A two-component theory of aerosol deposition in lung airways

The deposition of aerosol particles in the human lung airways is due to two distinct mechanisms. One is by direct deposition resulting from diffusion, sedimentation and impaction as the aerosol moves in and out of the lung. The other is an indirect mechanism by which particles are transported mechanically from the tidal air to the residential air and eventually captured by the airways due to intrinsic particle motion. This last mechanism is not well understood at present. Using a trumpet airway model constructed from Weibel's data, a two-component theory is developed. In this theory, the particle concentrations in the airways and the alveoli at a given airway depth are considered to be quantitatively different. This difference in concentrations will cause a net mixing between the tidal and residential aerosol as the aerosol is breathed in and out. A distribution parameter is then introduced to account for the distribution of ventilation. The effect of intrinsic particle motion on the aerosol mixing is also included. From this theory, total and regional deposition in the lung at the steady mouth breathing without pause is calculated for several different respiratory cycles. The results agree reasonably well with the experimental data.     

Respiratory deposition model of an inhaled aerosol bolus

The bolus delivery method is designed to deliver a dose to the desired location in the lung, and it has the advantage of fewer side effects and a more efficient way of delivery. Based upon the lung deposition model developed for continuously inhaling aerosols of constant concentration, a mathematical model of aerosol bolus deposition is proposed. The calculated results show that the recovery depends on the bolus penetration depth, flow rate, particle size, breath holding time and bolus volume. Three sets of published experimental data with different controlling factors (particle size, flow rate and breath holding time) are adopted to make the quantitative comparisons with the calculated results. The predictions and data for the low intrinsic motion particles (～1 μm) have good agreement, as do the coarse particles in the shallow airways region. For females, the recovery was found to be consistently lower than that for males.     

Respiratory deposition model of an inhaled aerosol bolus

The bolus delivery method is designed to deliver a dose to the desired location in the lung, and it has the advantage of fewer side effects and a more efficient way of delivery. Based upon the lung deposition model developed for continuously inhaling aerosols of constant concentration, a mathematical model of aerosol bolus deposition is proposed. The calculated results show that the recovery depends on the bolus penetration depth, flow rate, particle size, breath holding time and bolus volume. Three sets of published experimental data with different controlling factors (particle size, flow rate and breath holding time) are adopted to make the quantitative comparisons with the calculated results. The predictions and data for the low intrinsic motion particles (～1 μm) have good agreement, as do the coarse particles in the shallow airways region. For females, the recovery was found to be consistently lower than that for males.     

Measurement of urinary clusterin as an index of nephrotoxicity.

Measurements of tissue immunoassayable clusterin, a protein associated with programmed cell death and tissue reorganization, were performed in rats treated with nephrotoxic doses of gentamicin sulfate. Adult Lewis rats were treated with 100 mg/kg/day of gentamicin sulfate for 12 days. Urine, serum, and tissue levels of clusterin protein were measured, as were urinary N-acetyl beta-glucosaminidase (NAG) and serum creatinine levels. Induction of renal injury by gentamicin was detectable within 4 days by increased levels of urinary N-acetyl beta-glucosaminidase (from 280 +/- 66 (mean +/- SD) to 910 +/- 210 nmol/mg creatinine), and within 9 days of initiating gentamicin treatment by increased serum creatinine (from 0.5 +/- 0.1 to 1.2 +/- 0.4 mg/dl). Paralleling these changes, renal, urinary, and serum levels of clusterin increased 10-, 116-, and 3-fold (P less than 0.05). Treatment with gentamicin sulfate did not increase clusterin levels in the seminal vesicle, ventral prostate, testis, or epididymis. The measurement of urinary or serum clusterin may play a role in the early detection of renal injury.     

Theoretical evaluation of aerosol deposition in anatomical models of mammalian lung airways

A computational model to predict deposition of a wide variety of particulate pollutants in several species of mammals is presented. The model incorporates breathing pattern and detailed anatomical models of the respiratory tract based on extensive morphometric measurements of individual airways. The predicted deposition from this general model is in close agreement with observed deposition of monodisperse aerosols in rats. Particle size and density and respiratory breathing patterns are the critical parameters affecting regional deposition.     

Persistence of enhanced aerosol deposition in the lung after recovery from carbachol-induced airway obstruction

Time course recovery from induced airway obstruction by carbachol infusion (CI; 0.2 microgram.kg-1.min-1 for 40 min), carbachol aerosol (CA; 10 breaths of 2% solution), and histamine aerosol (HA; 25-50 breaths of 5% solution) challenge was investigated in conscious sheep (n = 6 each). Total lung aerosol deposition and airway caliber as assessed by pulmonary airflow resistance (RL) were measured every 20-30 min up to 4 h after the challenges. Aerosol deposition was measured by monitoring aerosol concentration continuously with a laser aerosol photometer while the sheep rebreathed 1.0-micron-diam inert oil droplets delivered by a 0.25-liter bag-in-box system driven by a respiratory pump at a breathing frequency of 30 breaths/min. Total accumulated deposition at the fifth breath (AD5) as percentage of the initial aerosol concentration was determined and used as an aerosol deposition index. Percent changes in AD5 from baseline were compared with corresponding changes in RL. Both RL and AD5 increased after Cl, CA, and HA: 192-477% for RL and 23-44% for AD5 (P less than 0.05). Mean RL return to baseline values 1 h after CI and HA and 2 h after CA. Mean AD5 returned to baseline at 1 h post-HA. In contrast, mean AD5 remained elevated for 2-4 h after CI and CA (P less than 0.05), and the increased AD5 could not be reversed by a bronchodilator aerosol. The persistence of enhanced aerosol deposition long after the return of RL to baseline suggests that complete recovery of airway conditions after CI and CA takes much longer than predicted by RL.(ABSTRACT TRUNCATED AT 250 WORDS)     

Maximization of pulmonary hygroscopic aerosol deposition

A newly developed computer model is used to predict the aqueous salt solution concentration, breathing pattern, and inhaled droplet size distribution parameters that will maximize pulmonary deposition of hygroscopic medicinal aerosols. The parameter values providing maximum pulmonary deposition include 1) a NaCl concentration in the aerosolized solution of 0.035 g/ml or higher if the subject can tolerate it, 2) as nearly a monodispersed inhaled aerosol size distribution as possible, 3) an aerosol mass median diameter of 2-3 micron, and 4) slow (7 breaths/min) uninterrupted breathing of 1.5-2 liters of aerosol/breath. With these values, the model predicts that pulmonary deposition can be increased by greater than 100% relative to the deposition achieved in conventional inhalation therapy with isotonic saline-based medications.     

Targeted drug aerosol deposition analysis for a four-generation lung airway model with hemispherical tumors

One important research area of broad interest is the development of highly efficient drug delivery systems for desired site deposition and uptake. For example, controlled drug aerosol release and targeting to specific regions of the lung is a novel way to combat lung diseases, diabetes, virus infections, cancers, etc. Determination of feasible air-particle streams is a prerequisite for the development of such delivery devices, say, smart inhalers. The concept of "controlled particle release and targeting" is introduced and results are discussed for a representative model of bronchial lung airways afflicted with hemispherical tumors of different sizes and locations. It is shown that under normal particle inlet conditions a particle mass fraction of only up to 11% may deposit on the surface of a specific tumor with critical radius r/R approximately 1.25, while a controlled particle release achieves deposition fractions of 35 to 92% for a realistic combination of inlet Stokes and Reynolds numbers, depending mainly on tumor size. Furthermore, with the controlled release and targeting approach nearby healthy tissue is hardly impacted by the typically aggressive drug aerosols. Assuming laminar, quasi-steady, three-dimensional air flow and spherical non-interacting micron-particles in sequentially bifurcating rigid airways, the results were obtained using a validated commercial finite-volume code with user-enhanced programs on a high-end engineering workstation. The new concept is generic and hence should be applicable to other regions of the respiratory system as well.     

Assessment of papain-induced lung injury in isolated lungs by measurements of aerosol deposition and mixing.

Aerosol bolus inspirations were used to assess lung injury in 15 isolated dog lungs exposed to low (0-375 units) or high doses (600-1,200 units) of papain. Effective air space size (EAD) was determined from aerosol deposition during a 5-s breath hold. Convective mixing was assessed by the spreading of the expired bolus with respect to expired volume, quantified by a coefficient of dispersion (CD) equal to the square root of the difference in the variances of the expired and inspired boluses divided by the volumetric penetration of the bolus. After exposure, CD measured with deeply penetrating boluses increased by an average of 2.5% in the low-exposure group (P greater than 0.05) and 28.0% in the high-exposure group (P less than 0.0001). CD measured with shallowly penetrating boluses decreased by 4.3% (P less than 0.0001) in the low-exposure group and increased by an average of 18.3% in the high-exposure group (P less than 0.05). Papain exposure caused EAD to increase in some lungs and decrease in others. For deep bolus penetrations, EAD changed by an average of -0.8% in the low-exposure group (P greater than 0.05) and +21.1% in the high-exposure group (P greater than 0.05). Both EAD and CD appeared to be sensitive to lung injury. However, changes in EAD were less consistent than those in CD, possibly due to changes caused by lung injury in the regional distribution of inspired aerosol.     

The sulphate-S/total S ratio in plants as an index of their sulphur status

Summary Several authors are advocating the use of the SO₄–S/total S ratio in the plant as the best index of S status. We have traced the arguments put forward in support of this index, and we show that they are based either on unfair comparisons with other indices, such as SO₄–S or total S alone, or inappropriate statistical treatment.The SO₄–S/total S index has two fundamental disadvantages compared with SO₄–S or total S alone: (1) the numerator (SO₄–S) is the major variable in the denominator, so the ratio is likely to be less sensitive than either of the measurements alone; (2) its determination involves twice as much analytical work as either measurement alone.Examination of some of the source references indicates that SO₄–S by itself is the most satisfactory S index. Whenever whole plants are analysed, any index which includes organic S is subject to variation due to tissue age.     

Measurement of F(2)-isoprostanes as an index of oxidative stress in vivo

In 1990 we discovered the formation of prostaglandin F(2)-like compounds, F(2)-isoprostanes (F(2)-IsoPs), in vivo by nonenzymatic free radical-induced peroxidation of arachidonic acid. F(2)-IsoPs are initially formed esterified to phospholipids and then released in free form. There are several favorable attributes that make measurement of F(2)-IsoPs attractive as a reliable indicator of oxidative stress in vivo: (i) F(2)-IsoPs are specific products of lipid peroxidation; (ii) they are stable compounds; (iii) levels are present in detectable quantities in all normal biological fluids and tissues, allowing the definition of a normal range; (iv) their formation increases dramatically in vivo in a number of animal models of oxidant injury; (v) their formation is modulated by antioxidant status; and (vi) their levels are not effected by lipid content of the diet. Measurement of F(2)-IsoPs in plasma can be utilized to assess total endogenous production of F(2)-IsoPs whereas measurement of levels esterified in phospholipids can be used to determine the extent of lipid peroxidation in target sites of interest. Recently, we developed an assay for a urinary metabolite of F(2)-IsoPs, which should provide a valuable noninvasive integrated approach to assess total endogenous production of F(2)-IsoPs in large clinical studies.     

Effect of microgravity and hypergravity on deposition of 0.5-to 3-m-diameter aerosol in the human lung

Darquenne, Chantal, Manuel Paiva, John B. West, and G. KimPrisk. Effect of microgravity and hypergravity on deposition of0.5- to 3-µm-diameter aerosol in the human lung. J. Appl. Physiol. 83(6): 2029-2036, 1997.Wemeasured intrapulmonary deposition of 0.5-, 1-, 2-, and 3-µm-diameterparticles in four subjects on the ground (1 G) and during parabolicflights both in microgravity (µG) and at ~1.6 G. Subjects breathed aerosols at a constant flow rate (0.4 l/s) and tidalvolume (0.75 liter). At 1 G and ~1.6 G, deposition increased withincreasing particle size. In µG, differences in deposition as afunction of particle size were almost abolished. Deposition was anearly linear function of the G level for 2- and 3-µm-diameterparticles, whereas for 0.5- and 1.0-µm-diameter particles, depositionincreased less between µG and 1 G than between 1 G and ~1.6 G. Comparison with numerical predictions showed good agreement for 1-, 2-, and 3-µm-diameter particles at 1 and ~1.6 G, whereas the modelconsistently underestimated deposition in µG. The higher depositionobserved in µG compared with model predictions might be explained bya larger deposition by diffusion because of a higher alveolarconcentration of aerosol in µG and to the nonreversibility of theflow, causing additional mixing of the aerosols.

     

Serum copper concentration as an index of lung injury in rats exposed to hemithorax irradiation

Serum copper concentration was evaluated as an index of lung injury (monitored by lung prostacyclin production) with respect to the effects of time, dose, dose fractionation, and penicillamine dose modification in rats irradiated to the right hemithorax. Both lung PGI2 production and serum Cu concentration increased with increasing 60Co gamma-ray dose in animals sacrificed 2 or 6 months postirradiation, and the highest values for both responses were observed at the latter autopsy time. At 2 months postirradiation, the elevations in lung PGI2 production and serum Cu concentration also were spared similarly when total radiation doses were delivered in five equal daily fractions as compared to single doses. Finally, the ability of D-penicillamine to ameliorate the radiation-induced hyperproduction of PGI2 by rat lung was accompanied by an attenuation of the dose-dependent increase in serum Cu concentration at 2 months postirradiation in the drug-treated rats. In contrast, serum iron concentration was independent of time, dose, and penicillamine. At 2 months after irradiation, there also was a dose-dependent increase in lung hydroxyproline (collagen) content, the magnitude of which correlated closely with serum copper concentration in individual animals. Thus serum copper concentration is an accurate and minimally invasive index of lung injury in rats irradiated to the hemithorax and can predict lung hydroxyproline (collagen) content in individual irradiated rats.     

Effect of gravity on aerosol dispersion and deposition in the human lung after periods of breath holding.

To determine the extent of the role that gravity plays in dispersion and deposition during breath holds, we performed aerosol bolus inhalations of 1-microm-diameter particles followed by breath holds of various lengths on four subjects on the ground (1G) and during short periods of microgravity (microG). Boluses of approximately 70 ml were inhaled to penetration volumes (V(p)) of 150 and 500 ml, at a constant flow rate of approximately 0.45 l/s. Aerosol concentration and flow rate were continuously measured at the mouth. Aerosol deposition and dispersion were calculated from these data. Deposition was independent of breath-hold time at both V(p) in microG, whereas, in 1G, deposition increased with increasing breath hold time. At V(p) = 150 ml, dispersion was similar at both gravity levels and increased with breath hold time. At V(p) = 500 ml, dispersion in 1G was always significantly higher than in microG. The data provide direct evidence that gravitational sedimentation is the main mechanism of deposition and dispersion during breath holds. The data also suggest that cardiogenic mixing and turbulent mixing contribute to deposition and dispersion at shallow V(p).