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A biophysical basis for mucus solids concentration as a candidate biomarker for airways disease.

Hill DB, Vasquez PA, Mellnik J, McKinley SA, Vose A, Mu F, Henderson AG, Donaldson SH, Alexis NE, Boucher RC, Forest MG - PLoS ONE (2014)

Bottom Line: There is a clear need for simple and effective clinical biomarkers of airways disease that correlate with these properties.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.

View Article: PubMed Central - PubMed

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.

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.

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Related in: MedlinePlus

Concentration (wt% solids including salts) of sputum for normal, COPD, and cystic fibrosis samples.The data yields: for normal sputum, 1.7±0.56 wt% from 17 samples; for COPD sputum, 3.7±2.3 wt% from 47 samples; and for cystic fibrosis, 7.0%±2.3 wt% from 21 samples. The red lines on the figure at 1.5% and 5% show the range of HBE mucus solids concentrations assayed in this study.
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pone-0087681-g001: Concentration (wt% solids including salts) of sputum for normal, COPD, and cystic fibrosis samples.The data yields: for normal sputum, 1.7±0.56 wt% from 17 samples; for COPD sputum, 3.7±2.3 wt% from 47 samples; and for cystic fibrosis, 7.0%±2.3 wt% from 21 samples. The red lines on the figure at 1.5% and 5% show the range of HBE mucus solids concentrations assayed in this study.

Mentions: 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]–[3]. The underlying causes of increased mucus solids concentration are diverse, ranging from depletion of the airway surface liquid due to genetic defects in ion channels as in cystic fibrosis [4] to hypersecretion of mucins in chronic obstructive pulmonary disorders [5], or a combination of both. 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.


A biophysical basis for mucus solids concentration as a candidate biomarker for airways disease.

Hill DB, Vasquez PA, Mellnik J, McKinley SA, Vose A, Mu F, Henderson AG, Donaldson SH, Alexis NE, Boucher RC, Forest MG - PLoS ONE (2014)

Concentration (wt% solids including salts) of sputum for normal, COPD, and cystic fibrosis samples.The data yields: for normal sputum, 1.7±0.56 wt% from 17 samples; for COPD sputum, 3.7±2.3 wt% from 47 samples; and for cystic fibrosis, 7.0%±2.3 wt% from 21 samples. The red lines on the figure at 1.5% and 5% show the range of HBE mucus solids concentrations assayed in this study.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3928107&req=5

pone-0087681-g001: Concentration (wt% solids including salts) of sputum for normal, COPD, and cystic fibrosis samples.The data yields: for normal sputum, 1.7±0.56 wt% from 17 samples; for COPD sputum, 3.7±2.3 wt% from 47 samples; and for cystic fibrosis, 7.0%±2.3 wt% from 21 samples. The red lines on the figure at 1.5% and 5% show the range of HBE mucus solids concentrations assayed in this study.
Mentions: 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]–[3]. The underlying causes of increased mucus solids concentration are diverse, ranging from depletion of the airway surface liquid due to genetic defects in ion channels as in cystic fibrosis [4] to hypersecretion of mucins in chronic obstructive pulmonary disorders [5], or a combination of both. 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.

Bottom Line: There is a clear need for simple and effective clinical biomarkers of airways disease that correlate with these properties.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.

View Article: PubMed Central - PubMed

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.

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.

Show MeSH
Related in: MedlinePlus