Deposition of micrometer particles in pulmonary airways during inhalation and breath holding

We investigated how breath holding increases the deposition of micrometer particles in pulmonary airways, compared with the deposition during inhalation period. A subject-specific airway model with up to thirteenth generation airways was constructed from multi-slice CT images. Airflow and particle transport were simulated by using GPU computing. Results indicate that breath holding effectively increases the deposition of 5μm particles for third to sixth generation (G3-G6) airways. After 10s of breath holding, the particle deposition fraction increased more than 5 times for 5μm particles. Due to a small terminal velocity, 1μm particles only showed a 50% increase in the most efficient case. On the other hand, 10μm particles showed almost complete deposition due to high inertia and high terminal velocity, leading to an increase of 2 times for G3-G6 airways. An effective breath holding time for 5μm particle deposition in G3-G6 airways was estimated to be 4-6s, for which the deposition amount reached 75% of the final deposition amount after 10s of breath holding.     

Investigation of inhalation and exhalation flow pattern in a realistic human upper airway model by PIV experiments and CFD simulations

Biomechanics and Modeling in Mechanobiology - In this study, flow field characteristics in the trachea region in a realistic human upper airway model were firstly measured by particle image...     

Convective and diffusive gas transport in canine intrapulmonary airways.

The significance of convective and diffusive gas transport in the respiratory system was assessed from the response of combined inert gas and particle boluses inhaled into the conducting airways. Particles, considered as "nondiffusing gas," served as tracers for convection and two inert gases with widely different diffusive characteristics (He and SF6) as tracers for convection and diffusion. Six-milliliter boluses labeled with monodisperse di-2-ethylhexyl sebacate droplets of 0.86-microns aerodynamic diameter, 2% He, and 2% SF6 were inspired by three anesthetized mechanically ventilated beagle dogs to volumetric lung depths up to 170 ml. Mixing between inspired and residual air caused dispersion of the inspired bolus, which was quantified in terms of the bolus half-width. Dispersion of particles increased with increasing lung depth to which the boluses were inhaled. The increase followed a power law with exponents less than 0.5 (mean 0.39), indicating that the effect of convective mixing per unit volume was reduced with depth. Within the pulmonary dead space, the behavior of the inert gases He and SF6 was similar to that of the particles, suggesting that gas transport was almost solely due to convection. Beyond the dead space, dispersion of He and SF6 increased more rapidly than dispersion of particles, indicating that diffusion became significant. The gas and particle bolus technique offers a suitable approach to differential analysis of gas transport in intrapulmonary airways of lungs.     

Response to acetylcholine and myosin content of isolated canine airways

Contractility of tracheal smooth muscle strips and spiral strips of fourth to fifth generation bronchi was studied in organ baths. The relationship among contractility, airway smooth muscle myosin, and smooth muscle thickness was also examined. The trachea was divided into three segments, each consisting of 12-14 rings. Smooth muscle strips from each of the three regions (top, middle, and bottom of the trachea) and from fourth to fifth generation bronchi were studied. Acetylcholine (ACh) sensitivity (-log EC50) was 8.1, 7.1, 7.9, and 6.1 for the top, middle, and bottom of the trachea and the bronchi, respectively. At P = 0.01, the EC50 ACh value of the top of the trachea differed from the EC50 value of the bronchi. Maximal tension (Tmax) generated in bronchi (3.2 g) was lower (P less than 0.01) than in the top (10.4 g), middle (7.1 g), and bottom of the trachea (5.1 g). Differences between trachea and bronchi disappeared when Tmax was corrected for smooth muscle myosin content. Thickness of smooth muscle in bronchi was less (P less than 0.01) than in the three regions of trachea. Tmax was significantly correlated with airway smooth muscle thickness (r = 0.56; P less than 0.05). These results suggest that in mongrel dogs sensitivity to ACh shows a gradient from the top of the trachea to the bronchi and that Tmax is greater in the trachea than in the bronchi and is significantly correlated with thickness of smooth muscle.     

Conservation of bronchiolar wall area during constriction and dilation of human airways

Mitchell, R. W., E. Rühlmann, H. Magnussen, N. M. Muñoz, A. R. Leff, and K. F. Rabe. Conservation ofbronchiolar wall area during constriction and dilation of humanairways. J. Appl. Physiol. 82(3):954-958, 1997.We assessed the effect of smooth musclecontraction and relaxation on airway lumen subtended by the internalperimeter(A_i)and total cross-sectional area (A_o)of human bronchial explants in the absence of the potential lungtethering forces of alveolar tissue to test the hypothesis thatbronchoconstriction results in a comparable change ofA_i andA_o.Luminal area (i.e.,A_i) andA_owere measured by using computerized videomicrometry, and bronchial wallarea was calculated accordingly. Images on videotape were captured;areas were outlined, and data were expressed as internal pixel numberby using imaging software. Bronchial rings were dissected in 1.0- to1.5-mm sections from macroscopically unaffected areas of lungs frompatients undergoing resection for carcinoma, placed in microplate wellscontaining buffered saline, and allowed to equilibrate for 1 h.Baseline, A_o[5.21 ± 0.354 (SE)mm²], andA_i(0.604 ± 0.057 mm²) weremeasured before contraction of the airway smooth muscle (ASM) withcarbachol. MeanA_inarrowed by 0.257 ± 0.052 mm²in response to 10 µM carbachol (P = 0.001 vs. baseline). Similarly, A_onarrowed by 0.272 ± 0.110 mm²in response to carbachol (P = 0.038 vs. baseline; P = 0.849 vs. change inA_i).Similar parallel changes in cross-sectional area forA_iandA_owere observed for relaxation of ASM from inherent tone of otherbronchial rings in response to 10 µM isoproterenol. We demonstrate aunique characteristic of human ASM; i.e., both luminal and totalcross-sectional area of human airways change similarly on contractionand relaxation in vitro, resulting in a conservation of bronchiolarwall area with bronchoconstriction and dilation.

     

Hyaluronan distribution in the human and canine intervertebral disc and cartilage endplate

A biotinylated complex of aggrecan G1-domain and link protein was used to characterize the distribution of hyaluronan in paraffin-embedded sections of adult human and canine intervertebral disc and cartilage endplate. Limited chondroitinase ABC and trypsin digestions of the sections before staining was utilized to expose hyaluronan potentially masked by aggrecan. Hyaluronan concentration and hyaluronan to uronic acid ratio in different parts of the discs were measured as a background for the histological analysis.Hyaluronan staining was strong in the nucleus pulposus and inner parts of annulus fibrosus of both species, corroborated by biochemical assays of the same compartments. Particularly in human samples, hyaluronan in the interterritorial matrix of nucleus pulposus and annulus fibrosus was readily accessible to the probe without enzyme treatments. In contrast, the cell-associated hyaluronan signal was enhanced after trypsin or limited chondroitinase ABC-treatment of the sections, suggesting that pericellular hyaluronan was more masked by aggrecan than in the distant matrix. A puzzling feature of canine cartilage endplate cells was their intensive cell-associated hyaluronan signal, part of which appeared intracellular. Hyaluronan was abundant between the collagenous lamellae in annulus fibrosus, perhaps important in the plasticity of this tissue.     

A comparison of the dose-response behavior of canine airways and parenchyma

We compared the histamine responsiveness of canine airways and parenchymal tissues in six anesthetized paralyzed open-chest mongrel dogs, partitioning total lung resistance (RL) into airway resistance (Raw) and tissue viscance (Vti). Pressure was measured during tidal breathing (frequency was 0.3 Hz) at the trachea and in three alveolar regions by use of alveolar capsules. Measurements were taken before and after the delivery of increasing concentrations of aerosolized histamine (0.1-30 mg/ml). We found that Vti accounted for 78 +/- 8% of RL under base-line conditions; this proportion remained relatively constant throughout the histamine concentration-response curve. There was a significant correlation between percent change in Vti and percent change in Raw at all levels of histamine-induced constriction (P less than 0.001). Moreover, the sensitivity of the tissues and airways (defined as the concentration of histamine required to double resistance) was remarkably similar. We conclude that, at this frequency of ventilation, Vti accounts for the major portion of RL both under base-line conditions and after histamine-induced constriction. Although increases in RL cannot be attributed solely to events occurring in the airways, the close correlation between changes in Raw and Vti and the similar sensitivities of the two support the use of indexes reflecting changes in airway caliber as an indicator of overall lung histamine responsiveness.     

Epithelial cell distribution and abundance in rhesus monkey airways during postnatal lung growth and development.

Lung development is both a pre- and postnatal process. Although many lung diseases have their origins in early childhood, few quantitative data are available on the normal growth and differentiation of both the conducting airways and the airway epithelium during the postnatal period. We examined rhesus monkey lungs from five postnatal ages: 4-6 days and 1, 2, 3, and 6 mo. Airways increase significantly in both length and circumference as monkeys increase significantly in body weight from 5 days to 6 mo. In this study we asked: as basement membrane surface area increases, does the epithelial cell organization change? To answer this question, we quantified total epithelial cell mass using high-resolution light micrographs and morphometric techniques on sections from defined airway regions: trachea, proximal intrapulmonary bronchus (generations 1 or 2), and distal intrapulmonary bronchus (generations 6-8). Epithelial thickness decreased in the smaller, more distal, airways compared with trachea but did not change with age in the trachea and proximal bronchus. The volume fraction of all cell types measured did not change significantly. Ciliated cells in the distal bronchus and goblet cells in the trachea both decreased in abundance with increasing age. Overall, the epithelial cell populations changed little in terms of mass or relative abundance to each other during this period of active postnatal lung growth. Regarding the proximal conducting airway epithelium, we conclude that 1) the steady-state abundance is tightly regulated to keep the proportion of cell types constant, and 2) establishment of these cell types occurs before 4-6 days postnatal age. We conclude that growth of the proximal airways occurs primarily in length and lags behind that of the lung parenchyma.     

Bioelectric properties and ion transport across excised canine fetal and neonatal airways

Knowledge of liquid secretion by fetal lung stems from studies of sheep. We extended these studies to dogs and examined the persistence of the fetal pattern of airway epithelial permeability and ion transport in the neonatal animal. Plasma and lung liquid from fetal dogs were analyzed for Na+, K+, Cl-, and HCO3-. Only the Cl- concentration of fetal lung liquid (129 meq/l) was significantly different from that of fetal plasma (111 meq/l). Segments of trachea from fetal and neonatal (less than 1, 7-10, and 21-46 days after birth) dogs were excised and mounted in flux chambers. The transepithelial potential difference (PD) of all tissues was oriented lumen negative (9.8-14.8 mV). Under short-circuit conditions, unidirectional Na+ flows were symmetrical. Cl- was secreted, and the secretion was equivalent to short-circuit current (Isc). Cl- secretion persisted under open-circuit conditions. Lobar bronchi from 21- to 46-day neonates absorbed Na+ (1.9 mueq.cm-2.h-1), but unidirectional flows of Cl- were symmetrical. Amiloride (10(-4) M) reduced Isc of neonatal bronchi by 47% but did not affect fetal bronchi. Isoproterenol increased Isc of both fetal (33%) and neonatal (40%) bronchi. These responses suggest that fetal bronchi do not absorb Na+ but can be stimulated to secrete Cl-. We conclude that Cl- secretion by epithelium of large airways may contribute to fetal lung liquid production, but it is unlikely that the tracheal epithelium is involved in fluid absorption at birth. Whereas fetal bronchi appear to secrete Cl-, neonatal bronchi absorb Na+.(ABSTRACT TRUNCATED AT 250 WORDS)     

Rapid increase in mast cell numbers in canine central and peripheral airways

In preliminary studies of antigen-induced airway inflammation, we noted an apparent increase in peribronchiolar mast cell number. Experiments were thus undertaken to investigate the nature of this migration of mast cells into the central and peripheral airway epithelium and to determine its time course. The tracheae and small airways of 10 anesthetized mongrel dogs were exposed via a bronchoscope to Ascaris suum antigen (Ag), fMet-Leu-Phe (fMLP), ovalbumin (OVA), and isotonic saline (SAL). In the central airways, all stimuli provoked a significant increase (P less than 0.05) in mast cell numbers at the base of the airway epithelium within 3 h. In the peripheral airways, only Ag aerosol stimulated a significant mast cell increase compared with unexposed tissue. In a second series of experiments, the trachea of seven dogs were exposed to 0.026, 0.26, and 2.6 micrograms of Ag. The tissue was collected at 1, 3, 6, and 10 h after exposure. In these experiments, there was a significant mast cell increase seen within 1 h but it was not dose dependent. By 6-10 h after exposure, mast cell counts were not significantly different from the unexposed condition, which is consistent with the idea that some of the cells either degranulated or migrated into the airway lumen. We conclude that mast cell migration is an acute response that can be demonstrated within 1 h of stimulation with Ag. The observation that nonimmunological stimuli may, in some cases, also stimulate mast cell movement affords the possibility that this process represents a generalized response to airway irritation.     

Selective permeability changes in the lungs and airways of sheep after toxic smoke inhalation

The effect of toxic smoke inhalation on selective microvascular sieving of macro-molecules and lymph protein flux was assessed in adult sheep to determine whether the time course of microvascular dysfunction differs between the lung and trachea. Protein flux across the lung increased sixfold 48 h after inhalation of the products of incomplete cotton combustion, whereas tracheal protein flux increased fivefold 8 h after exposure and returned to near base line 48 h after exposure. The lung and trachea selectively retained some sieving to three different protein macromolecules with molecular radii of 36, 54, and 123 A. In the lungs the sieving selectivity for these macromolecules was least 48 h after injury, and in the trachea molecular selectivity was least 8 h after injury. These data suggest that the time course of microvascular injury differs for the trachea and the lung; microvascular changes are detected earlier in the trachea than in the lung. The inhalation injury described thus permits the characterization of the time course of airway and lung microvascular changes.     

Longitudinal distribution of chlorine absorption in human airways: a comparison to ozone absorption.

The bolus inhalation method was used to measure the fraction of inhaled chlorine (Cl(2)) and ozone (O(3)) absorbed during a single breath as a function of longitudinal position in the respiratory system of 10 healthy nonsmokers during oral and nasal breathing at respired flows of 150, 250, and 1,000 ml/s. At all experimental conditions, <5% of inspired Cl(2) penetrated beyond the upper airways and none reached the respiratory air spaces. On the other hand, larger penetrations of O(3) beyond the upper airways occurred as flow increased and during nasal than during oral breathing. In the extreme case of oral breathing at 1,000 ml/s, 35% of inhaled O(3) penetrated beyond the upper airways and approximately 10% reached the respiratory air spaces. Mass transfer theory indicated that the diffusion resistance of the tissue phase was negligible for Cl(2) but important for O(3). The gas phase resistances were the same for Cl(2) and O(3) and were directly correlated with the volume of the nose and mouth during nasal and oral breathing, respectively.     

Convective dispersion during steady flow in the conducting airways of the human lung

The adverse health effects of inhaled particulate matter from the environment depend on its dispersion, transport, and deposition in the human airways. Similarly, precise targeting of deposition sites by pulmonary drug delivery systems also relies on characterizing the dispersion and transport of therapeutic aerosols in the respiratory tract. A variety of mechanisms may contribute to convective dispersion in the lung; simple axial streaming, augmented dispersion, and steady streaming are investigated in this effort. Flow visualization of a bolus during inhalation and exhalation, and dispersion measurements were conducted during steady flow in a three-generational, anatomically accurate in vitro model of the conducting airways to support this goal. Control variables included Reynolds number, flow direction, generation, and branch. Experiments illustrate transport patterns in the lumen cross section and map their relation to dispersion metrics. These results indicate that simple axial streaming, rather than augmented dispersion, is the dominant steady convective dispersion mechanism in symmetric Weibel generations 7-13 during normal respiration. Experimental evidence supports the branching nature of the airways as a possible contributor to steady streaming in the lung.     

Longitudinal distribution of chlorine absorption in human airways: comparison of nasal and oral quiet breathing.

The fraction of an inspired chlorine (Cl2) bolus absorbed during a single breath (Lambda) was measured as a function of bolus penetration (VP) into the respiratory system of five male and five female nonsmokers during both nasal and oral breathing at a quiet respiratory flow of 250 ml/s. The correspondence between VP and specific anatomic landmarks was found for each subject by a combination of acoustic reflection and nitrogen washout measurements. For both nasal and oral breathing, Lambda reached approximately 0. 95 at the distal end of the upper airways and reached 1.00 within the lower conducting airways. The values of a regional mass transfer parameter computed from the Lambda-VP data indicated that the resistance to Cl2 diffusion in the airway mucosa was negligible compared with the diffusion resistance in the respired gas. Changing the peak inhaled Cl2 concentration from 0.5 to 3.0 parts/million did not significantly affect the distribution of Cl2 absorption, suggesting that the underlying mass transport and chemical reaction processes were linear with respect to Cl2 concentration.