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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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Mucus Gel Point.A) Cartoon illustrating the mucus network changes for increasing macromolecule (mucin) concentration. The gel point (GP) is the point at which the strength of the chains interacting with one another engenders the elastic moduli () to be comparable in magnitude to the viscous moduli (). B) Master curve of ensemble-averaged MSDs. The solids concentration for sol-gel transition is obtained following [36], in this case breaking of the slope in the master curve indicates the sol-gel transition occurs at a solids concentration between 4.0 and 5.0 wt%.
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pone-0087681-g006: Mucus Gel Point.A) Cartoon illustrating the mucus network changes for increasing macromolecule (mucin) concentration. The gel point (GP) is the point at which the strength of the chains interacting with one another engenders the elastic moduli () to be comparable in magnitude to the viscous moduli (). B) Master curve of ensemble-averaged MSDs. The solids concentration for sol-gel transition is obtained following [36], in this case breaking of the slope in the master curve indicates the sol-gel transition occurs at a solids concentration between 4.0 and 5.0 wt%.

Mentions: Potential signatures of qualitative transitions in viscoelastic and diffusive biophysical properties from these microbead rheology tools were also sought. The protocol proposed by Larsen and Furst [36] was employed to detect a signature of a sol-gel transition from the comprehensive MSD data as a function of mucus wt%. The point at which this transition occurs is known as the gel point. In the context of 1 µm particles, the gel point was defined as the wt% at which mucus underwent a change from a viscous-dominated sol (fluid), for which for all , to an elastic-dominated gel, for which for all frequencies . The Larsen-Furst protocol requires scaling each wt% MSD curve onto a master MSD curve by scaling the axes by factors a (horizontal) and b (vertical). The scaled MSD figures versus wt%, therefore, have axes and , as in [36] and Figure 6. The gel point (GP) is defined as the solids concentration at which the logarithmic slope, or power law, of the shifted master curve “breaks” from one slope below GP to another above GP [36]. Note that these metrics are based on the ensemble MSD scaling behavior versus lag time across multiple samples, rather than the macrorheology standard based on a comparison of and across a frequency spectrum, which require transforms of the MSD data.


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)

Mucus Gel Point.A) Cartoon illustrating the mucus network changes for increasing macromolecule (mucin) concentration. The gel point (GP) is the point at which the strength of the chains interacting with one another engenders the elastic moduli () to be comparable in magnitude to the viscous moduli (). B) Master curve of ensemble-averaged MSDs. The solids concentration for sol-gel transition is obtained following [36], in this case breaking of the slope in the master curve indicates the sol-gel transition occurs at a solids concentration between 4.0 and 5.0 wt%.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0087681-g006: Mucus Gel Point.A) Cartoon illustrating the mucus network changes for increasing macromolecule (mucin) concentration. The gel point (GP) is the point at which the strength of the chains interacting with one another engenders the elastic moduli () to be comparable in magnitude to the viscous moduli (). B) Master curve of ensemble-averaged MSDs. The solids concentration for sol-gel transition is obtained following [36], in this case breaking of the slope in the master curve indicates the sol-gel transition occurs at a solids concentration between 4.0 and 5.0 wt%.
Mentions: Potential signatures of qualitative transitions in viscoelastic and diffusive biophysical properties from these microbead rheology tools were also sought. The protocol proposed by Larsen and Furst [36] was employed to detect a signature of a sol-gel transition from the comprehensive MSD data as a function of mucus wt%. The point at which this transition occurs is known as the gel point. In the context of 1 µm particles, the gel point was defined as the wt% at which mucus underwent a change from a viscous-dominated sol (fluid), for which for all , to an elastic-dominated gel, for which for all frequencies . The Larsen-Furst protocol requires scaling each wt% MSD curve onto a master MSD curve by scaling the axes by factors a (horizontal) and b (vertical). The scaled MSD figures versus wt%, therefore, have axes and , as in [36] and Figure 6. The gel point (GP) is defined as the solids concentration at which the logarithmic slope, or power law, of the shifted master curve “breaks” from one slope below GP to another above GP [36]. Note that these metrics are based on the ensemble MSD scaling behavior versus lag time across multiple samples, rather than the macrorheology standard based on a comparison of and across a frequency spectrum, which require transforms of the MSD data.

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