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Patients on high inspired O 2 concentrations are at risk of atelectasis, a problem that has been quantitatively assessed using analysis of ratio of ventilation to perfusion (V̇a/Q̇) equations. This approach ignores the potential of the elastic properties of the lung to support gas exchange through "apneic" oxygenation in units with no tidal ventilation, and is based on an error in the conservation of mass equations. To fill this gap, we correct the error and compare the pressure drops associated with apneic gas exchange with the pressure differences that can be supported by lung recoil. We analyze a worst case scenario: a small test unit in the Weibel model A tree structure with zero tidal ventilation, 100% inspired O 2 , the rest of the lung being normally ventilated tidally. We first computed the gas flux to the (unventilated) test unit and estimated the associated pressure drops. We then computed the difference in local gas pressure relative to the surrounding lung that would cause the unit to collapse. We compared these two, and finally computed the degree of airway narrowing that would effect change from the stable (apneic gas exchange) regime to the unstable regime leading to collapse. We find that except under extreme conditions of loss of airway caliber exceeding roughly 90%, lung recoil is sufficient to maintain oxygenation through convective transport alone. We further argue that the fundamental V̇a/Q̇ equations are invalid in these circumstances, and that the issue of atelectasis in low V̇a/Q̇ will require modifications to account for this additional mode of gas exchange. NEW & NOTEWORTHY Breathing high concentrations of oxygen increases the likelihood of atelectasis because of oxygen absorption, which is thought to be inevitable in regions with relatively low ventilation/perfusion ratios. However, airspaces of the lung resist collapse because of the forces of interdependence, and can, with low or even zero active tidal ventilation, draw in an inspiratory flow of oxygen sufficient to replace the oxygen consumed, thus preventing collapse of airspaces served by all but the most narrowed airways.

Inhomogeneous inflation or deflation of the lungs can cause dynamic pressure differences between regions and lead to interregional airflows known as pendelluft. This work first uses analytical tools to clarify the theoretical limits of pendelluft at a single bifurcation. It then explores the global and regional pendelluft that may occur throughout the bronchial tree in a realistic example using an in silico model of bronchoconstriction. The theoretical limits of pendelluft volume exchanged at a local bifurcation driven by sinusoidal breathing range from 15.5% to 41.4% depending on the relative stiffness of the subtended regions. When nonsinusoidal flows are considered, pendelluft can be as high as 200% inlet tidal volume (Vin). At frequencies greater than 10 Hz, the inertia of the air in the airways becomes important, and the maximal local pendelluft is theoretically unbounded, even with sinusoidal breathing. In a single illustrative numerical simulation of bronchoconstriction with homogenous compliances, the overall magnitude of global pendelluft volume was <2% of the tidal volume. Despite the small overall magnitude, pendelluft volume exchange was concentrated in poorly ventilated regions of the lung, including local pendelluft at bifurcations of up to 13% Vin. This example suggests that pendelluft may be an important phenomena contributing to regional gas exchange, irreversible mixing, and aerosol deposition patterns inside poorly ventilated regions of the lung. The analytical results support the concept that pendelluft may be more prominent in diseases with significant heterogeneity in both resistance and compliance., (Copyright © 2014 the American Physiological Society.)

Bronchial wall area percent (WA% = 100 × wall area/total bronchial cross sectional area) is a standard computed tomographic (CT) measure of central airway morphology utilized in smokers with chronic obstructive pulmonary disease (COPD). Although it provides significant clinical correlations, the range of reported WA% is narrow. This suggests limited macroscopic change in response to smoking or that remodeling proportionally affects the airway wall and lumen dimensions such that their ratio is preserved. The objective of this study is to assess central airway wall area (WA), lumen area (Ai), and total bronchial area (Ao) from CT scans of 5,179 smokers and 92 never smoking normal subjects. In smokers, WA, Ai, and Ao were positively correlated with forced expiratory volume in 1 s (FEV1) expressed as a percent of predicted (FEV1%), and the WA% was negatively correlated with FEV1% (P < 0.0001 for all comparisons). Importantly, smokers with lower FEV1% tended to have airways of smaller cross-sectional area with lower WA. The increases in the WA% across GOLD stages of chronic obstructive pulmonary disease (COPD) can therefore not be due to increases in WA. The data suggest two possible origins for the WA% increases: 1) central airway remodeling resulting in overall reductions in airway caliber in excess of the decreased WA or 2) those with COPD had smaller native airways before they began smoking. In both cases, these observations provide an explanation for the limited range of values of WA% across stages of COPD.

The unidirectional airflow patterns in the lungs of birds have long been considered a unique and specialized trait associated with the oxygen demands of flying, their endothermic metabolism and unusual pulmonary architecture. However, the discovery of similar flow patterns in the lungs of crocodilians indicates that this character is probably ancestral for all archosaurs--the group that includes extant birds and crocodilians as well as their extinct relatives, such as pterosaurs and dinosaurs. Unidirectional flow in birds results from aerodynamic valves, rather than from sphincters or other physical mechanisms, and similar aerodynamic valves seem to be present in crocodilians. The anatomical and developmental similarities in the primary and secondary bronchi of birds and crocodilians suggest that these structures and airflow patterns may be homologous. The origin of this pattern is at least as old as the split between crocodilians and birds, which occurred in the Triassic period. Alternatively, this pattern of flow may be even older; this hypothesis can be tested by investigating patterns of airflow in members of the outgroup to birds and crocodilians, the Lepidosauromorpha (tuatara, lizards and snakes). Here we demonstrate region-specific unidirectional airflow in the lungs of the savannah monitor lizard (Varanus exanthematicus). The presence of unidirectional flow in the lungs of V. exanthematicus thus gives rise to two possible evolutionary scenarios: either unidirectional airflow evolved independently in archosaurs and monitor lizards, or these flow patterns are homologous in archosaurs and V. exanthematicus, having evolved only once in ancestral diapsids (the clade encompassing snakes, lizards, crocodilians and birds). If unidirectional airflow is plesiomorphic for Diapsida, this respiratory character can be reconstructed for extinct diapsids, and evolved in a small ectothermic tetrapod during the Palaeozoic era at least a hundred million years before the origin of birds.

This tribute is dedicated to Lynne M. Reid, M.D. It is a précis of a special lecture given by her at the 4th International Workshop for Pulmonary Functional Imaging, held at Harvard Medical School in Boston, Sept. 24-26, 2009. Dr. Reid's remarks include those of an historical nature as well as thematic presentations of the growth and remodeling of pulmonary airways and vessels both physiologically and pathophysiologically. The role of hyperoxia and hypoxia in adaptive and pathological settings were emphasized. The theme throughout Dr. Reid's lecture was the relationship between structure and function, and how each serves and is consequent on the other., (Copyright © 2013. Published by Elsevier Ireland Ltd.)

Purpose: To implement and characterize a single-breath xenon transfer contrast (SB-XTC) method to assess the fractional diffusive gas transport F in the lung: to study the dependence of F and its uniformity as a function of lung volume; to estimate local alveolar surface area per unit gas volume S(A)/V(Gas) from multiple diffusion time measurements of F; to evaluate the reproducibility of the measurements and the necessity of B(1) correction in cases of centric and sequential encoding., Materials and Methods: In SB-XTC three or four gradient echo images separated by inversion/saturation pulses were collected during a breath-hold in eight healthy volunteers, allowing the mapping of F (thus S(A)/V(Gas)) and correction for other contributions such as T(1) relaxation, RF depletion and B(1) inhomogeneity from inherently registered data., Results: Regional values of F and its distribution were obtained; both the mean value and heterogeneity of F increased with the decrease of lung volume. Higher values of F in the bases of the lungs in supine position were observed at lower volumes in all volunteers. Local S(A)/V(Gas) (with a mean ± standard deviation of S(A)/V(Gas) = 89 ± 30 cm(-1)) was estimated in vivo near functional residual capacity. Calibration of SB-XTC on phantoms highlighted the necessity for B(1) corrections when k-space is traversed sequentially; with centric ordering B(1) distribution correction is dispensable., Conclusion: The SB-XTC technique is implemented and validated for in vivo measurements of local S(A)/V(Gas)., (Copyright © 2012 Wiley Periodicals, Inc.)

In a study visualizing ventilation with hyperpolarized (3)He magnetic resonance imaging (MRI) in elite breath hold divers, the dynamic MRI images in one subject exhibited an apparent alternation of the image intensity between left and right lung. We hypothesized that the alternation resulted from alternating variations in inspiratory flow rate to left and right lungs. Analysis showed that the alternation was not due to random uncorrelated temporal fluctuations of intensity (p<0.001). The frequency of alternation was approximately 56 min(-1), suggesting a cardiac origin. Similar alternation of ventilation was confirmed retrospectively in 4 of 6 additional subjects. These observations are consistent with previous studies showing cardiogenic mixing of gas in the lung. We speculate that cardiogenic pendelluft, possibly from ballistic lateral motion of the beating heart, could cause alternating variations of inspiratory flow to the lungs., (Copyright © 2012 Elsevier B.V. All rights reserved.)

A 33-year-old woman underwent a right-sided pneumonectomy in 1995 for treatment of a lung adenocarcinoma. As expected, there was an abrupt decrease in her vital capacity, but unexpectedly, it increased during the subsequent 15 years. Serial computed tomographic (CT) scans showed progressive enlargement of the remaining left lung and an increase in tissue density. Magnetic resonance imaging (MRI) with the use of hyperpolarized helium-3 gas showed overall acinar-airway dimensions that were consistent with an increase in the alveolar number rather than the enlargement of existing alveoli, but the alveoli in the growing lung were shallower than in normal lungs. This study provides evidence that new lung growth can occur in an adult human.

The lung surface is an ideal pathway to the bloodstream for nanoparticle-based drug delivery. Thus far, research has focused on the lungs of adults, and little is known about nanoparticle behavior in the immature lungs of infants. Here, using nonlinear dynamical systems analysis and in vivo experimentation in developing animals, we show that nanoparticle deposition in postnatally developing lungs peaks at the end of bulk alveolation. This finding suggests a unique paradigm, consistent with the emerging theory that as alveoli form through secondary septation, alveolar flow becomes chaotic and chaotic mixing kicks in, significantly enhancing particle deposition. This finding has significant implications for the application of nanoparticle-based inhalation therapeutics in young children with immature lungs from birth to 2 y of age.

Cyclic ventilatory instabilities are widely attributed to an increase in the sensitivity or loop gain of the chemoreflex feedback loop controlling ventilation. A major limitation in the conventional characterization of this feedback loop is the need for labor-intensive methodologies. To overcome this limitation, we developed a method based on trivariate autoregressive modeling using ventilation, end-tidal Pco(2) and Po(2); this method provides for estimation of the overall "loop gain" of the respiratory control system and its components, chemoreflex gain and plant gain. Our method was applied to recordings of spontaneous breathing in 15 anesthetized, tracheostomized, newborn lambs before and after administration of domperidone (a dopamine D(2)-receptor antagonist that increases carotid body sensitivity). We quantified the known increase in hypoxic ventilatory sensitivity in response to domperidone; controller gain for O(2) increased from 0.06 (0.03, 0.09) l·min(-1)·mmHg(-1) to 0.09 (0.08, 0.13) l·min(-1)·mmHg(-1); median (interquartile-range). We also report that domperidone increased the loop gain of the control system more than twofold [0.14 (0.12, 0.22) to 0.40 (0.15, 0.57)]. We observed no significant changes in CO(2) controller gain, or plant gains for O(2) and CO(2). Furthermore, our estimate of the cycle duration of periodic breathing compared favorably with that observed experimentally [measured: 7.5 (7.2, 9.1) vs. predicted: 7.9 (7.0, 9.2) breaths]. Our results demonstrate that model-based analysis of spontaneous breathing can 1) characterize the dynamics of the respiratory control system, and 2) provide a simple tool for elucidating an individual's propensity for ventilatory instability, in turn allowing potential therapies to be directed at the underlying mechanisms.

Punctate reopening of the lung from subresidual volumes (sub-RV) is commonly observed in excised lung preparations, either degassed or collapsed to zero transpulmonary pressure, and in the course of reinflation of human lungs when the chest is open, secondary to traumatic or surgical pneumothoraxes. In the course of physiological studies on two elite breath-hold divers, who are able to achieve lung volumes well below traditional RV with glossopharyngeal exsufflation, we used MRI lung imaging with inhaled hyperpolarized (129)Xe to visualize ventilatory patterns. We observed strikingly inhomogeneous inhalation patterns with small inhalation volumes from sub-RV, consistent with reopening of frankly closed airways. On the other hand, two age-matched and two older controls, inhaling from just above RV, showed a much more homogeneous pattern. Our results demonstrate the concept of frank airway closure below RV in young healthy adults with an intact chest wall.

We measured regional ventilation at 1l above functional residual capacity (FRC+1L) and total lung capacity (TLC) in three normal subjects and four elite breath-hold divers, and above TLC after glossopharyngeal insufflation (TLC+GI) in the divers. Hyperpolarized (3)He MRI was used to map the local ventilation per unit volume over the entire lung. At TLC and above, there was markedly increased regional ventilation of the lungs in the pericardial region compared with the relatively uniform ventilation throughout the rest of the lung. The distribution of fractional ventilation regionally was relatively uniform at FRC+1L, with a small non-gravitational cephalocaudal gradient of specific ventilation in the supine posture. Our observations at high lung volumes are consistent with the effect of high pleural tension in the concave pericardial region, which promotes expansion of the subjacent lung, leading to a higher local effective compliance and a higher specific ventilation.

Rationale and Objectives: Using a novel (129)Xe polarizer with high throughput (1-2 L/hour) and high polarization (approximately 55%), our objective was to demonstrate and characterize human pulmonary applications at 0.2T. Specifically, we investigated the ability of (129)Xe to measure the alveolar surface area per unit volume of gas, S(A)/V(gas)., Materials and Methods: Variable spin echo time (TE) gradient and radiofrequency (RF) echoes were used to obtain estimates of the lung's contribution to both T(2)* and T(2). Standard multislice ventilation images were obtained and signal-to-noise ratio (SNR) determined. Whole-lung, time-dependent measurements of (129)Xe diffusion from gas to septal tissue were obtained with a chemical shift saturation recovery (CSSR) method. Four healthy subjects were studied, and the Butler et al CSSR formalism (J Phys Condensed Matter 2002; 14:L297-L304) was used to calculate S(A)/V(gas). A single-breath version of the xenon transfer contrast (SB-XTC) method was implemented and used to image (129)Xe diffusion between alveolar gas and septal tissue. A direct comparison of CSSR and SB-XTC was performed., Results: T(2)*=135+/-29 ms amd T(2)=326.2+/-9.5 ms. Maximum SNR=36 for ventilation images from inhalation of 1L 86% (129)Xe and voxel volume =0.225 mL. CSSR analysis showed S(A)/V(gas) decreased with increasing lung volume in a manner very similar to that observed from histology measurements; however, the absolute value of S(A)/V(gas) was approximately 40% smaller than histology values. SB-XTC images in different postures demonstrate gravitationally dependent values. Initial comparison of CSSR with XTC showed fairly good agreement with expected ratios., Conclusions: Hyperpolarized (129)Xe human imaging and spectroscopy are very promising methods to provide functional information about the lung.

The majority of researchers investigating hyperpolarized gas MRI as a candidate functional lung imaging modality have used (3)He as their imaging agent of choice rather than (129)Xe. This preference has been predominantly due to, (3)He providing stronger signals due to higher levels of polarization and higher gyromagnetic ratio, as well as its being easily available to more researchers due to availability of polarizers (USA) or ease of gas transport (Europe). Most researchers agree, however, that hyperpolarized (129)Xe will ultimately emerge as the imaging agent of choice due to its unlimited supply in nature and its falling cost. Our recent polarizer technology delivers vast improvements in hyperpolarized (129)Xe output. Using this polarizer, we have demonstrated the unique property of xenon to measure alveolar surface area noninvasively. In this article, we describe our human protocols and their safety, and our results for the measurement of the partial pressure of pulmonary oxygen (pO(2)) by observation of (129)Xe signal decay. We note that the measurement of pO(2) by observation of (129)Xe signal decay is more complex than that for (3)He because of an additional signal loss mechanism due to interphase diffusion of (129)Xe from alveolar gas spaces to septal tissue. This results in measurements of an equivalent pO(2) that accounts for both traditional T(1) decay from pO(2) and that from interphase diffusion. We also provide an update on new technological advancements that form the foundation for an improved compact design polarizer as well as improvements that provide another order-of-magnitude scale-up in xenon polarizer output.

Throughout life, most mammals breathe between maximal and minimal lung volumes determined by respiratory mechanics and muscle strength. In contrast, competitive breath-hold divers exceed these limits when they employ glossopharyngeal insufflation (GI) before a dive to increase lung gas volume (providing additional oxygen and intrapulmonary gas to prevent dangerous chest compression at depths recently greater than 100 m) and glossopharyngeal exsufflation (GE) during descent to draw air from compressed lungs into the pharynx for middle ear pressure equalization. To explore the mechanical effects of these maneuvers on the respiratory system, we measured lung volumes by helium dilution with spirometry and computed tomography and estimated transpulmonary pressures using an esophageal balloon after GI and GE in four competitive breath-hold divers. Maximal lung volume was increased after GI by 0.13-2.84 liters, resulting in volumes 1.5-7.9 SD above predicted values. The amount of gas in the lungs after GI increased by 0.59-4.16 liters, largely due to elevated intrapulmonary pressures of 52-109 cmH(2)O. The transpulmonary pressures increased after GI to values ranging from 43 to 80 cmH(2)O, 1.6-2.9 times the expected values at total lung capacity. After GE, lung volumes were reduced by 0.09-0.44 liters, and the corresponding transpulmonary pressures decreased to -15 to -31 cmH(2)O, suggesting closure of intrapulmonary airways. We conclude that the lungs of some healthy individuals are able to withstand repeated inflation to transpulmonary pressures far greater than those to which they would normally be exposed.

To account for cytoskeleton remodeling as well as smooth muscle length adaptation, here we represent the cytoskeleton as a two-dimensional network of links (contractile filaments or stress fibers) that connect nodes (dense plaques or focal adhesions). The network evolves in continuous turnover with probabilities of link formation and dissolution. The probability of link formation increases with the available fraction of contractile units, increases with the degree of network activation, and decreases with increasing distance between nodes, d, as 1/d(s), where s controls the distribution of link lengths. The probability of link dissolution decays with time to mimic progressive cytoskeleton stabilization. We computed network force (F) as the vector summation of link forces exerted at all nodes, unloaded shortening velocity (V) as being proportional to the average link length, and network compliance (C) as the change in network length per change in elastic force. Imposed deformation caused F to decrease transiently and then recover dynamically; recovery ability decreased with increasing time after activation, mimicking observed biological behavior. Isometric contractions showed small sensitivity of F to network length, thus maintaining high force over a wide range of lengths; V and C increased with increasing length. In these behaviors, link length regulation, as described by the parameter s, was found to be crucial. Concerning length adaptation, all phenomena reported thus far in the literature were captured by this extremely simple network model.

The human lung and its functions are extremely sensitive to gravity; however, the conventional high-field magnets used for most laser-polarized (3)He MRI of the human lung restrict subjects to lying horizontally. Imaging of human lungs using inhaled laser-polarized (3)He gas is demonstrated in an open-access very-low-magnetic-field (<5 mT) MRI instrument. This prototype device employs a simple, low-cost electromagnet, with an open geometry that allows variation of the orientation of the imaging subject in a two-dimensional plane. As a demonstration, two-dimensional lung images were acquired with 4-mm in-plane resolution from a subject in two orientations: lying supine and sitting in a vertical position with one arm raised. Experience with this prototype device will guide optimization of a second-generation very-low-field imager to enable studies of human pulmonary physiology as a function of subject orientation., (Copyright 2005 Wiley-Liss, Inc.)

To address the role of the parietal pleura in reduction of mesothelial shear stresses during breathing, we measured the stiffness of the parietal pleural surface of mammalian chest walls using microindentation. The pleural surface was indented over ribs and intercostal spaces with rigid flat punches (tip radii of 0.01, 0.02, and 0.1 cm) to probe stiffness at length scales comparable with those of surface asperities. We found a tissue shear modulus of 6700 dyn/cm2 and pleural membrane tension of 4900 dyn/cm, with a geometric standard deviation of 0.42. These values are similar to those measured for the lung by Hajji et al., using indentation (Hajji MA, Wilson TA, and Lai-Fook SJ. J Appl Physiol Respirat Environ Exerc Physiol 47: 175-181, 1979). Surprisingly, the pleural surface over ribs and intercostal spaces exhibited similar stiffness. In addition, caudal regions exhibited lower stiffness than cranial regions. In the context of elastohydrodynamic lubrication, these results suggest that shear-induced pressures during breathing deform the chest wall and lung surfaces to a similar extent, promoting spatial uniformity of pleural fluid thickness and reducing shear stresses.

To examine effects of lung motion on the separation of pleural surfaces during breathing, we modeled the pleural space in two dimensions as a thin layer of fluid separating a stationary elastic solid and a sliding flat solid surface. The undeformed elastic solid contained a series of bumps, to represent tissue surface features, introducing unevenness in fluid layer thickness. We computed the extent of deformation of the solid as a function of sliding velocity, solid elastic modulus, and bump geometry (wavelength and amplitude). For physiological values of the parameters, significant deformation occurs (i.e. bumps are 'flattened') promoting less variation in fluid thickness and decreased fluid shear stress. In addition, deformation is persistent; bumps of sufficient wavelength, once deformed, require a recovery time longer than a typical breath-to-breath interval to return near their undeformed configuration. These results suggest that in the pleural space during normal breathing, separation of pleural surfaces is promoted by the reciprocating sliding of lung and chest wall.

The pleural space is modeled in two dimensions as a thin layer of fluid separating a deformable membrane and a rigid surface containing a bump. We computed the steady-state membrane configuration and fluid pressure distribution during relative sliding of the two surfaces. For physiologically relevant values of membrane tension, shear flow-induced pressures near the bump and far-field pressure gradients are similar to those measured in vivo within the pleural space (e.g. Lai-Fook et al.) [J. Appl. Physiol.: Respirat. Environ. Exercise Physiol. 56 (1984) 1633-1639]. Deformation of the membrane over the bump suggests that the pressure field generated by the sliding motion promotes an even layer of fluid in the pleural space, preventing asperities from touching. Results also suggest a possible mechanism for pleural fluid redistribution during breathing, whereby irreversible fluid motion is associated with the deformability of the membrane.

Our current understanding of the transport and deposition of aerosols (viruses, bacteria, air pollutants, aerosolized drugs) deep in the lung has been grounded in dispersive theories based on untested assumptions about the nature of acinar airflow fields. Traditionally, these have been taken to be simple and kinematically reversible. In this article, we apply the recently discovered fluid mechanical phenomenon of irreversible low-Reynolds number flow to the lung. We demonstrate, through flow visualization studies in rhythmically ventilated rat lungs, that such a foundation is false, and that chaotic mixing may be key to aerosol transport. We found substantial alveolar flow irreversibility with stretched and folded fractal patterns, which lead to a sudden increase in mixing. These findings support our theory that chaotic alveolar flow--characterized by stagnation saddle points associated with alveolar vortices--governs gas kinematics in the lung periphery, and hence the transport, mixing, and ultimately the deposition of fine aerosols. This mechanism calls for a rethinking of the relationship of exposure and deposition of fine inhaled particles.

Current theories describe aerosol transport in the lung as a dispersive (diffusion-like) process, characterized by an effective diffusion coefficient in the context of reversible alveolar flow. Our recent experimental data, however, question the validity of these basic assumptions. In this study, we describe the behavior of fluid particles (or bolus) in a realistic, numerical, alveolated duct model with rhythmically expanding walls. We found acinar flow exhibiting multiple saddle points, characteristic of chaotic flow, resulting in substantial flow irreversibility. Computations of axial variance of bolus spreading indicate that the growth of the variance with respect to time is faster than linear, a finding inconsistent with dispersion theory. Lateral behavior of the bolus shows fine-scale, stretch-and-fold striations, exhibiting fractal-like patterns with a fractal dimension of 1.2, which compares well with the fractal dimension of 1.1 observed in our experimental studies performed with rat lungs. We conclude that kinematic irreversibility of acinar flow due to chaotic flow may be the dominant mechanism of aerosol transport deep in the lungs.

We have investigated the basis and implications of pneumoconstriction by measuring disposition and quantities of alpha-smooth muscle actin in rat and guinea pig lungs and modeling its effects on lung recoil and compliance. A robust marker of contractility, alpha-smooth muscle actin appears in smooth muscle or myofibroblast-like cells in pleura, airways, blood vessels, and alveolar ductal tissues. In each site, we measured its transected area by immunofluorescent staining and frequency-modulated scanning confocal microscopy. We incorporated these data in a model of the parenchyma consisting of an extensive elastic network with embedded contractile structures. We conclude that contraction at any one of these sites alone can decrease parenchymal compliance by 20-30% during tidal breathing. This is due mostly to the stiffness of activated contractile elements undergoing passive cycling; constant muscle tension would have little effect. The magnitude of the effect corresponds with known responses of the lung to hypocapnia, consistent with a homeostatic function in which gas exchange is defended by redistributing ventilation away from overventilated units.

The large diffusion coefficients of gases result in significant spin motion during the application of gradient pulses that typically last a few milliseconds in most NMR experiments. In restricted environments, such as the lung, this rapid gas diffusion can lead to violations of the narrow pulse approximation, a basic assumption of the standard Stejskal-Tanner NMR method of diffusion measurement. We therefore investigated the effect of a common, biologically inert buffer gas, sulfur hexafluoride (SF(6)), on (129)Xe NMR and diffusion. We found that the contribution of SF(6) to (129)Xe T(1) relaxation in a 1:1 xenon/oxygen mixture is negligible up to 2 bar of SF(6) at standard temperature. We also measured the contribution of SF(6) gas to (129)Xe T(2) relaxation, and found it to scale inversely with pressure, with this contribution approximately equal to 1 s for 1 bar SF(6) pressure and standard temperature. Finally, we found the coefficient of (129)Xe diffusion through SF(6) to be approximately 4.6 x 10(-6) m(2)s(-1) for 1 bar pressure of SF(6) and standard temperature, which is only 1.2 times smaller than the (129)Xe self diffusion coefficient for 1 bar (129)Xe pressure and standard temperature. From these measurements we conclude that SF(6) will not sufficiently reduce (129)Xe diffusion to allow accurate surface-area/volume ratio measurements in human alveoli using time-dependent gas diffusion NMR.

There is a surprisingly substantial amount of aerosol mixing and deposition deep in the lung, which cannot be explained by classic transport mechanisms such as streamline crossing, inertial impaction, or gravitational sedimentation with reversible acinar flow. Mixing associated with "stretch and fold" convective flow patterns can, however, be a potent source of transport. We show such patterns in experimental preparations using rat lungs and in the theoretical Baker Transform. In both cases, mixing is associated with the temporal evolution of two length scales. The first is the slowly increasing diffusive length scale. The second is the rapidly decreasing lateral length scale, due to "stretching and folding," over which diffusion must take place. This interaction leads to aerosol mixing in much shorter times than previously appreciated. Finally, we propose a new method by which to quantify the state of mixing, using an approximation to the entropy of the aerosol concentration distribution. The results of the analysis suggest that stretching and folding may be a key feature underlying peripheral aerosol transport.

Changes in local pulmonary capillary blood volume (Vc) and oxygen saturation (S) have been difficult to measure in live animals. By utilizing the differences in absorption of light at two wavelengths (650 and 800 nm), we estimated the fractional change in Vc and S during the course of the cardiac cycle in eight anesthetized, ventilated rabbits at low and high lung volumes. Observations were made of the pattern of diffusely backscattered light, from an approximately 1-cm3 volume of lung illuminated with a point source placed on the pleural surface through a thoracotomy. At low lung volume, the fractional change in Vc was approximately 13%, the change in S was approximately 4.6%, and the mean S was close to 77%. The fluctuations in Vc and S lagged behind peak systemic blood pressure by about one-fifth and three-fifths of a cycle, respectively. At high lung volume, there were no important fluctuations in Vc or S, and the mean S was approximately 82%. These results are consistent with fluctuations in pulmonary capillary pressure and gas exchange over the cardiac cycle, and with decreasing capillary compliance with increasing lung volume.

Alveolar parenchyma comprises two interacting tensile systems: the cable system (a network of linear condensations of connective tissue) and the membrane system (a network of quasiplanar alveolar septa). Inferences can be drawn about the mechanics of this structure from it configuration. We reported earlier (E.H. Oldmixon, J.P. Butler, and F.G. Hoppin, Jr. J. Appl. Physiol. 64: 299-307, 1988) that the angles between alveolar septa at the common three-way junctions (J) are nearly uniform, indicating that septal tensions are also nearly uniform. We now report on the interseptal angles at the next most common class of septal junction (B), a structure where two septa meet along a segment of the cable system. We find, first, that the distributions of interseptal angles at B junctions have means > 120 degrees, are narrow, and have few, if any, angles < 120 degrees. The findings of uniform 120 degrees angles at J junctions and a cutoff below 120 degrees at B junctions are also characteristic of soap films supported on a frame, which follows the physical principle of surface area minimization. We suggest that this principle may be operative in parenchymal development and remodeling.

Using an anisotropic theory of diffuse light scattering in lungs, we measured the fractional changes in geometric mean linear intercepts in orthogonal directions when freshly excised rabbit lungs were subjected to isovolume uniaxial strains. Results from the optical technique were compared with morphometric estimates of fractional changes in mean linear intercepts from the same strained and unstrained (control) lobes, with the conclusion that diffuse light scattering is adequate to estimate changes in mean free paths in different directions. We compared optical estimates of fractional changes in mean linear intercepts with the macroscopic strain field measured by displacements of pleural markers; this relationship did not significantly differ from the line of identity. We conclude that the microscopic strain field is closely matched to the macroscopic strain field during uniaxial distortion. This suggests that surface reorientation may not play a large role in the origin of the low shear modulus of the lung, but this cannot be definitively stated without comparison of these experimental results to specific model predictions of the changes in mean linear intercepts in shear deformation.

It is unknown how the in vivo alveolar surface area-to-volume ratio (S/V) changes in low-pressure pulmonary edema. Here, the S/V is the area of the air-tissue interface per unit total volume (air plus tissue). We hypothesized that in oleic acid (OA)-induced edema inactivation of the pulmonary surfactant may increase surface tension and decrease the S/V at any given lung volume. OA (0.04 mg/kg) was intravenously injected into dogs. We measured the in vivo S/V (equivalent to the inverse of optical mean free path by light-scattering stereology and the pressure-volume (PV) curve 60-90 min after OA administration. OA administration decreased the lung volume at each transpulmonary pressure and increased the wet-to-dry weight ratio. The S/V decreased after OA administration (optical mean free path increased). The air-filled PV curves shifted downward after OA, but the saline-filled PV curves after OA administration did not differ significantly from control saline-filled curves. The difference in transpulmonary pressure between air- and saline-filled PV curves (an index of the magnitude of surface tension) was increased in OA-induced pulmonary edema. This study suggests that in OA-induced pulmonary edema the alveolar surface tension increases and the S/V decreases, presumably due to inactivation of surfactant by serum leakage to alveoli.

We investigated the dynamic history dependence of lung surface area-to-volume ratio (S/V) during tidal breathing in live rabbits with use of our recently developed technique of diffuse optical scattering. We also examined the effect of methacholine (continuous intravenous infusion, 1-10 micrograms.kg-1.min-1) on lung micromechanics with the same technique. Animals were anesthetized, tracheostomized, and mechanically ventilated, and the left lung was exposed through a thoracotomy. An optical fiber delivering light from a He-Ne laser was attached normal to the pleural surface, producing a circular light pattern on the pleural surface from diffusively scattered light within the parenchyma. The pattern of light intensities was measured using a CCD video camera connected to a computer. S/V during tidal breathing changed in a manner qualitatively consistent with geometric similarity. There was a small but significant hysteresis in S/V vs. volume, with S/V inspiration greater than S/V expiration at the same volume. However, during methacholine challenge, the sense of hysteresis reversed; S/V inspiration was less than S/V expiration at isovolume points. Moreover, S/V during methacholine challenge systematically decreased at all lung volumes compared with control. These findings suggest that 1) during normal tidal breathing, stress hysteresis in ductal tissue is larger than septal stress hysteresis (septal tissue plus surface tension) and 2) the effect of methacholine on tissue in the septa is greater than the corresponding effect in ductal tissue.

The regional pleural surface expansion of an excised dog lung was measured during high-frequency ventilation (HFV) using synchronized stroboscopic photography to stop lung motion at 20 evenly spaced intervals over a respiratory cycle during ventilation at 1 Hz with a volume of 100 ml, 15 Hz with 100 ml, or 30 Hz with 50 ml. The lungs were also photographed during quasi-static deflation. The pleural surface was marked with ink dots to form 84 approximately square figures. The side lengths and areas of each of the 84 "squares" were measured for each frame of each photo sequence. At 1 Hz and during the quasi-static deflation the lung ventilated nearly synchronously, although minor nonuniformities were noted on both small and large length scales. At 15 and 30 Hz, the lung expanded asynchronously and nonuniformly, with a 78% increase in surface expansion per 100 ml of tracheal tidal volume, as frequency was increased from 1 to 30 Hz. These nonuniformities in expansion suggest marked interregional airflow and elastic wave propagation in the parenchyma during HFV.

The non-reversing gas flow pattern in the avian lung has been attributed to 'aerodynamic valves'. A fundamental property of all aerodynamic valves is their dependence on inertial forces in the gas stream: sufficient reduction of inertial forces will cause aerodynamic valves to fail. If valving in the avian lung is aerodynamic, it should fail when gas stream momentum is reduced. We tested the dependence of the inspiratory valves in the goose lung on gas density and gas flow velocity. A bolus of tracer gas was placed in the tracheal cannula during an end-expiratory pause. Tracer gas appearance in a cranial air sac during the following inspiration and pause was used to deduce failure of the 'inspiratory valve' in cyclically ventilated geese. Little or no tracer entered the sac under control conditions, which approximated resting breathing, indicating highly effective valving. Lower flow rate or lower gas density caused increased tracer appearance, indicating valve failure. These results demonstrate the importance of gas inertial forces to normal valve function, and are direct evidence for the aerodynamic nature of the avian inspiratory valve.

To clarify the mechanics of alveolar parenchyma, we undertook a stereological and topological study in perfusion-fixed canine lungs of the borders of alveolar septa. We defined the principal borders as those along which one septum 1) joins two others (J), 2) joins one other at a distinct angle (B), or 3) joins no other structure (E). E and B borders are invariably reinforced with heavy connective tissue cables; J borders are not. Relative net lengths, determined from the number of traces per section area, were J, 45%; E, 19%; and B, 25%. These were remarkably constant over 10 canine lobes (5 animals, 4 volumes). Parenchyma, then, departs from the simple models that comprise only Js and Es. Bs are important; their net length exceeds that of Es. With lobe deflation, E shortened somewhat more than required to maintain geometric similarity, suggesting that the alveolar duct contracted disproportionately. A three-dimensional reconstruction was made from serial sections, and individual border segments were followed through the reconstruction. Typical lengths of individual J, B, and E borders were nearly equal. To characterize how the network of borders were interconnected, we counted the nodes at which they meet by class, e.g., EBE for the meeting of one B, two Es. The most common are JJJJ, 26%; EEEJ, 10%; EBJ, 24%; EBE, 8%; BBJJ, 12%. If parenchyma were constructed only from free-standing entrance rings and septal junctions, only JJJJ and EEEJ would be anticipated. The presence of EBJ, EBE, and BBJJ underscores parenchymal complexity. Only 7% of septa examined were bordered entirely by Js. Connective tissue cables were not confined to the alveolar duct's lumen but often extended to the primary septa at the periphery of the ductal unit. They rarely linked adjacent alveolar ducts; only 1 in 200 cable segments crossed from one duct to another. These observations support the concept that the parenchyma is an elastic network, characterized in part by a serial mechanical linkage from connective tissue cable to septal membrane to cable again.

The presence of unidirectional flow in the avian lung is thought to be effected by aerodynamic 'valves'. First we review the history of this hypothesis and summarize existing evidence. Second, we present a semiquantitative treatment of the various fluid dynamic factors that may be involved in directing fluid flow. The resulting calculations show in some detail how the inspiratory valve may work, and upon what mechanisms it may depend. Our calculations suggest that gas convective inertial forces are sufficient to effect inspiratory valving. Finally, we give some heuristic arguments regarding the mechanisms of expiratory valving.

A simple theory of lung elasticity and its interaction with bronchi was developed which led to the specific results. The experimental procedure for establishing these results used lobar bronchi from excised dog lungs, following Takishima, et al. ((1975) J. Appl. Physiol., 38: 875-881). First, we found a semi-direct technique for measuring Poisson's ratio (sigma) of lung parenchyma and the effect of lung parenchyma on bronchi (interdependence). Sigma was measured at 0.424 +/- 0.045; no correlation was observed between sigma and the elastic recoil pressure of the lung (PL). The interdependence increased with a corresponding increase in PL and reduced bronchial volume. Second, we predict that a relationship exists between the specific compliances of intact and excised bronchi, and the specific compliance of the surrounding parenchyma. We suggest that the parenchyma is more important than the bronchus itself in determining the specific compliance of the intact bronchi.

The pattern of light backscattered by lung tissue should depend strongly on the size of air spaces and equivalently on the internal surface area of the lung. To verify and apply this, we shone a laser beam into excised lungs through the pleural surface and measured the backscattered light surrounding the beam with a focused photodetector. The intensity, I, fell off as a function of distance, r, from the point of entry of light. The configurations of I(r) curves corresponded closely to theory over a 3-decade range of I. I(r) changed systematically with lung volume. The optical mean free path, lambda, was calculated from I(r) curves in a series of canine lobes fixed immediately after optical scanning and was compared with stereological measurement of mean linear intercept, Lm, an index of alveolar size. At high lung volumes the relation of lambda to Lm was consistent with reflection by alveolar septa. At lower lung volumes there appeared to be, additionally, a substantial refractive component. This technique is independent of current stereological methods and has the advantages of being noninvasive, continuous, and potentially applicable to dynamic events in unfixed lungs.

We present a theoretical treatment of backscattered light from the interior of a lung illuminated by a thin beam of light normally incident on the pleural surface. An approximate formula is developed describing how the backscattered intensity varies with distance from the point of light entry. This is shown to depend markedly on the optical mean free path and on the effective extinction coefficient. We attempt to relate the optical mean free path to the mean alveolar size. This relationship is found to depend primarily on septal reflection and refraction. Reflection is treated quantitatively. Refraction is much more difficult and may have to be approached empirically. We present here the rudiments of a technique with implications for the possibility of dynamic stereology.

We sought a technique to preserve lung tissue for micrography with air-space dimensions unchanged from the fresh state. In our hands, conventional techniques were problematical. Aware of the possibility that distortion might be caused by inadequate mechanical fixation of elastin, we dehydrated the still-inflated lung by intravascular perfusion with graded ethanols. Canine and rabbit lungs so prepared had straighter alveolar septa, greater air-space dimensions, and an improved correlation with light-scattering measurements. Bovine ligamentum nuchae (mostly elastin) was only partially fixed by glutaraldehyde or osmium tetroxide but was effectively stiffened by dehydration. We conclude that perfusion dehydration aids in the faithful preservation of parenchymal configuration, probably by mechanical fixation of elastin.

By means of backscattered light from a pointlike source on the pleural surface, we investigated the dynamic behavior of the surface-to-volume ratio (S/V) in excised dog lobes subjected to small volume steps both in and out on both the inflation and deflation limb of standard pressure-volume maneuvers. The technique utilizes the established correlation of the pattern of backscattered light with morphometric mean linear intercept and is suitable for dynamic studies. We hypothesized that 1) there would be a difference in the timing of stress relaxation or recovery between alveolar septa and the fibromuscular tissue in the alveolar duct that would reveal itself as a temporally changing S/V after a step-volume change and 2) that geometric hysteresis (looping of S/V with volume), as seen with large volume excursion histories, would be similarly present in small tidal volume loops. Our experimental results contradicted both hypotheses. In particular, we found virtually no change in S/V after a step-volume change, even in the presence of substantial stress adaptation. In addition, when geometric hysteresis of small loops was present, it was always in the sense opposite to the geometric hysteresis of large loops. We conclude that 1) there is a functional "matching" of the stress-adaptive timing between alveolar septa and ductal mouths and 2) during small volume looping, the stress hysteresis (looping of stress with volume) in the ductal tissue may be larger than that of the septa, including surface tension.

Consideration of the lung as an elastic continuum led us to investigate the possible propagation of elastic waves. Here the relevant stiffness and density are given by the Lamé constants and density of the parenchyma. To test this hypothesis, we measured propagation velocities (c) in dog lobes by recording transit times of a velocity impulse on one side of the lobe and the subsequent arrival on the other side. We compared our measured values of c with elastic longitudinal wave velocities (c long) predicted by values of elastic moduli given by Lai-Fook et al. (J. Appl. Physiol. 40: 508-513, 1976) as a function of translobar pressure (PL) and our measured densities. Good agreement was found between c and c long. Typical values of c ranged from 250-1,500 cm/s as PL ranged from 2-20 cmH2O. No systematic difference in the c-c long relation was found between inflation and deflation, suggesting that the elastic moduli of lungs are essentially a function of pressure. No significant effect was observed by changing the physical properties of the gas within the lobe [air vs. He vs. sulfur hexafluoride (SF6)], suggesting that indeed we were observing waves associated with the coupling of parenchymal density to parenchymal stiffness.

We assessed various aerodynamic factors which might influence inspiratory valve function in the avian lung. During inspiration, no flow enters the proximal segments of the ventrobronchi connecting the primary bronchus to cranial sacs. Instead, all flow in the primary bronchus continues through the mesobronchus. This pattern of flow past the ventrobronchi into the mesobronchus is called inspiratory aerodynamic valving. Introducing steady inspiratory flows into simplified plastic models of a bifurcation, we altered geometry, downstream resistance, flow rate and gas density while we measured the resulting flow partitioning between downstream branches. We found that these models did reproduce the inspiratory valving phenomenon. Gas flow rate, gas density and geometry upstream of the bifurcation played important roles in flow partitioning, but the geometry and branching angles of the ventrobronchi did not. These findings are consistent with the idea that convective inertia of the inspiratory gas stream promotes preferential axial flow (Butler et al., 1988) and may be the principal mechanism accounting for inspiratory aerodynamic valving in the avian lung.

Serial distribution of airway properties determines in part the response of the lung to high frequency oscillations. We measured the response of excised dog lungs and lobes between 156 and 10,000 Hz and determined the area-distance function of the acoustically equivalent structure having rigid walls, regular branching, and negligible internal losses. The utility of this techique was tested by determining the effects of air trapping, removal of pleura from a dried lung, central airway smooth muscle tone. A strong correlation was found between relative changes in equivalent acoustic area and relative area changes measured radiographically in individual airways at corresponding distances. We conclude that despite departures of the properties of the real lung from the characteristics of the acoustically equivalent structure, changes in the area-distance function computed by this technique provide reasonable estimates of the magnitude and serial distribution of actual changes in airway cross-sectional area.

The direct contribution of forces in tree structures in the lung to lung recoil pressure and changes in recoil pressure induced by alterations of the forces are analyzed. The analysis distinguishes the contributions of axial and circumferential tensions in the trees and indicates that only axial tensions directly contribute to static recoil. This contribution is derived from analysis of the axial forces transmitted across a random plane transecting the lung. The change in recoil pressure induced by changes in axial tension is similarly derived. Alterations of circumferential tensions in the trees indirectly change recoil by causing nonuniform deformations of the surrounding lung parenchyma, and a continuum elasticity solution for the stress induced by the deformations is derived. Sample calculations are presented for the airway tree based on available data on airway morphometric and mechanical properties. The increase in recoil pressure accompanying increases in axial and circumferential tensions with contraction of airway smooth muscle is also analyzed. The calculations indicate that axial stresses in the airway tree out to bronchioles directly contribute only a small fraction of the static recoil pressure. However, it is found that contraction of smooth muscle in these airways can increase recoil pressure appreciably (10-20%), mainly by the deformation of the parenchyma with increases in circumferential tension in smaller airways. The results indicate that the geometric and mechanical properties of the airway tree are such that only peripheral elements of the tree can substantially affect the elastic properties of the lung. The possible contributions of vascular trees for which data on mechanical and morphometric properties are more limited are also discussed.