids / Sputum / Transport / Viscoelasticity / Viscosity / Young Adult