Mucus Transport Research Articles

Inhibition of airway surface fluid absorption by cholinergic stimulation.

In upper airways airway surface liquid (ASL) depth and clearance rates are both increased by fluid secretion. Secretion is opposed by fluid absorption, mainly via the epithelial sodium channel, ENaC. In static systems, increased fluid depth activates ENaC and decreased depth inhibits it, suggesting that secretion indirectly activates ENaC to reduce ASL depth. We propose an alternate mechanism in which cholinergic input, which causes copious airway gland secretion, also inhibits ENaC-mediated absorption. The conjoint action accelerates clearance, and the increased transport of mucus out of the airways restores ASL depth while cleansing the airways. We were intrigued by early reports of cholinergic inhibition of absorption by airways in some species. To reinvestigate this phenomenon, we studied inward short-circuit currents (Isc) in tracheal mucosa from human, sheep, pig, ferret, and rabbit and in two types of cultured cells. Basal Isc was inhibited 20–70% by the ENaC inhibitor, benzamil. Long-lasting inhibition of ENaC-dependent Isc was also produced by basolateral carbachol in all preparations except rabbit and the H441 cell line. Atropine inhibition produced a slow recovery or prevented inhibition if added before carbachol. The mechanism for inhibition was not determined and is most likely multi-factorial. However, its physiological significance is expected to be increased mucus clearance rates in cholinergically stimulated airways.

Chest physiotherapy compared to no chest physiotherapy for cystic fibrosis.

Chest physiotherapy is widely used in people with cystic fibrosis in order to clear mucus from the airways. This is an updated version of previously published reviews. To determine the effectiveness and acceptability of chest physiotherapy compared to no treatment or spontaneous cough alone to improve mucus clearance in cystic fibrosis. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register which comprises references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings.Date of the most recent search of the Group's Cystic Fibrosis Trials Register: 02 June 2015. Randomised or quasi-randomised clinical studies in which a form of chest physiotherapy (airway clearance technique) were taken for consideration in people with cystic fibrosis compared with either no physiotherapy treatment or spontaneous cough alone. Both authors independently assessed study eligibility, extracted data and assessed the risk of bias in the included studies. There was heterogeneity in the published outcomes, with variable reporting which meant pooling of the data for meta-analysis was not possible. The searches identified 157 studies, of which eight cross-over studies (data from 96 participants) met the inclusion criteria. There were differences between studies in the way that interventions were delivered, with several of the intervention groups combining more than one treatment modality. One included study looked at autogenic drainage, six considered conventional chest physiotherapy, three considered oscillating positive expiratory pressure, seven considered positive expiratory pressure and one considered high pressure positive expiratory pressure. Of the eight studies, six were single-treatment studies and in two, the treatment intervention was performed over two consecutive days (once daily in one, twice daily in the other). This enormous heterogeneity in the treatment interventions prevented any meta-analyses from being performed. Blinding of participants, caregivers or clinicians in airway clearance studies is impossible; therefore this was not considered as a high risk of bias in the included studies. Lack of protocol data made assessment of risk of bias unclear for the majority of other criteria.Four studies, involving 28 participants, reported a higher amount of expectorated secretions during chest physiotherapy as compared to a control. One study, involving 18 participants, reported no significant differences in sputum weight. In five studies radioactive tracer clearance was used as an outcome variable. In three of these (28 participants) it was reported that chest physiotherapy, including coughing, increased radioactive tracer clearance as compared to the control period. One study (12 participants) reported increased radioactive tracer clearance associated with all interventions compared to control, although this was only reported to have reached significance for postural drainage with percussion and vibrations; and the remaining study (eight participants) reported no significant difference in radioactive tracer clearance between chest physiotherapy, without coughing, compared to the control period. Three studies, involving 42 participants reported no significant effect on pulmonary function variables following intervention; but one further study did report significant improvement in pulmonary function following the intervention in some of the treatment groups. The results of this review show that airway clearance techniques have short-term effects in the terms of increasing mucus transport. No evidence was found on which to draw conclusions concerning the long-term effects.

On the effect of mucus rheology on the muco-ciliary transport

A two dimensional numerical model is used to study the muco-ciliary transport process in human respiratory tract. Here, hybrid finite difference-lattice Boltzmann method is used to model the flow physics of the transport of mucus and periciliary liquid (PCL) layer in the airway surface liquid. The immersed boundary method is also used to implement the propulsive effect of the cilia and also the effects of the interface between the mucus and PCL layers. The main contribution of this study is on elucidating the role of the viscoelastic behavior of mucus on the muco-ciliary transport and for this purpose an Oldroyd-B model is used as the constitutive equation of mucus for the first time. Results show that the viscosity and viscosity ratio of mucus have an enormous effect on the muco-ciliary transport process. It is also seen that the mucus velocity is affected by mucus relaxation time when its value is less than 0.002 s. Results also indicate that the variation of these properties on the mucus velocity at lower values of viscosity ratio is more significant.

Cilium height difference between strokes is more effective in driving fluid transport in mucociliary clearance: A numerical study.

Mucociliary clearance is the first line of defense in our airway. The purpose of this study is to identify and study key factors in the cilia motion that influence the transport ability of the mucociliary system. Using a rod-propel-fluid model, we examine the effects of cilia density, beating frequency, metachronal wavelength, and the extending height of the beating cilia. We first verify that asymmetry in the cilia motion is key to developing transport in the mucus flow. Next, two types of asymmetries between the effective and recovery strokes of the cilia motion are considered, the cilium beating velocity difference and the cilium height difference. We show that the cilium height difference is more efficient in driving the transport, and the more bend the cilium during the recovery stroke is, the more effective the transport would be. It is found that the transport capacity of the mucociliary system increases with cilia density and cilia beating frequency, but saturates above by a threshold value in both density and frequency. The metachronal wave that results from the phase lag among cilia does not contribute much to the mucus transport, which is consistent with the experimental observation of Sleigh (1989). We also test the effect of mucus viscosity, whose value is found to be inversely proportional to the transport ability. While multiple parts have to interplay and coordinate to allow for most effective mucociliary clearance, our findings from a simple model move us closer to understanding the effects of the cilia motion on the efficiency of this clearance system.

The Relationship of Mucus Concentration (Hydration) to Mucus Osmotic Pressure and Transport in Chronic Bronchitis.

Chronic bronchitis (CB) is characterized by persistent cough and sputum production. Studies were performed to test whether mucus hyperconcentration and increased partial osmotic pressure, in part caused by abnormal purine nucleotide regulation of ion transport, contribute to the pathogenesis of CB. We tested the hypothesis that CB is characterized by mucus hyperconcentration, increased mucus partial osmotic pressures, and reduced mucus clearance. We measured in subjects with CB as compared with normal and asymptomatic smoking control subjects indices of mucus concentration (hydration; i.e., percentage solids) and sputum adenine nucleotide/nucleoside concentrations. In addition, sputum partial osmotic pressures and mucus transport rates were measured in subjects with CB. CB secretions were hyperconcentrated as indexed by an increase in percentage solids and total mucins, in part reflecting decreased extracellular nucleotide/nucleoside concentrations. CB mucus generated concentration-dependent increases in partial osmotic pressures into ranges predicted to reduce mucus transport. Mucociliary clearance (MCC) in subjects with CB was negatively correlated with mucus concentration (percentage solids). As a test of relationships between mucus concentration and disease, mucus concentrations and MCC were compared with FEV1, and both were significantly correlated. Abnormal regulation of airway surface hydration may slow MCC in CB and contribute to disease pathogenesis.

The Relationship of Mucus Concentration (Hydration) to Mucus Osmotic Pressure and Transport in Chronic Bronchitis

The Relationship of Mucus Concentration (Hydration) to Mucus Osmotic Pressure and Transport in Chronic Bronchitis

The Effects of N-Acetyl Cysteine on Nasal Mucociliary Clearance in Healthy Volunteers: A Randomized, Double-Blind and Placebo-Controlled Study

Background: Mucociliary clearance is an important host defense function of the upper respiratory tract that requires the coordinated beating of cilia and results in the transport of mucus to the oropharynx. N-Acetyl Cysteine is a mucolytic drug currently used in pulmonary diseases. In the present study we sought to assess the effects of N-Acetyl Cysteine nasal mucociliary clearance in healthy volunteers. Methods: A total of 100 healthy individuals (55 male) with the mean age of 34.21 (± 12.63) years were included in the present randomized, double-blind and placebo-controlled study. Participants were assigned into two groups of case and control. The Mucociliary Clearance Time (MCT) was measured by saccharine test; measuring the time in minutes required for the subject to taste a saccharin particle placed on the inferior turbinate of the nasal. The variables studied were nasal MCT before and after taking the placebo or NAC, age, and sex. Data were analyzed using SPSS V.16. Results: Wilcoxon signed ranks test demonstrated considerable different of Saccharine Test Time (STT) between before and after taking the NAC (p=0.021), and no significant different of STT between before and after taking the placebo (p=0.723). Conclusion: N-Acetyl Cysteine exerts measurable effect on nasal mucociliary clearance in healthy volunteers; therefore may be beneficial in conditions associated with disruption of mucociliary clearance such as rhinitis and sinusitis. However, further studies are suggested to achieve more conclusive results.

Radiological and functional characteristics of mucociliary clearance of the airway

The aim of this study was to develop a radiological model for visual assessment of morphology and function of the ciliated epithelium of the upper and lower airways and mucociliary clearance at whole in healthy and in patients with pulmonary tuberculosis, COPD and lung carcinoma. Methods. We examined 65 patients aged 23 to 58 years, of them 26 patients with limited lung lesions and normal airway mucosa as controls and 39 patients with extended lung lesions due to tuberculosis, chronic obstructive pulmonary disease or lung carcinoma as the study group. The airway mucosa functional properties were investigated using spray coating of tantalum microparticles. Results. In the control group, the time of complete clearance was 15 to 20 min for larynx and pharynx, 45 to 60 min for trachea and 1–3 to 20–24 h for different bronchi. Bronchial clearance of the particle was decreased in the study group. The airway clearance disorders were considered as moderate (in patients with acute inflammation such as tuberculous, non-specific pneumonia, acute bronchitis, etc.), severe (in patients with chronic bronchial and pulmonary disease such as cavitary fibrocaseous tuberculosis, chronic bronchitis, bronchiectasis) and very severe (in patients with lung carcinoma). The clearance time in these disorders was 24 to 48 h, 48 to 72 h and #> 72 h, respectively. Conclusion. Normally, the airway clearance rate is 60-65 times lower in small airways than in the upper airways (pharynx and laryngx). Clearance local disorders caused by tobacco smoking, pollutants, etc., greatly decrease bronchial mucus transport and prolong the complete airway clearance time that could provide occurrence and progression of inflammatory and neoplastic pulmonary diseases.

In vitro mucus transportability, cytogenotoxicity, and hematological changes as non-destructive physiological biomarkers in fish chronically exposed to metals

The biomonitoring of fish using biomarkers represents a useful tool for the assessment of aquatic pollution. This study evaluated the sublethal toxic effects of aquatic pollution on fish collected from a site contaminated by metals. Water and fish (Oreochromis niloticus) samples were collected from a pond in the Parque Ecológico do Tietê (PET) that lies along the Tietê River (São Paulo, Brazil), and from a control site (an experimental fish farm). The metal content of the water was evaluated, and fish were used to examine the properties of gill mucus and blood. The PET fish were evaluated for alterations in the in vitro transportability of mucus and changes in blood properties (e.g., cell volume, hemoglobin concentration, red blood cells, and white blood cell count). The results of the water analyzes indicated metal levels above the legal standards for Fe (0.71mg/L), Ni (0.06mg/L), Mn (0.11mg/L), and Pb (0.48mg/L). Compared to the controls, the hematologic parameter analyzes of PET fish revealed significantly higher numbers of erythrocytes (RBC), leukocytes (WBC), lymphocytes, erythroblasts, and Mean Corpuscular Volume (MCV); however, the hemoglobin content and Mean Corpuscular Hemoglobin Concentration (MCHC) values were significantly lower. The frequencies of nuclear abnormalities and micronuclei were significantly higher and the mucociliary transport was significantly lower in PET fish than in the controls. These results suggest that fish from the contaminated site exhibit a series of physiological responses, which probably indicate health disturbances. Furthermore, the results suggest that blood and mucus are promising, non-destructive targets for use in the monitoring of pollution.

Linking increased airway hydration, ciliary beating, and mucociliary clearance through ENaC inhibition.

Airway dehydration causes mucus stasis and bacterial overgrowth in cystic fibrosis and chronic bronchitis (CB). Rehydration by hypertonic saline is efficacious but suffers from a short duration of action. We tested whether epithelial sodium channel (ENaC) inhibition would rehydrate normal and dehydrated airways to increase mucociliary clearance (MCC) over a significant time frame. For this, we used a tool compound (Compound A), which displays nanomolar ENaC affinity and retention in the airway surface liquid (ASL). Using normal human bronchial epithelial cultures (HBECs) grown at an air-liquid interface, we evaluated in vitro potency and efficacy using short-circuit current (I(sc)) and ASL height measurements where it inhibited I(sc) and increased ASL height by ∼ 50% (0.052 μM at 6 h), respectively. The in vivo efficacy was investigated in a modified guinea pig tracheal potential difference model, where we observed an effective dose (ED50) of 5 μg/kg (i.t.), and by MCC measures in rats and sheep, where we demonstrated max clearance rates at 100 μg/kg (i.t.) and 75 μg/kg (i.t.), respectively. Acute cigarette smoke-induced ASL height depletion in HBECs was used to mimic the situation in patients with CB, and pretreatment prevented both cigarette smoke-induced ASL dehydration and lessened the decrease in ciliary beat frequency. Furthermore, when added after cigarette smoke exposure, Compound A increased the rate of ASL rehydration. In conclusion, Compound A demonstrated significant effects and a link between increased airway hydration, ciliary function, and MCC. These data support the hypothesis that ENaC inhibition may be efficacious in the restoration of mucus hydration and transport in patients with CB.

Effects of heat and moisture exchangers on tracheal mucociliary clearance in laryngectomized patients: a multi-center case-control study.

After total laryngectomy, inspired air is no longer optimally conditioned by the upper airways. Impaired mucociliary clearance and histological changes of respiratory epithelium, such as loss of ciliated cells, have been described in laryngectomized patients. Heat and moisture exchangers (HMEs) are passive humidifiers that re-condition the inspired air. Aim of this study was to assess the effect of HMEs on tracheal epithelium and tracheal mucus transport velocity (TMV). Tracheal brush biopsies were collected in three groups of TLE patients: 21 long-term HME users, 10 non-HME users, and 16 non-HME users before and after 4-9 months HME use. Tracheal epithelium biopsies were assessed using a digital high-speed camera mounted onto a light microscope. TMV was determined by scintigraphy in the first two patient groups. Significantly more ciliated cells were found in HME users compared to non-HME users (p = 0.05). TMV was higher in HME users (median 2 mm/min; 0-7.9) compared to non-HME users (median 0.8 mm/min; 0-12.3), but this difference was not significant (p = 0.37). One-hour breathing without HME in long-term HME users did not measurably decrease TMV (p = 0.13). The long-term use of an HME restores/prevents the loss of tracheal ciliated cells. A significant improvement in TMV was not found. Short-term (one hour) detachment of an HME has no measurable effect on TMV.

The effects of temperature and anesthetic agents on ciliary function in murine respiratory epithelia.

Background: Mucus transport mediated by motile cilia in the airway is an important defense mechanism for prevention of respiratory infections. As cilia motility can be depressed by hypothermia or exposure to anesthetics, in this study, we investigated the individual and combined effects of dexmedetomidine (dex), fentanyl (fen), and/or isoflurane (iso) at physiologic and low temperatures on cilia motility in mouse tracheal airway epithelia. These anesthetic combinations and low temperature conditions are often used in the setting of cardiopulmonary bypass surgery, surgical repair of congenital heart disease, and cardiac intensive care.Methods: C57BL/6J mouse tracheal epithelia were excised and cilia dynamics were captured by videomicroscopy following incubation at 15, 22–24, and 37°C with different combinations of therapeutic concentrations of dex (10 nM), fen (10 nM), and iso (0.01%). Airway ciliary motion was assessed and compared across conditions by measuring ciliary beat frequency and ciliary flow velocity. Statistical analysis was carried out using unpaired t-tests, analysis of variance, and multivariate linear regression.Results: There was a linear correlation between cilia motility and temperature. Fen exerted cilia stimulatory effects, while dex and iso each had ciliodepressive effects. When added together, fen + iso, dex + iso, and dex + fen + iso were all cilia inhibitory. In contrast fenl + dex did not significantly alter ciliary function.Conclusion: We show that ciliary motility is stimulated by fen, but depressed by dex or iso. However, when used in combination, ciliary motility showed changes indicative of complex drug–drug and drug–temperature interactions not predicted by simple summation of their individual effects. Similar studies are needed to examine the human airway epithelia and its response to anesthetics.

An autoregulatory mechanism governing mucociliary transport is sensitive to mucus load.

Mucociliary clearance, characterized by mucus secretion and its conveyance by ciliary action, is a fundamental physiological process that plays an important role in host defense. Although it is known that ciliary activity changes with chemical and mechanical stimuli, the autoregulatory mechanisms that govern ciliary activity and mucus transport in response to normal and pathophysiological variations in mucus are not clear. We have developed a high-speed, 1-μm-resolution, cross-sectional imaging modality, termed micro-optical coherence tomography (μOCT), which provides the first integrated view of the functional microanatomy of the epithelial surface. We monitored invasion of the periciliary liquid (PCL) layer by mucus in fully differentiated human bronchial epithelial cultures and full thickness swine trachea using μOCT. We further monitored mucociliary transport (MCT) and intracellular calcium concentration simultaneously during invasion of the PCL layer by mucus using colocalized μOCT and confocal fluorescence microscopy in cell cultures. Ciliary beating and mucus transport are up-regulated via a calcium-dependent pathway when mucus causes a reduction in the PCL layer and cilia height. When the load exceeds a physiological limit of approximately 2 μm, this gravity-independent autoregulatory mechanism can no longer compensate, resulting in diminished ciliary motion and abrogation of stimulated MCT. A fundamental integrated mechanism with specific operating limits governs MCT in the lung and fails when periciliary layer compression and mucus viscosity exceeds normal physiologic limits.

Effect of heated humidified ventilation on bronchial mucus transport velocity in general anaesthesia: a randomized trial.

To evaluate the effects of heated humidified ventilation on mucociliary function during general anaesthesia. Male patients (ASA physical status 1 or 2), scheduled for elective radical retropubic prostatectomy, were allocated to receive sevoflurane general anaesthesia with conventional or heated humidified ventilation. Bronchial mucus transport velocity was assessed via fibreoptic bronchoscope and methylene blue dye at 3h after induction of anaesthesia. Median (SE) bronchial mucus transport velocity was significantly higher in the heated humidified group (n = 26) than the conventional ventilation group (n = 24) (1.7 [0.3] mm/min vs 0.9 [0.1] mm/min). Heated humidified ventilation effectively maintains mucociliary clearance of patients during sevoflurane general anaesthesia.

Chlorogenic Acid: A Potential Activator of Dysfunctional Mucus Transport in Chronic Rhinosinusits

Objectives: Salubrious effects of the green coffee bean are purportedly secondary to high concentrations of chlorogenic acid (CA). CA has a molecular structure similar to bioflavanoid polyphenols known to activate transepithelial Cl- transport in sinonasal epithelia. In contrast to bioflavonoids, chlorogenic acid is freely soluble in water. The objectives of this study are to evaluate the Cl- secretory capability of CA and potential as a therapeutic activator of mucus clearance in sinus disease. Methods: CA was tested on primary murine nasal septal epithelial (MNSE) [CFTR+/+ and transgenic CFTR-/-] and human sinonasal epithelial(HSNE) [CFTR+/+ and F508del/F508del] cultures under pharmacologic conditions in Ussing chambers to evaluate effects on transepithelial Cl- transport. Changes in airway surface liquid depth and CFTR mRNA transcription were also measured. Results: CA stimulated transepithelial Cl- secretion [(change in short-circuit current(^†ISC)] in MNSE (13.11 ± 0.9 vs 0.1 ± 0.1, P < .05) and HSNE (34.3 ± 0.9 vs 0.0 ± 0.1, P < .05). The drug had a slow onset with peak effect at 15 minutes after application. Administration of the CFTR blocker INH-172 significantly reduced ISC (MNSE −16.4 ± 1.0 vs −9 ± 0.9 and HSNE (−44.6 ± 1.0 vs 34.1 ± 0.3, P < .05), indicating effects of the drug are likely mediated through CFTR. CA-mediated Cl- secretion was absent in CFTR-/- MNSE and F508del/F508del HSNE, confirming CFTR dependency. A modest increase in ASL depth was noted with 1 hour incubation (9.4 vs 8.3 µm). The compound did not alter CFTR mRNA levels when analyzed by quantitative reverse transcription polymerase chain reaction. Conclusions: CA is a water-soluble agent that promotes CFTR-mediated Cl- transport in sinonasal epithelium. Further in vivo evaluation as a therapeutic activator of mucus clearance is planned.

English

A two-layer fluid model is proposed to study the transport of mucus in the trachea and air motion by considering mucus as a viscoelastic fluid. The effect of air flow due to inspiration and expiration is considered by prescribing shear stress at the mucus-air interface. The resistance to flow has been computed for different constriction length and for different constriction height. Shear stress distribution along the axial distance has been computed for different constriction height. It has been shown that, axial velocity profile, resistance flow, wall shear stress and concentration increases as the size of the constricted trachea increases.

In vitro studies of a distillate of rectified essential oils on sinonasal components of mucociliary clearance.

Herbal remedies predate written history and continue to be used frequently for many common ailments. The essential oil mixture standardized is a phytopharmaceutical with a distillate of a mixture of rectified essential oils of eucalyptus, sweet orange, myrtle, and lemon as active ingredients used to treat respiratory diseases such as bronchitis and rhinosinusitis. We evaluated the pharmacologic effects of a distillate of rectified essential oils standardized on primary human upper respiratory epithelial cultures specifically addressing electrolyte transport, cilia beat frequency (CBF), airway surface liquid (ASL) hydration, and mucus transport velocity. Well-differentiated primary human sinonasal epithelial cultures grown at an air-liquid interface were treated on the apical or basolateral surface with varying concentrations of a distillate of rectified essential oils standardized. Changes in CBF were determined using the Sissons-Ammons Video Analysis system while changes in chloride flux were determined using the fluorescent dye 6-methoxy-N-(3-sulfopropyl)quinolinium. ASL hydration was quantified using Texas red dextran and mucociliary transport velocity was measured using fluorescent microspheres and time lapse photography. When applied to the basolateral surface, a distillate of rectified essential oils standardized activated chloride efflux and ciliary beat in a dose-dependent fashion, increasing ASL height and accelerating mucociliary transport velocity. The ancillary apical application of a distillate of rectified essential oils standardized had minimal effects on the CBF. Basolateral application of a distillate of rectified essential oils standardized stimulates both chloride efflux and cilia beat frequency resulting in a synergistic effect dramatically augmenting mucociliary transport velocity. These in vitro data support the clinical efficacy of this phytopharmaceutical in respiratory inflammatory disorders.

A novel serotonin-secreting cell type regulates ciliary motility in the mucociliary epidermis of Xenopus tadpoles

The embryonic skin of Xenopus tadpoles serves as an experimental model system for mucociliary epithelia (MCE) such as the human airway epithelium. MCEs are characterized by the presence of mucus-secreting goblet and multiciliated cells (MCCs). A third cell type, ion-secreting cells (ISCs), is present in the larval skin as well. Synchronized beating of MCC cilia is required for directional transport of mucus. Here we describe a novel cell type in the Xenopus laevis larval epidermis, characterized by serotonin synthesis and secretion. It is termed small secretory cell (SSC). SSCs are detectable at early tadpole stages, unlike MCCs and ISCs, which are specified at early neurulation. Subcellularly, serotonin was found in large, apically localized vesicle-like structures, which were entirely shed into the surrounding medium. Pharmacological inhibition of serotonin synthesis decreased the velocity of cilia-driven fluid flow across the skin epithelium. This effect was mediated by serotonin type 3 receptor (Htr3), which was expressed in ciliated cells. Knockdown of Htr3 compromised flow velocity by reducing the ciliary motility of MCCs. SSCs thus represent a distinct and novel entity of the frog tadpole MCE, required for ciliary beating and mucus transport across the larval skin. The identification and characterization of SSCs consolidates the value of the Xenopus embryonic skin as a model system for human MCEs, which have been known for serotonin-dependent regulation of ciliary beat frequency.

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

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.

A numerical study of muco-ciliary transport under the condition of diseased cilia

Structural and functional disorders of pulmonary cilia may result from genetic disorders and acquired insults. A two-dimensional numerical model based on the immersed boundary method coupled with the projection method is used to study the flow physics of muco-ciliary transport of the human respiratory tract under various abnormalities of cilia. The effects of the cilia beat pattern (CBP), ciliary length, immotile cilia, beating amplitude and uncoordinated beating of cilia are investigated. As expected, the mucus velocity decreases as the beating amplitude reduces. The windscreen wiper motion and rigid planar motion, which are two abnormal CBPs owing to genetic disorders, greatly reduce or almost stop the mucus transport. If the ciliary length varies from its standard length, the mucus velocity would decrease. The mucus velocity decreases rather linearly if the number of uniformly distributed immotile cilia increases. The numerical results show that the mucus velocity would be further reduced marginally when the uniformly distributed immotile cilia are rearranged as a cluster of immotile cilia. Furthermore, if half of the cilia are immotile and uniformly distributed and motile cilia beat at reduced amplitude, the incoordination between the active motile cilia would not significantly affect the mucus velocity.