Cough Clearance Research Articles

Role of phospholipid lining on respiratory mucus clearance by cough

Phospholipid lining, present at the respiratory mucus-mucosa interface, may have an important role in the protective function of the airways by its abhesive properties and may also facilitate mucus transport. To mimic respiratory mucus-mucosa interface, monolayers of three different forms of phosphatidylglycerol (PG) have been deposited on glass slides by the Langmuir-Blodgett technique. Mucus adhesion and clearance by cough of mucus on these PG-coated or noncoated surfaces have been analyzed and compared, using frog respiratory mucus as "normal" mucus. Among the three PG types studied, the phosphatidylglycerol distearoyl, which is the phospholipid with the longest saturated fatty acid chain, was found to significantly improve the mucus cough clearance by decreasing the mucus work of adhesion compared with the noncoated surfaces. On the other hand, phosphatidylglycerol dipalmitoyl did not improve mucus cough clearance although it decreased mucus adhesion, and phosphatidylglycerol dioleyl did not improve either mucus cough clearance or mucus adhesion.

A Pilot Study of Aerosolized Amiloride for the Treatment of Lung Disease in Cystic Fibrosis

Excessive active absorption of sodium is a unique abnormality of the airway epithelium in patients with cystic fibrosis. This defect is associated with thickened mucus and poor clearance of airway secretions and may contribute to the pulmonary disease in these patients. To study whether the inhibition of excessive absorption of sodium might affect the course of lung disease in cystic fibrosis, we performed a double-blind, crossover trial comparing aerosolized amiloride (5 mmol per liter; 3.5 ml four times daily), a sodium-channel blocker, with vehicle alone. Fourteen of the 18 adult patients initially enrolled in the study completed the one-year trial (25 weeks for each treatment). The mean (+/- SEM) loss of forced vital capacity (FVC) was reduced from 3.39 +/- 1.13 ml per day during treatment with vehicle alone to 1.44 +/- 0.67 ml per day during treatment with amiloride (P less than 0.04). A measured index of sputum viscosity and elasticity was abnormal during treatment with vehicle alone and improved during treatment with amiloride. Calculated indexes of mucociliary and cough clearance also improved during amiloride treatment. No systemic, respiratory, or subjective toxic effects of amiloride were noted. We conclude from this preliminary study that aerosolized amiloride can be safely administered to adults with cystic fibrosis. The slowing of the loss of FVC and the improvement in sputum viscosity and elasticity suggest a beneficial clinical effect. Aerosolized amiloride deserves further evaluation in the treatment of lung disease in patients with cystic fibrosis.

Acute and Long-term Amiloride Inhalation in Cystic Fibrosis Lung Disease: A Rational Approach to Cystic Fibrosis Therapy

Cystic fibrosis (CF) is the most common inherited fatal disorder among Caucasians. Bronchial mucus in CF contains more potassium and less sodium, which may be due to increased sodium absorption, resulting in a reduced airway water content. We studied 23 patients with CF after inhalation of normal saline or amiloride (10(-3) M), a sodium transport blocker. Mucociliary clearance (MC) and cough clearance (CC) were determined with a gamma camera that traced the movement of 99mTc-labeled, hardened erythrocytes over a 1-h period after the patients inhaled these particles as an aerosol. Before and after each investigation pulmonary function tests (PFT) and blood pressure (BP) were measured. Sputum thread formation was measured by means of a filancemeter. Six of the patients also completed a 3-wk trial of amiloride inhalation therapy. MC increased significantly (p less than 0.001) after acute amiloride inhalation (bronchial deposition, 0.07 mg amiloride) compared with that in the saline control. CC also increased, but not as much as MC. After 3 wk of amiloride inhalation (2 times a day) clearance values (both MC and CC) were markedly enhanced (p less than 0.01); after a similar period of saline inhalation, clearance values were not different from baseline. Sputum filance values also decreased significantly after amiloride inhalation. There were no adverse effects of the amiloride inhalation compared with saline. We conclude that amiloride inhalation administered as a single dose or as long-term therapy is able to increase MC and CC in CF airways and that the effect of 10(-3) M amiloride inhalation on MC lasts at least 40 min. (ABSTRACT TRUNCATED AT 250 WORDS)

Effect of Amiloride on Human Bronchial Ciliary Activity in vitro

Amiloride (AM) reduces mucociliary transport in the frog palate in vitro preparation, whereas in vivo inhalation of AM enhances mucociliary and cough clearance in cystic fibrosis patients. AM influences the bioelectric properties of the respiratory mucosa, and since electrical activity and ciliary activity are strictly related in the beating cell, an effect on ciliary function cannot be excluded. We have, therefore, investigated the effect of AM (10(-7) to 10(-3) M) in vitro on the ciliary activity of ten samples of healthy human bronchial epithelium at 37 degrees C. The baseline ciliary beat frequency was 13.7 +/- (SD) 1.0 Hz. At concentrations of AM of 10(-4) and 10(-3) M, small statistically significant (p less than 0.01) increases in ciliary beat frequency were recorded only after 1 min of exposure to the drug, with changes of +8.2 and +7.6%, respectively. We conclude that (1) AM affects the ciliary activity of the beating cell, but (2) because of the weakness and short duration of the effect, it is unlikely that AM plays a major role on mucociliary transport.

The role of mucus gel viscosity, spinnability, and adhesive properties in clearance by simulated cough.

We investigated the role of the viscoelastic and adhesive properties of mucus gel simulants on the clearance of mucus by simulated cough. Mucus-like gels with widely varying viscoelastic properties were prepared from polysaccharides crosslinked with sodium borate. Cough was simulated by opening a solenoid valve connecting a model trachea to a pressurized tank. The clearance of gels lining the model trachea was quantified by observing marker particle transport. Viscosity elastic modulus, relaxation time and yield stress were measured with a steady-shear viscoelastometer. Spinnability (thread formation) was determined with a filancemeter. Adhesivity (surface tension) was measured by the platinum ring technique. The viscoelastic and adhesive properties of the mucus gel simulants spanned the ranges observed for bronchial secretions from patients with COPD. The relationship between simulated cough clearance and the viscoelastic and adhesive properties of the gels was analyzed by stepwise linear regression of the non-zero data matrix. The major independent variable relating to clearance was viscosity. Secondary, but highly significant dependences, were also found for spinnability and adhesivity. Elastic modulus, relaxation time and yield stress had no independent effect on cough clearance over the investigated range. The results indicate that, in the absence of airway surface liquid, cough-type clearance relates primarily with mucus gel viscosity. For a given viscosity, clearance is also impaired by spinnability, i.e. the capacity of the mucus to form threads. At constant viscosity and spinnability, clearance is further impaired by an increase in the adhesivity of the mucus. The negative dependence of each of these physical factors can be rationalized in terms of their inhibitory effect on wave formation in the mucus lining layer during high velocity airflow interaction.

Impaired mucus clearance in patients with chronic bronchial sepsis, sinusitis and dextrocardia.

Published reports have indicated that patients with Kartagener's syndrome (dextrocardia, sinusitis and bronchiectasis) have no significant lung mucociliary clearance. With a radioaerosol technique we measured over a 6-hour observation period the tracheobronchial clearance of 8 patients with dextrocardia, chronic bronchial sepsis and chronic sinusitis (DC). The tracheobronchial clearance of these patients was significantly reduced (p less than 0.02) compared with that of 29 healthy subjects of similar age. However, even when allowance was made for productive coughing during the observation period, the reduced clearance was much better than anticipated from published reports in patients with Kartagener's syndrome, which confined their observations to a 2-hour period. The tracheobronchial clearance of the DC patients, adjusted for productive coughing, was as bad as that found in an older group of patients with chronic obstructive airways disease who refrained from expectorating during the equivalent test period. Our study implies one or more of the following possibilities: (a) a spectrum of mucociliary impairment in patients with DC; (b) an effective cough clearance deeper in the lung than hitherto believed, and (c) two-phase flow of mucus cephalad as an effective clearance mechanism in patients with DC.

The role of mucus viscoelasticity in cough clearance.

The relationships between mucus rheology, depth of mucus layer and clearance by simulated cough were examined in a study employing a model plexiglass trachea lined with gels formed from locust bean gum crosslinked with sodium tetraborate. The viscoelastic properties of the mucus simulants were determined by magnetic rheometry at 100 rad/s and expressed as mechanical impedance (dynamic stress/strain ratio) and loss tangent. Cough was simulated by opening a solenoid valve connecting the model trachea to a pressurized tank, using an upstream flow-constrictive element to shape the flow profile to approximate the pattern seen in a normal adult. Mucus clearance was quantitated by observing the movement of contrasting marker particles placed in the mucus layer. The median particle displacement was defined as the clearance index, Cl. For any initial depth of mucus, Cl increased with driving pressure in the tank, and for a given driving pressure, Cl increased linearly with increasing mucus depth. For a given driving pressure and depth, Cl decreased with increasing mechanical impedance of the mucus. At constant mechanical impedance, Cl increased with increasing loss tangent, in other words, cough clearance was impeded more by elasticity than viscosity. Mucus clearance was associated with transient wave formation in the lining layer. Thus dependence on viscoelasticity is consistent with observations that airflow-mucus interaction and wave formation are impeded by elasticity. The clearance vs. loss tangent relationship for cough is opposite to that found for ciliary clearance (Biorheology 1980, 17, 249), suggesting a natural balance in viscosity and elasticity for mucus to be cleared by both mechanisms.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of airway wall flexibility on clearance by simulated cough.

In our previous study, we investigated the relationship between mucus rheology, depth of mucus layer, and clearance by simulated cough. The purpose of the present study was to examine the effect of airway wall flexibility on the clearance of mucuslike gels. Transient airflows similar to cough were generated by both positive and negative pressure, the latter to mimic the dynamic compression that occurs during real cough. As in the previous study, the trachea was modeled as a trough of rectangular cross section with only the bottom lined with the mucus simulant. Clearance was followed by observing the displacement of marker particles. Since cough clearance is intimately related to wave formation in the mucus blanket, we hypothesized that clearance might be impeded if the wave formation occurred simultaneously in the wall and its lining layer. Thus, in one set of experiments the bottom rigid surface of the model trachea was replaced with a frame over which a flexible membrane could be drawn, whereas in the other set the rigid top was replaced by the frame. We also examined the effect of negative-pressure cough in excised canine tracheae, comparing the case where the tracheal membrane was free to deform vs. the case where it was secured. For the rigid-walled model, clearance by positive or negative pressure, with matched flow pattern, was the same. With the mucus simulant lining the flexible bottom surface, clearance increased with increasing membrane flexibility for negative-pressure cough and decreased for positive-pressure cough.(ABSTRACT TRUNCATED AT 250 WORDS)

Deposition of aerosols and bronchial clearance measurements.

A special inhalative device is described for reproducible deposition patterns of radioactive aerosols to measure mucociliary and tussive clearance and to evaluate the effect of drugs on the bronchial tree. Additive actions on mucus transport exist between beta 2-agonists and theophylline, but not in combination with inhalative quaternary ammonium compounds (ipatropium and oxitropium bromide). Mucolytics are generally less effective on mucociliary clearance than beta 2-agonists and theophylline, positive, negative and nonresponders are often seen due to the different viscoelastic properties of the mucus. Mucus transport is more than mucociliary clearance. Two-phase gas/liquid movement and coughing are also important transport mechanisms for bronchial mucus. Therefore, bronchodilators enhance mucus transport by increasing airway patency, which increases total and regional air flow and improves cough clearance.

Respiratory tract infections: Intrinsic risk factors

A complex system exists to provide defense of the respiratory tract against infection. The three major components of the respiratory defense system are mechanical (such as cough and mucociliary clearance), humoral (such as secretory immunoglobulins and complement), and cellular (such as alveolar macrophages, lymphocytes, and neutrophils). These components are important in both upper as well as lower airways, but their relative importance varies according to location. Along with an increased understanding of the mechanisms for respiratory host defense has been the demonstration of numerous intrinsic defects in this system. Increased frequency of respiratory infections has clearly been associated with intrinsic defects. These associations will be described.

New approaches to regulation of fluid secretion in airways.

Physiologic, morphologic, biochemical, and immunologic methods have been used to study cholinergic and adrenergic regulation of airway submucosal gland secretion. Using a newly developed micropipette method, we can now measure the rate of fluid flow from each individual gland duct and we can harvest these secretions for specific chemical analysis. Stimulation of both the cholinergic and adrenergic systems affect gland secretions. The vagus nerves are the pathways for many reflexes affecting secretion: laryngeal, gastric and carotid body chemoreceptor stimulation accelerate the fluid production, and lung inflation (Hering-Breuer reflex) inhibits fluid secretion. Stimulation by cholinergic, muscarinic agonists depletes both mucous and serous cells, so vagal reflexes probably produce mixed secretions. In contrast, alpha-adrenergic agonists deplete serous cell contents, release high concentrations of lysozyme and produce large volumes of fluid with a low protein concentration, while beta-adrenergic stimulation may selectively deplete mucous cells, releases little lysozyme and produces scanty fluid with a high protein concentration. The significance of this cholinergic and adrenergic modulation on cough and ciliary clearance are important subjects for future study.

The clinical physiology of the human bronchi. III. The effect of vagus section on the cough reflex, bronchial caliber, and clearance of bronchial secretions.

The clinical physiology of the human bronchi. III. The effect of vagus section on the cough reflex, bronchial caliber, and clearance of bronchial secretions.