Lung gas mixing during expiration following an inspiration of air

The airway system of the lung from the mouth to the pulmonary membrane is modelled by matching a cylindrical model of a pathway through the respiratory region of the lung onto a one-dimensional trumpet model for the conducting airways. The concentration of O₂ in gas expired from this model airway system is investigated following an inspiration of air at two different flow rates (10 litres/min and 85 litres/min). In each case, expiration occurs at the same constant flow rate as that during the previous inspiration. The inspirations, which are studied in an earlier paper, are each of 2 sec duration and begin at a lung volume of 2300 ml and a lung oxygen tension of 98 mm Hg. The equations are solved numerically and plots of expired O₂ concentration against time and against expired volume are shown. It is found that at 85 litres/min, gas mixing in the lung is complete after about 0.7 sec of expiration whereas at 10 litres/min, about 2.6 sec of expiration is required for complete equilibration. It is suggested that the experimental alveolar plateau slope is not in general caused by a slow approach to equilibrium of gas concentrations; except at very low flow rates in the early part of the concentration/time plateau.     

Aerosol deposition characteristics in distal acinar airways under cyclic breathing conditions

Although the major mechanisms of aerosol deposition in the lung are known, detailed quantitative data in anatomically realistic models are still lacking, especially in the acinar airways. In this study, an algorithm was developed to build multigenerational three-dimensional models of alveolated airways with arbitrary bifurcation angles and spherical alveolar shape. Using computational fluid dynamics, the deposition of 1- and 3-μm aerosol particles was predicted in models of human alveolar sac and terminal acinar bifurcation under rhythmic wall motion for two breathing conditions (functional residual capacity = 3 liter, tidal volume = 0.5 and 0.9 liter, breathing period = 4 s). Particles entering the model during one inspiration period were tracked for multiple breathing cycles until all particles deposited or escaped from the model. Flow recirculation inside alveoli occurred only during transition between inspiration and expiration and accounted for no more than 1% of the whole cycle. Weak flow irreversibility and convective transport were observed in both models. The average deposition efficiency was similar for both breathing conditions and for both models. Under normal gravity, total deposition was ~33 and 75%, of which ~67 and 96% occurred during the first cycle, for 1- and 3-μm particles, respectively. Under zero gravity, total deposition was ~2-5% for both particle sizes. These results support previous findings that gravitational sedimentation is the dominant deposition mechanism for micrometer-sized aerosols in acinar airways. The results also showed that moving walls and multiple breathing cycles are needed for accurate estimation of aerosol deposition in acinar airways.     

Adenosine 5'-monophosphate challenge elicits a more peripheral airway response than methacholine challenge

Adenosine 5'-monophosphate (AMP) and methacholine are commonly used to assess airway hyperreactivity. However, it is not fully known whether the site of airway constriction primarily involved during challenges with either agent is similar. Using a ventilation distribution test, we investigated whether the constriction induced by each agent involves the lung periphery in a similar fashion. Ventilation distribution was evaluated by the phase III slope (S) of the single-breath washout, using gases with different diffusivities like helium (He) and hexafluorosulfur (SF(6)). A greater postchallenge increase in S(He) reflects alterations at the level of terminal and respiratory bronchioles, while a greater increase in S(SF6) reflects alterations in alveolar ducts, increases to an equal extent reflecting alterations in more proximal airways where gas transport is still convective for both gases. S(SF6) and S(He) were measured in 15 asthma patients before and after airway challenges (20% forced expired volume in 1-s fall) with AMP and methacholine. S(He) increased to a greater extent than S(SF6) after AMP challenge (5.7 vs. 3.7%/l; P = 0.002), with both slopes increasing to an equal extent after methacholine challenge (3.1%/l; P = 0.959). The larger increase in S(He) following AMP challenge suggests distal ventilation impairment up to the level of terminal and respiratory bronchioles. With methacholine, the similar increases in S(He) and S(SF6) suggest a less distal impairment. AMP, therefore, seems to affect more extensively the very peripheral airways, whereas methacholine seems to have an effect on less distal airways.     

Distal projection of insufflated gas during tracheal gas insufflation.

Tracheal gas insufflation (TGI) flushes expired gas from the ventilator circuitry and central airways, augmenting CO2 clearance. Whereas a significant portion of this washout effect may occur distal to the injection orifice, the penetration and mixing behavior of TGI gas has not been studied experimentally. We examined the behavior of 100% oxygen TGI injected at set flow rates of 1-20 l/min into a simulated trachea consisting of a smooth-walled, 14-mm-diameter tube. Models incorporating a separate coaxial TGI injector, a rough-walled trachea, and a bifurcated trachea were also studied. One-hundred percent nitrogen, representing expiratory flow, passed in the direction opposite to TGI at set flow rates of 1-25 l/min. Oxygen concentration within the "trachea" was mapped as a function of axial and radial position. Three consistent findings were observed: 1) mixing of expiratory and TGI gases occurred close to the TGI orifice; 2) the oxygenated domain extended several centimeters beyond the endotracheal tube, even at high-expiratory flows, but had a defined distal limit; and 3) more distally from the site of gas injection, the TGI gas tended to propagate along the tracheal wall, rather than as a central projection. We conclude that forward-directed TGI penetrates a substantial distance into the central airways, extending the compartment susceptible to CO2 washout.     

Breath-by-breath alveolar gas exchange

A method is described for breath-by-breath measurement of alveolar gas exchange corrected for changes of lung gas stores. In practice, the subject inspires from a spirometer, and each expired tidal volume is collected into a rubber bag placed inside a rigid box connected to the same spirometer. During the inspiration following any given expiration the bag is emptied by a vacuum pump. A computer monitors inspiratory and expiratory tidal volumes, drives four solenoid valves allowing appropriate operation of the system, and memorizes end-tidal gas fractions as well as mixed expired gas composition analyzed by mass spectrometer. Thus all variables for calculating alveolar gas exchange, based on the theory developed by Auchincloss et al. (J. Appl. Physiol. 21: 810-818, 1966), are obtained on a single-breath basis. Mean resting and steady-state exercise gas exchange data are equal to those obtained by conventional open-circuit measurements. Breathing rates up to 30 X min-1 can be followed. The breath-to-breath variability of O2 uptake at the alveolar level is less (25-35%) than that measured at the mouth as the difference between the inspired and expired volumes, both at rest and during exercise up to 0.7 of maximum O2 consumption.     

Gas mixing in dog lungs studied by single-breath washout of He and SF6

Simultaneously measured helium (He) and sulfur hexafluoride (SF6) single-breath washout was studied in 16 anesthetized paralyzed dogs ventilated with a special hydraulically operated ventilatory servo system. After equilibration of lung gas with 1% He and 1% SF6, the maneuver consisting of inspiration of a test gas-free mixture at constant rate (VI), a variable time of breath holding, and an expiration at constant rate (VE), was performed. Fractional concentrations of He and SF6, recorded against expired volume, were analyzed in terms of slope of the alveolar plateau (S) and series (Fowler) dead space (VD). In control conditions (VI = 0.5 l/s, VE = 0.1 l/s) S was about 10% of alveolar-to-inspired concentration difference per liter expirate both for He and SF6. Both SHe and SSF6 were inversely related to VI and VE, the relative changes being more pronounced with varying VE. SHe/SSF6 was higher or lower than unity depending on VI and VE. Both SHe and SSF6 decreased with increasing preinspiratory lung volume. Breath holding up to 10 s slightly decreased SHe and SSF6 while SHe/SSF6 was unchanged. The contribution of continuing gas exchange to S assessed from comparative measurements using the reversed (single breath washin) technique ranged from 6 to 23% in the various conditions. The VDHe/VDSF6 ratio was 0.84 and was little affected in the various settings. Results indicate that the substantial alveolar gas inhomogeneity in the dog lung and the mechanism accounting for S are little diffusion dependent. By exclusion sequential filling and emptying of lung units is believed to constitute the most important mechanism responsible for the sloping alveolar plateau.     

A rat lung model of instilled liquid transport in the pulmonary airways.

When a liquid is instilled in the pulmonary airways during medical therapy, the method of instillation affects the liquid distribution throughout the lung. To investigate the fluid transport dynamics, exogenous surfactant (Survanta) mixed with a radiopaque tracer is instilled into tracheae of vertical, excised rat lungs (ventilation 40 breaths/min, 4 ml tidal volume). Two methods are compared: For case A, the liquid drains by gravity into the upper airways followed by inspiration; for case B, the liquid initially forms a plug in the trachea, followed by inspiration. Experiments are continuously recorded using a microfocal X-ray source and an image-intensifier, charge-coupled device image train. Video images recorded at 30 images/s are digitized and analyzed. Transport dynamics during the first few breaths are quantified statistically and follow trends for liquid plug propagation theory. A plug of liquid driven by forced air can reach alveolar regions within the first few breaths. Homogeneity of distribution measured at end inspiration for several breaths demonstrates that case B is twice as homogeneous as case A. The formation of a liquid plug in the trachea, before inspiration, is important in creating a more uniform liquid distribution throughout the lungs.     

Branching pattern of airways and air spaces of a single human terminal bronchiole.

A polyurethane-foam enlarged reconstruction was made from serial sections of a portion of young adult human lung parenchyman. Study of the progeny of a terminal bronchiole disclosed three generations of respiratory bronchioles and an irregular branching pattern of eight generations of alveolar ducts. Sacs and alveoli arose from the lateral and distal aspects of all generations of ducts. There were an average of 3.5 alveoli per sac. Considering the terminal bronchiole as the first generation branch of the acinus, over 60 per cent of the alveoli counted and predicted were members of the 10-12th generations. The acinus contained one terminal bronchiole and approximately 14 respiratory bronchioles, 1,200-1,500 ducts, 2,500-4,500 sacs, and 14,000-20,000 alveoli.     

Multibreath tracer species dynamics in the lung

By studying the behavior of various tracer species in the lungs, one can assess many important characteristics which distinguish normal and abnormal function. Quantitative evaluation of function depends on the use of an appropriate model in conjunction with experimental data. A multi-compartment model is derived from mass balances to describe dynamic as well as (breath-averaged) steady-state transport processes between the environment and pulmonary capillary blood. The breathing cycle is divided into three time periods (inspiration, expiration, and pause) so that the model equations are discrete in time. No other model of tracer species transport in the lungs deals simultaneously with species dynamics, variable breathing pattern, distribution inhomogeneities, and non-equilibrium between alveolar gas and capillary blood. Models currently in the literature are shown to be special cases of the model presented here.     

Cell type specific expression of Follistatin-like 1 (Fstl1) in mouse embryonic lung development

Follistatin like-1 (Fstl1) is a secreted glycoprotein and can be up-regulated by TGF-β1. To better study the function of Fstl1 in lung development, we examined Fstl1 expression in the developing lung, in a cell type specific manner, using a tamoxifen inducible Fstl1-reporter mouse strain. Our results show that Fstl1 is ubiquitously expressed at saccular stage in the developing lung. At E18.5, Fstl1 expression is robust in most type of mesenchymal cells, including airway smooth muscle cells surrounding airways, vascular smooth muscle cells, endothelial cells, and vascular pericytes from blood vessel, but not PDGFRα⁺ fibroblasts in the distal alveolar sacs. Meanwhile, relative weak and sporadic signals of Fstl1 expression are observed in epithelium, including a subgroup of club cells in proximal airways and a few type II alveolar epithelial cells in distal airways. Our data help to understand the critical role of Fstl1 in lung development and lung disease pathogenesis.     

Further considerations in a theoretical description of gas transport in lung airways

A discrete one-dimensional model of convection-diffusion in branching alveolar ducts is described and it is shown that, for a suitable choice of effective axial dispersion, the solution closely approximates that for an axially symmetric representation, at least for Peclet numbers Pe<1. Following earlier work a composite model of a uniform lung is formed by matching such a respiratory pathway (now having the more convenient one-dimensional form) onto a trumpet representation of the conducting airways. Enhanced mixing due to heart action, and isotropic volume changes of trumpet (in addition to the pathway) during breathing are additional factors included. Calculations are made of O₂ concentrations during steady-state breathing and of the concentration of inert gas during single breath wash-out of a gas mixture containing it. Predicted alveolar levels in each case agree extremely well with published data, although no alveolar slope is obtained for the inert gas.     

Lung structure parameters estimated from modeling aerosol deposition in isolated dog lungs

A three-compartment model predicting the recovery of aerosol boli (i.e., the ratio of the number of particles expired to the number inspired) as a function of breath-holding time and bolus penetration was fitted to experimental data measured in nine isolated dog lungs. For each lung, the diameters of alveoli and alveolar ducts, as well as the volume fractions of alveoli, alveolar ducts, and airways, were determined as parameters providing the best fit. Parameter values were alveolar diameter = 0.116 +/- 0.007 (SE) mm, alveolar duct diameter = 0.284 +/- 0.015 mm, total alveolar volume/total lung capacity (TLC) = 0.68 +/- 0.02, total alveolar duct volume/TLC = 0.24 +/- 0.02, and total airway volume/TLC = 0.09 +/- 0.01. These values agreed with published values for linear dimensions and volumetric fractions in the canine lung. The mean alveolar diameter determined by the model in the nine lungs agreed closely with a mean value of 0.115 +/- 0.002 mm determined by morphometric analysis of photographs of the subpleural alveoli in the same lungs. The procedure of fitting the model to experimental data appears to have promise as a noninvasive probe of the lung periphery. However, aerosol-derived dimensions were more variable than morphometric ones, possibly because of interlung differences in aerosol distribution not accounted for in the model.     

Cardiogenic oscillations in He and SF6 expirograms during airway and venous loading

Cardiogenic oscillations in the expired partial pressure profiles of two inert gases (He and SF6) were monitored in seven anesthetized paralyzed mechanically ventilated dogs. He and SF6 were administered either intravenously by a membrane oxygenator and partial arteriovenous bypass [venous loading (VL)] or by washin into lung gas [airway loading (AL)]. The single-breath expirograms obtained during constant-flow expiration after inspiration of test gas-free air displayed distinct and regular cardiogenic oscillations. The relative oscillation amplitude (ROA), calculated as oscillation amplitude divided by mixed expired-inspired partial pressure difference, was in the range of 1-8%. The ROA for both He and SF6 was approximately 4.2 times higher in VL than in AL, which indicated that among lung units that emptied sequentially in the cardiac cycle, the effects of alveolar ventilation-perfusion (VA/Q) inequality were more pronounced than those of alveolar ventilation-alveolar volume (VA/VA) inequality. In AL, He and SF6 oscillations were 180 degrees out of phase compared with CO2 and O2 oscillations and with He and SF6 oscillations in VL, which suggests that regions with low VA/VA had high VA/Q and very low Q/VA. The ROA was practically unaffected by breath holding in both AL and VL, which indicates that there was little diffusive or convective (cardiogenic) mixing between the lung units that were responsible for cardiogenic oscillations. The ROA was consistently higher for He than for SF6, and the He-to-SF6 ratio was independent of route of test gas loading, averaging 1.6 in both AL and VL. This result may be explained by laminar Taylor dispersion, whereby oscillations generated in peripheral lung regions are dissipated in inverse proportion to diffusion coefficient during transit through the proximal (larger) airways.     

Morphology of the airways and lung parenchyma in hatchlings of the loggerhead sea turtle,Caretta caretta

Light microscopy as well as scanning and transmission electron microscopy revealed the lungs of loggerhead sea turtle (Caretta caretta), hatchlings to be multichambered with several separate open chambers communicating with a cartilage-reinforced central intrapulmonary bronchus. This central bronchus is structurally analogous to an oversized mammalian respiratory bronchiole. The subsequent branching airways, chambers and niches, are in many ways structurally and functionally similar to mammalian alveolar ducts and alveolar sacs, respectively. The airways are lined by a pseudostratified, columnar epithelium comprised of ciliated, nonciliated secretory, and basal cells. Histochemically, the epithelium is found to contain cells secreting both sialomucins and sulfomucins, as well as a neutral serous secretion. Small granule cells, a type of neuroendocrine cell similar to those seen in mammals, are scattered among the other airway cells. The gas-exchange areas, termed ediculae, are lined by the respiratory type I and type II pneumocytes, as in mammals. Abundant smooth muscle is seen in the trabeculae and interedicular septa of the lung tissue. © 1996 Wiley-Liss, Inc.     

Gas absorption in pulmonary airways at low Peclet number

A mathematical model is presented that investigates the mass transport of a diffusible and soluble gas contaminant through a liquid-lined tube when the Peclet number is small. The transport is determined by four dimensionless parameters: lambda, the tube aspect ratio; d, the relative difference in end concentrations; gamma, the radial transport coefficient; and Pe, the Peclet number. The problem is formulated for arbitrary gamma, but in the case of ozone and nitrous oxides the value of gamma is small. An asymptotic analysis for Pe much less than 1 and gamma much less than 1 is presented which yields the concentration field and transport characteristics we seek. It also provides a low Peclet number analysis for the conjugate problem of mass and heat transfer that is not currently available in the literature. The application to transport in the small airways of the lung is discussed, particularly the radial absorption differences in inspiratory and expiratory flow. Depending on the relative sizes of gamma and Pe, fractional uptake decreases with increasing Pe during inspiration but can increase during expiration.     

A three-dimensional model of the human pulmonary acinus.

A three-dimensional (3-D) model of the human pulmonary acinus, a gas exchange unit, is constructed with a labyrinthine algorithm generating branching ducts that fill a given space completely. Branching down to the third respiratory bronchioles is generated with the proposed algorithm. A subacinus, a region supplied by the last respiratory bronchiole, is approximated to be a set of cubic cells with a side dimension of 0.5 mm. The labyrinthine algorithm is used to determine a pathway through all cells only once, except at branching points with the smallest path lengths. In choosing each step of a pathway, random variables are used. Resulting labyrinths have equal mean path lengths and equal surface areas of inner walls. An alveolus can be generated by attaching alveolar septa, 0.25 mm long and 0.1 mm wide, to the inner walls. Total alveolar surface area and numbers of alveolar ducts, alveolar sacs, and alveoli in our 3-D acinar model are in good accordance with those reported in the literature.     

The effect of inspired oxygen concentration on the ventilation-perfusion distribution in inhomogeneous lungs

The coupled conservation of mass equations for oxygen, carbon dioxide and nitrogen are written down for a lung model consisting of two homogeneous alveolar compartments (with different ventilation-perfusion ratios) and a shunt compartment. As inspired oxygen concentration and oxygen consumption are varied, the flux of oxygen, carbon dioxide and nitrogen across the alveolar membrane in each compartment varies. The result of this is that the expired ventilation-perfusion ratio for each compartment becomes a function of inspired oxygen concentration and oxygen consumption as well as parameters such as inspired ventilation and alveolar perfusion. Another result is that the "inspired ventilation-perfusion ratio and the "expired ventilation-perfusion ratio differ significantly, under some conditions, for poorly ventilated lung compartments. As a consequence, we need to distinguish between the "inspired ventilation-perfusion distribution, which is independent of inspired oxygen concentration and oxygen consumption, and the "expired ventilation-perfusion distribution, which we now show to be strongly dependent on inspired oxygen concentration and less dependent oxygen consumption. Since the multiple inert gas elimination technique (MIGET) estimates the "expired ventilation-perfusion distribution, it follows that the distribution recovered by MIGET may be strongly dependent on inspired oxygen concentration.     

Morphometric changes in the human pulmonary acinus during inflation

Despite decades of research into the mechanisms of lung inflation and deflation, there is little consensus about whether lung inflation occurs due to the recruitment of new alveoli or by changes in the size and/or shape of alveoli and alveolar ducts. In this study we use in vivo (3)He lung morphometry via MRI to measure the average alveolar depth and alveolar duct radius at three levels of inspiration in five healthy human subjects and calculate the average alveolar volume, surface area, and the total number of alveoli at each level of inflation. Our results indicate that during a 143 ± 18% increase in lung gas volume, the average alveolar depth decreases 21 ±5%, the average alveolar duct radius increases 7 ± 3%, and the total number of alveoli increases by 96 ± 9% (results are means ± SD between subjects; P < 0.001, P < 0.01, and P < 0.00001, respectively, via paired t-tests). Thus our results indicate that in healthy human subjects the lung inflates primarily by alveolar recruitment and, to a lesser extent, by anisotropic expansion of alveolar ducts.