Revisited Physicochemical and Transport Properties of Respiratory Mucus in Genotyped Cystic Fibrosis Patients

Deneuville, E.; Perrot-Minot, Catherine; Pennaforte, F; Roussey, M.; Zahm, Jean‐Marie; Clavel, Christine; Puchelle, Édith; Bentzmann, Sophie de

doi:10.1164/ajrccm.156.1.9606123

Cited by 43 publications

(35 citation statements)

References 27 publications

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“…However, we estimated the percent dry weight (percentage of solids) of normal mucus at ϳ1.5-2.5% and of thick CF-like mucus at ϳ6 -15%, based on data reported from cell culture (26), a mouse model (4), and human studies (27)(28)(29)(30)(31)(32)(33). Mucus of 1.5% solids may be less than the normal optimal concentration because the network of mucin fibers and transport were heterogeneous (Fig.…”

Section: Figurementioning

confidence: 99%

“…1C), may reflect the concentration of mucins that occurs in larger airways due to increased mucin secretion and ASL volume absorption (36). The higher concentration of mucus we operationally chose to mimic CF, 6.5%, likely represents the minimum concentration found in CF airways before infection (29,30,32,33). Mucus transport assays demonstrated that 6.5% mucus was too thick to be transported by cilia, mimicking a key feature of CF mucus (2).…”

Section: Figurementioning

confidence: 99%

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Reduced Three-Dimensional Motility in Dehydrated Airway Mucus Prevents Neutrophil Capture and Killing Bacteria on Airway Epithelial Surfaces

Matsui¹,

Verghese²,

Kesımer

et al. 2005

The Journal of Immunology

129

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Cystic fibrosis (CF) lung disease is characterized by persistent lung infection. Thickened (concentrated) mucus in the CF lung impairs airway mucus clearance, which initiates bacterial infection. However, airways have other mechanisms to prevent bacterial infection, including neutrophil-mediated killing. Therefore, we examined whether neutrophil motility and bacterial capture and killing functions are impaired in thickened mucus. Mucus of three concentrations, representative of the range of normal (1.5 and 2.5% dry weight) and CF-like thickened (6.5%) mucus, was obtained from well-differentiated human bronchial epithelial cultures and prepared for three-dimensional studies of neutrophil migration. Neutrophil chemotaxis in the direction of gravity was optimal in 1.5% mucus, whereas 2.5% mucus best supported neutrophil chemotaxis against gravity. Lateral chemokinetic movement was fastest on airway epithelial surfaces covered with 1.5% mucus. In contrast, neutrophils exhibited little motility in any direction in thickened (6.5%) mucus. In in vivo models of airway mucus plugs, neutrophil migration was inhibited by thickened mucus (CF model) but not by normal concentrations of mucus (“normal” model). Paralleling the decreased neutrophil motility in thickened mucus, bacterial capture and killing capacity were decreased in CF-like thickened mucus. Similar results with each mucus concentration were obtained with mucus from CF cultures, indicating that inhibition of neutrophil functions was mucus concentration dependent not CF source dependent. We conclude that concentrated (“thick”) mucus inhibits neutrophil migration and killing and is a key component in the failure of defense against chronic airways infection in CF.

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Section: Figurementioning

confidence: 99%

Section: Figurementioning

confidence: 99%

Reduced Three-Dimensional Motility in Dehydrated Airway Mucus Prevents Neutrophil Capture and Killing Bacteria on Airway Epithelial Surfaces

Matsui¹,

Verghese²,

Kesımer

et al. 2005

The Journal of Immunology

129

View full text Add to dashboard Cite

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“…Although measurements of mucus concentration, i.e., the percentage of solids content, from CF subjects before infection have not been reported, estimates from cell cultures (11) and sputum (12)(13)(14)(15)(16)(17)(18) suggest that CF mucus is at least three or four times more concentrated than normal. Therefore, mucus was obtained from well differentiated human airway cultures and was isotonically concentrated (1) to produce mucus of normal (2.5% solids wt/wt) and CF-like (8%) concentrations (Fig.…”

mentioning

confidence: 99%

A physical linkage between cystic fibrosis airway surface dehydration and Pseudomonas aeruginosa biofilms

Matsui¹,

Wagner

Hill³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

217

228

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A vexing problem in cystic fibrosis (CF) pathogenesis has been to explain the high prevalence of Pseudomonas aeruginosa biofilms in CF airways. We speculated that airway surface liquid (ASL) hyperabsorption generates a concentrated airway mucus that interacts with P. aeruginosa to promote biofilms. To model CF vs. normal airway infections, normal (2.5% solids) and CF-like concentrated (8% solids) mucus were prepared, placed in flat chambers, and infected with an Ϸ5 ؋ 10 3 strain PAO1 P. aeruginosa. Although bacteria grew to 10 10 cfu/ml in both mucus concentrations, macrocolony formation was detected only in the CF-like (8% solids) mucus. Biophysical and functional measurements revealed that concentrated mucus exhibited properties that restrict bacterial motility and small molecule diffusion, resulting in high local bacterial densities with high autoinducer concentrations. These properties also rendered secondary forms of antimicrobial defense, e.g., lactoferrin, ineffective in preventing biofilm formation in a CF-like mucus environment. These data link airway surface liquid hyperabsorption to the high incidence of P. aeruginosa biofilms in CF via changes in the hydration-dependent physical-chemical properties of mucus and suggest that the thickened mucus gel model will be useful to develop therapies of P. aeruginosa biofilms in CF airways.mucus ͉ rheology C ystic fibrosis (CF) lung disease reflects the chronic bacterial infection of intrapulmonary airways with Pseudomonas aeruginosa biofilms (1, 2). P. aeruginosa biofilms have mostly been studied in flow chambers (3-7) that are good models for the biofilms that form on venous or urethral catheters under conditions of high flow rates and relatively high oxygen tensions. However, biofilms in CF airways form in thickened (concentrated) mucus gels that are relatively hypoxic and adherent to airway surfaces (see Fig. 1A) (8, 9). Recently, Sriramulu et al. (10) investigated the role autoregulators and amino acids play in the tightness of biofilm formation in a mucus stimulant of constant hydration. For the present study, we designed a culture system to investigate whether dehydration of the CF mucus environment may predispose to P. aeruginosa biofilm formation.A key aspect of the model was the selection of mucus concentrations that mimic normal and CF mucus. Although measurements of mucus concentration, i.e., the percentage of solids content, from CF subjects before infection have not been reported, estimates from cell cultures (11) and sputum (12-18) suggest that CF mucus is at least three or four times more concentrated than normal. Therefore, mucus was obtained from well differentiated human airway cultures and was isotonically concentrated (1) to produce mucus of normal (2.5% solids wt/wt) and CF-like (8%) concentrations (Fig. 1B). Aliquots of each were deposited in (i) an open chamber to model a mucus plaque adherent to CF airway surfaces with a residual lumen allowing airflow and (ii) a closed chamber to mimic a mucus plug occluding a CF airway (Fig. 1 A). P....

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“…15 In our study the evaluation of macroscopic appearance of the secretions was always performed by 2 investigators. To reduce the subjectivity of those evaluations we used the scale described by Deneuville et al 9 Regarding the samples from the without-lung-disease subjects, the mucus analysis was difficult, because small amounts were collected, so for this group we applied the method described by Rubin et al, 8 in which mucus is collected from the endotracheal tube used during a short surgical procedure in without-lung-disease subjects. The characteristics of the mucus deposited inside and outside the tube was compared.…”

Section: Discussionmentioning

confidence: 99%

“…The mucus was assessed for purulence with a score based on a previously described numerical visual scale, 9 which ranges from 1 (mucoid) to 5 (yellow/green). Samples with a purulence index between 1 and 3 were classified as mucoid, and samples with scores of 4 or 5 were classified as purulent.…”

Section: Purulencementioning

confidence: 99%

The Influence of Purulence on Ciliary and Cough Transport in Bronchiectasis

et al. 2013

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BACKGROUND: Individuals with bronchiectasis exhibit colonization and infection of the respiratory system, with a consequent alteration of the macroscopic appearance of secretions, which ranges from mucoid to purulent. Purulence is related to the structural conformation, rheological profile, and transport indexes of mucus. We analyzed and compared the transport properties of respiratory secretions with mucoid appearance versus those with purulent appearance in patients with bronchiectasis and in subjects without lung disease. METHODS: In a simulated cough machine we assessed the mucociliary transport and contact angle of 32 mucoid and 19 purulent samples from subjects with bronchiectasis, and 21 samples from subjects without lung disease. RESULTS: Mucociliary transport was lower in the mucoid samples (0.78 ؎ 0.22) and in the purulent samples (0.73 ؎ 0.22) than in the samples from subjects without lung disease (1 ؎ 0.19). The purulent samples had less displacement in the simulated cough machine (7.57 ؎ 3 cm) than did the mucoid samples (23 ؎ 15 cm) or the samples from subjects without lung disease (34 ؎ 8.4 cm), as did the mucoid samples compared to the samples from subjects without lung disease. The purulent samples had a higher contact angle (25 ؎ 6.1°) than the mucoid samples (17 ؎ 7.8°) or the samples from subjects without lung disease (10 ؎ 2.5°), as did the mucoid samples compared to the samples from subjects without lung disease. CONCLUSIONS: Respiratory secretions in individuals with bronchiectasis have poor transport properties, which manifest as reduced mucociliary transport, reduced mucus transport by cough, and higher contact angle. These features were more accentuated in the purulent samples. This simple classification can be used by therapists to plan treatments, and by researchers to obtain more homogeneity between groups of subjects.

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Revisited Physicochemical and Transport Properties of Respiratory Mucus in Genotyped Cystic Fibrosis Patients

Cited by 43 publications

References 27 publications

Reduced Three-Dimensional Motility in Dehydrated Airway Mucus Prevents Neutrophil Capture and Killing Bacteria on Airway Epithelial Surfaces

Reduced Three-Dimensional Motility in Dehydrated Airway Mucus Prevents Neutrophil Capture and Killing Bacteria on Airway Epithelial Surfaces

A physical linkage between cystic fibrosis airway surface dehydration and Pseudomonas aeruginosa biofilms

The Influence of Purulence on Ciliary and Cough Transport in Bronchiectasis

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