Klas Philipson

A Comparison of Nasal and Tracheobronchial Clearance

Tracheobronchial clearance and nasal clearance were compared in 13 pairs of monozygotic twins and 11 nontwins. Tracheobronchial clearance was studied by having the subjects inhale, by mouth, a test aerosol of 6μmol particles tagged with technetium Tc 99m (99mTc) and making external measurements of the radioactivity. Nasal clearance was studied with two methods: (1) a 0.6-mm anion resin particle tagged with 99mTc was externally followed at five different points along the nasal passage and (2) a saccharine particle was placed on the mucociliary mucosa anteriorly in the nose and the time was registered until the subject noted a sweet taste. A weak positive association existed between tracheobronchial clearance and nasal clearance as studied with the saccharine particle method, but no association was found between tracheobronchial clearance and nasal clearance as tested by the tagged resin particle method.

Negligible clearance of ultrafine particles retained in healthy and affected human lungs

Ambient particles are believed to be a specific health hazard, although the underlying mechanisms are not fully understood. There are data in the literature indicating fast and substantial systemic uptake of particles from the lung. The present authors have developed an improved method to produce ultrafine particles with more stable radiolabelling and defined particle size range. Fifteen subjects inhaled technetium 99m (99mTc)-labelled carbonaceous particles of 100 nm in size. Radioactivity over the lung was followed for 70 h. The clearance of these ultrafine particles from the lungs and specifically translocation to the circulation was tested. Lung retention for all subjects at 46 h was mean±sd 99±4.6%. Cumulative leaching of 99mTc activity from the particles was 2.6±0.96% at 70 h. The 24-h activity leaching in urine was 1.0±0.55%. No evidence of a quantitatively important translocation of 100-nm particles to the systemic circulation from the lungs was found. More research is needed to establish if the ∼1% cleared activity originates from leached activity or insoluble translocated particles, and whether a few per cent of translocated particles is sufficient to cause harmful effects.

No Significant Translocation of Inhaled 35-nm Carbon Particles to the Circulation in Humans

Human pulmonary retention of 35 nm 99mTc-labeled carbonaceous particles, produced with a modified Technegas generator, was followed for 24 h using a gamma camera imaging technique. Nine healthy subjects and four asthmatics inhaled the test particles. Particle labeling stability was tested in vitro during 48 h. We also measured in vivo leaching in blood and in urine for 24 h. One additional subject was exposed to particles with unstable labeling. There were no significant differences between healthy and asthmatic subjects in any of the parameters studied. Particle retention after 24 h was 102% (SD ± 4.7). Cumulative in vitro leaching of 99mTc activity from the particles was 1.7% (±1.1) after 24 h. In blood samples, 80 min after exposure, 1.1% (± 0.4) of initially deposited activity was detected and 91% of the activity was not bound to particles. In urine sampled during the first 24 h after exposure, 3.6% (± 0.9) of lung deposited activity was detected. Lung retention was 30% after 1 h in the subject exposed to the leaching aerosol (n = 1). Thirty-one percent of the deposited activity was detected in the blood after 80 min and 80% was not bound to particles. Fifty percent of the activity was excreted with urine within 24 h. On gamma camera images the activity visibly translocated from lungs to thyroid and gastrointestinal tract. In conclusion, over a 24-h period there was no significant translocation of inhaled 35-nm particles to the systemic circulation.

Increased Mucociliary Transport by Cholinergic Stimulation

Tracheobronchial clearance of inhaled 6mum Teflon particles (density 2 gm/cu cm) tagged with technetium 99m was studied in healthy subjects by external measurement of the radioactivity in the lungs for two hours. Clearance, salivary secretion, blood pressure, and heart rate were determined in eight subjects after double-blind, subcutaneous administration of 0.25 mg terbutaline sulfate, a beta-adrenoceptor stimulating compound and vehicle, respectively, in a crossover study. Terbutaline produced a marked increase in clearance and a slight increase in heart rate, but had no important effect on salivary secretion or blood pressure. The result indicates that the blood concentrations of catecholamines might be of importance for the regulation of the mucociliary transport rate.

Human Lung Deposition of Particles Suspended in Air or in Helium/Oxygen Mixture

Deposition in mouth and throat and the fraction of alveolarly deposited particles in the lung of 3.6- to 3.8-microns Teflon particles labeled with 99mTc were estimated in nine healthy subjects. The particles were inhaled in air or helium/oxygen mixture with a flow of 0.5 l/s by subjects with or without induced bronchoconstriction. The bronchoconstriction (two- to threefold increase in airway resistance) was induced by an aerosol of methacholine bromide. As the Reynolds number is three times lower for the helium/oxygen mixture than for air, and the sedimentation rate of the particles is about the same in both, a different regional deposition between particles suspended in air and helium/oxygen mixture should be due to turbulence. Deposition in mouth and throat did not differ significantly between air and the helium/oxygen mixture. The alveolarly deposited fraction tended to be larger for unconstricted airways and was significantly larger for constricted airways for inhalations in the helium/oxygen mixture compared to air. In real life, air pollutants and therapeutic aerosols may be inhaled with larger flow rates and broncho-constriction may be more pronounced in patients, so that deposition of particles due to turbulence can be important.

Deposition of Large Particles in Human Lung

Twenty-four nonsmoking males, all without history of pulmonary disease, were randomly divided into four groups of six subjects each. The subjects in each group inhaled monodisperse Teflon particles labelled with 111In (half-life 2.83 days); 8.2, 11.5, 13.7 and 16.4 micron aerodynamic diameter, respectively. Radioactivity in head and throat, lung and stomach was determined after 0, 3 and 24 hrs using a profile scanner. For some subjects radioactivity was also determined using a whole-body scanner at 3.5 and 24 hrs. After the 24-hr determination the subjects inhaled labelled Teflon particles again, this time with a filter in front of the mouth. Average values for total deposition in the body, obtained using a profile scanner, whole-body scanner and filter measurements, agreed fairly well. Lung retention values obtained by whole-body and profile scanning also agreed well. The average deposition in the lung, expressed as a percentage of total deposition, was 49, 31, 21 and 13% for the four particle sizes (8.2-16.4 micron). Alveolar deposition, determined as retention at 24 hrs and expressed in percent of total deposition, was 15, 4, 4 and 1%. For the smallest particle sizes the deposition values agreed with earlier investigations. However, for the larger particles the two deposition values were higher than expected when compared to earlier studies.

Long-term clearance from small airways decreases with age

The prevalence of respiratory symptoms increases with age. Age has been found to be negatively associated with large airway clearance. The small airways region is considered important for development of airway disease. Clearance after the first 24 h was studied in 46 healthy subjects with a wide age distribution, (mean 42, range 19–81 yrs). All subjects inhaled monodisperse 6 μm Teflon particles labelled with 111In, with an extremely slow inhalation flow (0.05 L·s−1). The particles were mainly deposited in the small conducting airways. Lung retention was measured at 0 and 24 h, and at 7, 14 and 21 days after inhalation. Significant relationships were found for the individual 24 h “large” airway clearance in per cent of initial lung deposition with age, forced expiratory volume in one second and forced vital capacity. Age was negatively associated with “small” airway clearance after 24 h as estimated at 2, 7, 14 and 21 days. Using stepwise linear regression only age remained significantly associated to clearance. In conclusion, small airway clearance over 21 days was found to decrease with age. This might be one factor associated with the high prevalence of respiratory symptoms associated among the elderly.

Human Deposition and Clearance of 6-μm Particles Inhaled with an Extremely Low Flow Rate

In human experimental data, tracheobronchial deposition reaches its maximum for particles of about 6 microns inhaled at 0.5 L/s. The purpose of the present study was to investigate if tracheobronchial deposition of 6-microns particles could be increased, especially in the smaller bronchi, using an extremely slow inhalation rate. Six healthy nonsmokers inhaled monodisperse 6-microns (aerodynamic diameter) Teflon particles labeled with 111In at 0.04 L/s. Radioactivity in mouth and throat, lung, and stomach was measured immediately after inhalation by profile scanning and in the lung also after 24, 48, 72, and 96 h. There was a substantial clearance between 24 and 72 h; around 20% of the total clearance occurred between 24 and 72 h. This is in contrast to earlier studies in which only around 1% of 6-microns particles inhaled at 0.5 L/s cleared between 24 and 72 h. This indicates a markedly higher deposition in the smaller bronchi at 0.04 L/s than at 0.5 L/s. The total tracheobronchial deposition was 50%, compared to about 30% when particles were inhaled at 0.5 L/s. These findings could be therapeutic use. They also implicate the possibility of developing a diagnostic model that can separate between bronchial reactivity in large and small bronchi.

Deposition of inhaled particles in the mouth and throat of asthmatic subjects

We previously studied the deposition of inhaled particles in the mouth and throat of asthmatic patients, and found large, reproducible differences among subjects. In the present study, we examined whether anatomical and/or functional differences in the pharynx and larynx could underlie this interindividual variation. Deposition in the mouth and throat, and in the lung was estimated in 16 asthmatic subjects after inhalation of 3.6 microns (aerodynamic diameter) monodisperse Teflon particles labelled with 111In. The particles were inhaled at a flow rate of 0.5 l.s-1 with maximally deep breaths. Radioactivity was measured by external scanning over head and neck, lungs and stomach, immediately after the inhalation. Radioactivity in the lungs was also measured 24 h later. A measure of the total amount of particles deposited in the mouth and throat was obtained from the added activities in mouthwash, head and neck, and stomach, immediately after the inhalation of the test particles. Pharynx and larynx function was examined by fibreoptic laryngoscopy performed during a corresponding inhalation procedure. Deposition in the mouth and throat varied widely among the subjects, ranging 9-76% (median 12%). We found two subpopulations, 13 subjects in the range 9-34%, and 3 subjects with > 70% deposition. Deviations in pharyngeal configuration during inhalation were significantly related to high mouth and throat deposition, whereas functional differences in the larynx were not. Our study shows that mouth and throat deposition may be extremely high in some asthmatics, and that pharyngeal configuration affects deposition of particles in the mouth and throat.

Tracheobronchial Clearance in Smoking-Discordant Twins

Tracheobronchial clearance has been studied with a test aerosol of approximately 6µ particles of fluorinated ethylene propylene tagged with technetium 99m and external measurement of radioactivity in the lungs. Ten monozygotic pairs of twins, discordant with regard to cigarette smoking, were studied. In five of the pairs, the smoker had a markedly slower clearance than the nonsmoker, whereas in the other five pairs the smoker had a clearance similar to that of the nonsmoker. Clearance was on the average significantly slower in the smokers than in the non-smokers; and the slower clearance in the smokers was considered to be due to reduced mucociliary transport.