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.
Highlights
There has been a longstanding observation that mucus solids concentration (% solids by weight including salts, denoted wt%) rises with increasing severity of many lung diseases such as chronic obstructive pulmonary disease and cystic fibrosis (See Figure 1) [1,2,3]
(30 s) of each dataset, we found that the single particle and ensemble Mean Squared Displacement (MSD) data were remarkably well approximated by a uniform power law, as shown in Figure 2 and, consistent with a scaling of the form, SDr2ðtÞT~DfBmta: ð4Þ
The wt% from 28 chronic obstructive pulmonary disease (COPD) subjects (47 total samples from patients ranging in age between 52 and 70, average age 60.5 years) were,26 higher (3.5%) with a broader range (62.3%)
Summary
There has been a longstanding observation that mucus solids concentration (% solids by weight including salts, denoted wt%) rises with increasing severity of many lung diseases such as chronic obstructive pulmonary disease (chronic bronchitis phenotype) and cystic fibrosis (See Figure 1) [1,2,3]. The consequences of mucus hyper-concentration for disease pathogenesis appear to be reduced mucus clearance and a higher incidence of lung infection [6,7]. Despite these correlations, an understanding of the explicit biophysical and cell biologic roles for increased mucus solids concentration in airways disease pathogenesis has not been established. The net result of the interactions of mucins with other mucins, as well as other biomolecules present in the mucus layer, is a viscoelastic material that is responsive to a wide frequency range of forcing (breathing, cilia, cough) and to trapped particles whose diffusive paths are controlled by the thermal fluctuations of the mucus molecular network
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