Effect of increased static lung recoil on bronchial dimesions of excised lungs.

We measured bronchial diameters and lengths during static deflation and inflation in eight excised dog lobes before and after static lung recoil (Pst(L)) had been significantly increased by cooling the lobe for 48 h at 4 degrees C and ventilating it for 3 h. In control lobes, bronchial diameters were the same at any volume even though Pst(L) was different during inflation and deflation. These results agree with those of Hughes et al. (J. Appl. Physiol. 32: 25-35, 1972). However, when Pst(L) was increased, diameters at a given volume were significantly increased over control values; diameters at a given pressure were nearly the same as the controls. Therefore, under these conditions, bronchial diameter did not conform to lung volume. The ventilation process appeared to alter the circumferential elastic properties of the bronchi because diameters at all pressures were slightly larger after ventilation. Bronchial length-volume relationships were the same in both control and ventilated lobes. Thus, when Pst(L) was markedly increased, diameter corresponded best to lung recoil and length to lung volume.     

Variability of parenchymal expansion measured by computed tomography

Computed tomography scans of isolated dog lung lobes at different lobe volumes were used to determine the variability of parenchymal tissue density and the variability of parenchymal volume changes on the scale of a voxel, a cube 1.5 mm on a side. The variability of tissue density increased with decreasing lobe volume. The variability of tissue density of neighboring voxels was positively correlated; the spatial correlation decreased exponentially with distance with an exponential scale of 0.3 cm. The ratio of the volume of the parenchyma within a voxel to its volume at total lobe capacity was calculated from the tissue density data at two lobe volumes. At a lobe volume of 40% total lobe capacity, the local fractional volumes were 0.42 +/- 0.12. The variability of ventilation that corresponds to this variability of fractional volume is large enough to explain the inefficiency of mixing in the isolated lobe and the slope of the alveolar plateau of nitrogen concentration in the expirate after a breath of oxygen. These results are consistent with data reported earlier on the variability of parenchymal volumes at a scale of 1-10 cm3.     

Measurement of alveolar gas volume by ambient pressure changes in isolated lungs

Alveolar gas volume (AGV) may be measured in humans (Peslin et al., J. Appl. Physiol. 62: 359-363, 1987) by applying very slow sinusoidal variations of ambient pressure (delta Pam) around the body and studying the relationship between delta Pam and the resulting gas displacement at the mouth (delta Vaw): AGVapc = (PB.delta Vaw)/(delta Pam.cos phi), where AGVapc is AGV measured by ambient pressure changes, PB is barometric minus alveolar water vapor pressure, and phi is the phase angle between Pam and Vaw. The applicability of this method to excised lungs at various transpulmonary pressures was assessed in six rabbit lungs and three dog lobes by reference to AGV measurements by He dilution (AGVdil) and by a volumetric method (AGVvol). Except in one instance, AGVapc did not change significantly when the frequency of delta Pam was varied from 0.02 to 0.2 Hz. AGVapc was highly correlated (P less than 0.001) to both AGVdil and AGVvol. It did not differ significantly from AGVdil (81.4 +/- 50.6 vs. 80.2 +/- 44.2 ml) and was only marginally higher than AGVvol (64.6 +/- 26.9 vs. 62.4 +/- 24.4 ml, P less than 0.05). We conclude that the method usually provides accurate results in excised lung preparations. Its main advantages are that it does not require manipulating the lung or changing its volume and that the measurement takes less than 1 min.     

Longitudinal elastic wave propagation in pulmonary parenchyma

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.     

Effects of heterogeneities on the partitioning of airway and tissue properties in normal mice.

We measured the mechanical properties of the respiratory system of C57BL/6 mice using the optimal ventilation waveform method in closed- and open-chest conditions at different positive end-expiratory pressures. The tissue damping (G), tissue elastance (H), airway resistance (Raw), and hysteresivity were obtained by fitting the impedance data to three different models: a constant-phase model by Hantos et al. (Hantos Z, Daroczy B, Suki B, Nagy S, Fredberg JJ. J Appl Physiol 72: 168-178, 1992), a heterogeneous Raw model by Suki et al. (Suki B, Yuan H, Zhang Q, Lutchen KR. J Appl Physiol 82: 1349-1359, 1997), and a heterogeneous H model by Ito et al. (Ito S, Ingenito EP, Arold SP, Parameswaran H, Tgavalekos NT, Lutchen KR, Suki B. J Appl Physiol 97: 204-212, 2004). Both in the closed- and open-chest conditions, G and hysteresivity were the lowest and Raw the highest in the heterogeneous Raw model, and G and H were the largest in the heterogeneous H model. Values of G, Raw, and hysteresivity were significantly higher in the closed-chest than in the open-chest condition. However, H was not affected by the conditions. When the tidal volume of the optimal ventilation waveform was decreased from 8 to 4 ml/kg in the closed-chest condition, G and hysteresivity significantly increased, but there were smaller changes in H or Raw. In summary, values of the obtained mechanical properties varied among these models, primarily due to heterogeneity. Moreover, the mechanical parameters were significantly affected by the chest wall and tidal volume in mice. Contribution of the chest wall and heterogeneity to the mechanical properties should be carefully considered in physiological studies in which partitioning of airway and tissue properties are attempted.     

Inhomogeneity during deflation of excised canine lungs. I. Alveolar pressures

Factors both intrinsic and extrinsic to the lung may cause inhomogeneity of alveolar pressures during deflation. Wilson et al. (J. Appl. Physiol. 59: 1924-1928, 1985) predicted that any such inhomogeneity would be limited by interdependence of regional expiratory flows. To test this hypothesis and to explore how the pleural pressure gradient might affect inhomogeneity of alveolar pressures, we deflated at submaximal flows excised canine lobes that first were suspended in air and then were immersed in foams that simulated the vertical gradient of pleural pressure. Interregional inhomogeneity of regional transpulmonary pressures was measured with use of an alveolar capsule technique. Flow-dependent inhomogeneity of alveolar pressures was present, with differences in alveolar pressure quickly relaxing to a constant limiting value at each flow. Foam immersion increased inhomogeneity at a given flow. We conclude that factors intrinsic to the lung cause significant inhomogeneity of alveolar pressures at submaximal expiratory flows and that this inhomogeneity is enhanced by the extrinsic gradient of pleural pressure. These observations are consistent with the interdependence of flow proposed by Wilson et al.     

Comparison of amounts of collagen and elastin in pleura and parenchyma of dog lung

Pressure-volume characteristics of the lung have been thought to be due primarily to the properties of the network of alveolar septa. However, Hajji et al. (J. Appl. Physiol.: Respirat . Environ. Exercise Physiol. 47: 175-181, 1979) attributed a substantial role to the visceral pleura. Seeking a structural explanation for this result, we compared the relative amounts of collagen fibrils and elastin fibers in the visceral pleura and alveolar parenchyma using stereological measurements in five canine lobes. We found about one-fifth as much collagen and one-tenth as much elastin in the pleura as in the alveolar parenchyma. This structural result confirms the functional conclusions of Hajji et al. We argue that such a substantial structure is not needed for protection against overinflation but may have to do with stabilization of lobe shape or handling of frictional forces.     

Developmental signals do not further accentuate nonuniform postpneumonectomy compensatory lung growth.

Mechanical forces imposed on lung tissue constitute major stimuli for normal lung development and postpneumonectomy (PNX) compensatory growth and remodeling. Superimposing developmental signals on PNX signals augments compensatory alveolar growth but exaggerates airway-parenchymal dissociation (i.e., dysanaptic lung growth); the latter tends to offset benefits derived from the former. In adult dogs after PNX, lobar expansion and growth of the remaining lobes were markedly non-uniform (Ravikumar et al. J Appl Physiol 97:1567-1574, 2004). We hypothesized that superimposing developmental and post-PNX signals further accentuates nonuniformity of lobar growth. We used high-resolution computed tomography (HRCT) to follow regional lung expansion and growth in foxhounds undergoing right PNX at 2.5 mo of age compared with litter-matched control (Sham) animals; scans were performed 4 and 10 mo following surgery, i.e., before and after somatic maturity. Air and tissue volumes were measured in each lobe; tissue volume estimated by HRCT includes air-free tissue and blood in small vessels <1 mm. Interlobar nonuniformity of tissue volume was absent at 4 mo but evident 10 mo after PNX; growth of the remaining left lower lobe gradually lagged behind other lobes. At maturity, nonuniformity of lobar growth in pneumonectomized puppies was similar to that previously reported in pneumonectomized adults. We conclude that superimposing developmental and post-PNX signals enhances some aspects of compensatory lung growth and remodeling without altering its nonuniform spatial distribution.     

Breath-by-breath measurement of the volume displaced by diaphragm motion.

To develop an accurate method to measure the volume displaced by diaphragm motion (DeltaVdi) breath by breath, we compared DeltaVdi measured by a previously evaluated biplanar radiographic method (Singh B, Eastwood PR, and Finucane KE. J Appl Physiol 91: 1913-1923, 2001) at several lung volumes during vital capacity inspirations in 10 healthy and nine hyperinflated subjects with 1) DeltaVdi measured from the same chest X-rays by two previously described uniplanar methods (Petroll WM, Knight H, and Rochester DF. J Appl Physiol 69: 2175-2182, 1990; Verschakelen JA, Deschepper K, and Demendts M. J Appl Physiol 72: 1536-1540, 1992) and a proposed method that considered actual cross-sectional shape of the rib cage and spinal volume (DeltaVdi(S)); and 2) DeltaVdi(S) measured by lateral fluoroscopy in the same 10 healthy subjects. Relative to biplanar DeltaVdi, DeltaVdi(S) values from lateral chest X-rays and fluoroscopy were not different, whereas DeltaVdi values of Petroll et al. and Verschakelen et al. were increased by (means +/- SD) 1.98 +/- 1.59 and 1.16 +/- 0.82 liters, respectively (both P < 0.001). During quiet breathing, DeltaVdi(S) by lateral fluoroscopy was 66 +/- 16% of tidal volume and similar to that between functional residual capacity and one-half inspiratory capacity by the biplanar radiographic method. We conclude that accurate breath-by-breath measurements of DeltaVdi can be made by using lateral fluoroscopy.     

Computational model of rib movement and its application in studying the effects of age-related thoracic cage calcification on respiratory system

A 3D finite element model of rib cage movement is developed and used to study the role of age-related costal cartilage and sternocostal joint calcification, as well as respiratory muscle weakness on the ‘bucket-handle’ movement of human rib. The volume displacement of the rib cage is related to changes in its circumference using an empirical equation presented by Agostoni et al. (1965, J Appl Physiol, 20:1179–1186). A systematic study is carried out to quantify the role of costal cartilage, sternocostal joint calcification and muscle weakness on the volume displacement of the rib cage. The results provide insight into some of the mechanisms underlying age-related changes in the respiratory system.     

Effect of shape and size of lung and chest wall on stresses in the lung.

Conflicting results have been reported on the changes in the distribution of pleural pressures caused by alterations of chest shape. To understand better the effect of shape and size of lung and chest wall on the distribution of stresses, strains, and surface pressures, we analyzed a theoretical model using the technique of finite elements. The study was in two parts. First we investigated the effects of changing the chest wall shape during expansion, and second we studied lungs of a variety of inherent shapes and sizes. We found that, in general, the distributions of alveolar size, mechanical stresses, and surface pressures in the lungs were dominated by the weight of the lung and that changing the shape of the lung or chest wall had relatively little effect. Only at high states of expansion where the lung was very stiff did changing the shape of the chest wall cause substantial changes. Altering the inherent shape of the lung generally had little effect but the topographical differences in stresses and surface pressures were approximately proportional to lung height. The results are generally consistent with those found in dog by Hoppin et al. (J. Appl. Physiol. 27: 863-873, 1969).     

Cytokine immunoreactivity in plasma does not change after moderate endurance exercise.

We investigated whether increased concentrations of circulating cytokines may be responsible for exercise-induced priming of blood neutrophils (J. A. Smith et al. Int. J. Sports Med. 11: 179-187, 1990). The plasma concentrations of tumor necrosis factor-alpha, interleukin- (IL) 1 beta, IL-6, granulocyte-macrophage colony-stimulating factor, and neopterin in trained and untrained human subjects were measured by immunoassay before and after 1 h of cycling at 60% of maximal oxygen uptake. C-reactive protein and creatine kinase (CK) were also measured before and 24 h after exercise as markers of the "acute-phase response" and muscle damage (C. Taylor et al. J. Appl. Physiol. 62: 464-469, 1987), respectively. The small changes in the plasma concentrations of cytokines or neopterin observed after exercise in both trained and untrained subjects were not significantly different to those found in a control group of nonexercised subjects. However, untrained subjects did exhibit an acute-phase response (P = 0.04) 24 h after exercise without additional release of CK into plasma. Baseline training differences were confined to a twofold elevation in CK activity (P = 0.04). The results show that circulating cytokines are unlikely to be responsible for the priming of neutrophil microbicidal activity observed after moderate endurance exercise (J. A. Smith et al. Int. J. Sports Med. 11: 179-187, 1990).     

Effects of chest wall on volume and strain patterns in canine lungs

Lobar functional residual capacity-to-total lung capacity ratios (FRC/TLC) and strains in five supine anesthetized dogs were determined from volumes and side lengths of tetrahedra formed by multiple intraparenchymal markers whose positions were determined roentgenographically. Strain is related to fractional changes in length of elements in a Cartesian coordinate system and was used to describe parenchymal distortion. Volumes and strain patterns were compared in three states: intact dogs, after transection of forelimb structures to relieve traction on the chest wall, and in dogs' excised lungs. Removing traction (NT) decreased the plethysmographically determined FRC and the upper-to-lower lobe ratio (UL/LL) for FRC/TLC. The ratio in the NT state was more like the ratio in the excised lungs (UL/LL approximately equal to 1) than in the intact dog (UL/LL greater than 1). Strain patterns were similar between the intact and the NT states, indicating no lobar shape change at FRC between these two states. Strain in the excised lungs differed greatly from strains in the intact and NT states. We conclude that forelimb traction alters volume distribution between lobes and that lung-chest wall interactions are important in determining volume and strain patterns.     

Anatomically based three-dimensional model of airways to simulate flow and particle transport using computational fluid dynamics.

We have studied gas flow and particle deposition in a realistic three-dimensional (3D) model of the bronchial tree, extending from the trachea to the segmental bronchi (7th airway generation for the most distal ones) using computational fluid dynamics. The model is based on the morphometrical data of Horsfield et al. (Horsfield K, Dart G, Olson DE, Filley GF, and Cumming G. J Appl Physiol 31: 207-217, 1971) and on bronchoscopic and computerized tomography images, which give the spatial 3D orientation of the curved ducts. It incorporates realistic angles of successive branching planes. Steady inspiratory flow varying between 50 and 500 cm(3)/s was simulated, as well as deposition of spherical aerosol particles (1-7 microm diameter, 1 g/cm(3) density). Flow simulations indicated nonfully developed flows in the branches due to their relative short lengths. Velocity flow profiles in the segmental bronchi, taken one diameter downstream of the bifurcation, were distorted compared with the flow in a simple curved tube, and wide patterns of secondary flow fields were observed. Both were due to the asymmetrical 3D configuration of the bifurcating network. Viscous pressure drop in the model was compared with results obtained by Pedley et al. (Pedley TJ, Schroter RC, and Sudlow MF. Respir Physiol 9: 387-405, 1970), which are shown to be a good first approximation. Particle deposition increased with particle size and was minimal for approximately 200 cm(3)/s inspiratory flow, but it was highly heterogeneous for branches of the same generation.     

Effect of transrespiratory pressure on PETCO2-PaCO2 and ventilatory reflexes in humans

Inspiratory muscle activity increases when lung volume is increased by continuous positive-pressure breathing in conscious human subjects (Green et al., Respir. Physiol. 35: 283-300, 1978). Because end-tidal CO2 pressure (PETCO2) does not change, these increases have not been attributed to chemoreflexes. However, continuous positive-pressure breathing at 20 cmH2O influences the end-tidal to arterial CO2 pressure differences (Folkow and Pappenheimer, J. Appl. Physiol. 8: 102-110, 1955). We have compared PETCO2 with arterial CO2 pressure (PaCO2). We have compared PETCO2 with arterial CO2 pressure (PaCO2) in healthy human subjects exposed to continuous positive airway pressure (10 cmH2O) or continuous negative pressure around the torso (-15 cmH2O) sufficient to increase mean lung volume by about 650 ml. The difference between PETCO2 and PaCO2 was not decreased, and we conclude that PETCO2 is a valid measure of chemical drive to ventilation in such circumstances. We observed substantial increases in respiratory muscle electromyograms during pressure breathing as seen previously and conclude this response must originate by proprioception. On average, the compensation of tidal volume thus afforded was complete, but the wide variability of individual responses suggests that there was a large cerebral cortical component in the responses seen here.     

The epithelial Na(+) channel (ENaC) is related to the hypertonicity-induced Na(+) conductance in rat hepatocytes

The epithelial Na(+) channel (ENaC) is composed of the subunits alpha, beta, and gamma [Canessa et al., Nature 367 (1994) 463-467] and typically exhibits a high affinity to amiloride [Canessa et al., Nature 361 (1993) 467-470]. When expressed in Xenopus oocytes, conflicting results were reported concerning the osmo-sensitivity of the channel [Ji et al., Am. J. Physiol. 275 (1998) C1182-C1190; Hawayda and Subramanyam, J. Gen. Physiol. 112 (1998) 97-111; Rossier, J. Gen. Physiol. 112 (1998) 95-96]. Rat hepatocytes were the first system in which amiloride-sensitive sodium currents in response to hypertonic stress were reported [Wehner et al., J. Gen. Physiol. 105 (1995) 507-535; Wehner et al., Physiologist 40 (1997) A-4]. Moreover, all three ENaC subunits are expressed in these cells [B?hmer et al., Cell. Physiol. Biochem. 10 (2000) 187-194]. Here, we injected specific antisense oligonucleotides directed against alpha-rENaC into single rat hepatocytes in confluent primary culture and found an inhibition of hypertonicity-induced Na(+) currents by 70%. This is the first direct evidence for a role of the ENaC in cell volume regulation.     

Modeling of respiratory system impedances in dogs

Mechanical impedances between 4 and 64 Hz of the respiratory system in dogs have been reported (A.C. Jackson et al. J. Appl. Physiol. 57: 34-39, 1984) previously by this laboratory. It was observed that resistance (the real part of impedance) decreased slightly with frequency between 4 and 22 Hz then increased considerably with frequency above 22 Hz. In the current study, these impedance data were analyzed using nonlinear regression analysis incorporating several different lumped linear element models. The five-element model of Eyles and Pimmel (IEEE Trans. Biomed. Eng. 28: 313-317, 1981) could only fit data where resistance decreased with frequency. However, when the model was applied to these data the returned parameter estimates were not physiologically realistic. Over the entire frequency range, a significantly improved fit was obtained with the six-element model of DuBois et al. (J. Appl. Physiol. 8: 587-594, 1956), since it could follow the predominate frequency-dependent characteristic that was the increase in resistance. The resulting parameter estimates suggested that the shunt compliance represents alveolar gas compressibility, the central branch represents airways, and the peripheral branch represents lung and chest wall tissues. This six-element model could not fit, with the same set of parameter values, both the frequency-dependent decrease in Rrs and the frequency-dependent increase in resistance. A nine-element model recently proposed by Peslin et al. (J. Appl. Physiol. 39: 523-534, 1975) was capable of fitting both the frequency-dependent decrease and the frequency-dependent increase in resistance. However, the data only between 4 and 64 Hz was not sufficient to consistently determine unique values for all nine parameters.     

A model evaluation of estimates of breath-to-breath alveolar gas exchange

A mathematical model has been implemented for evaluation of methods for estimating breath-to-breath alveolar gas exchange during exercise in humans. This model includes a homogeneous alveolar gas exchange compartment, a dead space compartment, and tissue spaces for CO2 (alveolar and dead space). The dead space compartment includes a mixing portion surrounded by tissue and an unmixed (slug flow) portion which is partitioned between anatomical and apparatus contributions. A random sinusoidal flow pattern generates a breath-to-breath variation in pulmonary stores. The Auchincloss algorithm for estimating alveolar gas exchange (Auchincloss et al., J. Appl. Physiol. 21: 810-818, 1966) was applied to the model, and the results were compared with the simulated gas exchange. This comparison indicates that a compensation for changes in pulmonary stores must include factors for alveolar gas concentration change as well as alveolar volume change and thus implies the use of end-tidal measurements. Although this algorithm yields reasonable estimates of breath-to-breath alveolar gas exchange, it does not yield a "true" indirect measurement because of inherent error in the estimation of a homogeneous alveolar gas concentration at the end of expiration.     

Error due to dead-space admixture in single-breath method for estimation of pulmonary blood flow

The single-breath method of Kim et al. (J. Appl. Physiol. 21: 1338-1344, 1966) for the estimation of pulmonary blood flow is based on a single-alveolus lung model for which an analytical relationship has been established between the kinetic behavior of the alveolar O2 and CO2 tensions and the pulmonary blood flow. The analysis is based on the assumption that the dead-space contribution to the expirate is negligible after expiration of a predefined volume. We have examined the influence of this assumption on the estimation of pulmonary blood flow by computer simulation in a lung model that incorporates deadspace contribution to the expirate. Data on the fractional contribution of the dead space to the expired gas were obtained from Tsunoda et al.'s study (J. Appl. Physiol. 32: 644-649, 1972) on the emptying pattern of normal adult lungs. The results show that failure to take account of the dead-space contribution can cause an underestimation in the pulmonary blood flow of greater than 30%. The error can be reduced by ignoring the first part of the expiration but only at the cost of an increase in the sensitivity of the single-breath method to measurement noise. This property of the system is demonstrated experimentally. The error due to dead-space admixture depends on the total volume of dead-space gas, the measurement noise, the pulmonary blood flow, and the emptying characteristics of the dead-space compartment during expiration. In normal subjects it is possible to optimize the experimental design so that the systematic error is less than 5% and the coefficient of variation is less than 10%.(ABSTRACT TRUNCATED AT 250 WORDS)     

Periodic flow at airway bifurcations. I. Development of steady pressure differences

In studies of large-amplitude periodic flows at an airway bifurcation, we found an appreciable steady-state pressure difference between the terminal units. To elucidate the fluid dynamic origins of such steady-state pressure differences, we studied single asymmetric bifurcation models with various area ratios and branching angles. The daughter ducts were identical in size and were terminated into identical elastic loads. Sinusoidal flow oscillations were applied at the parent duct so that the upstream Reynolds number ranged from 30 to 77,000 and the Womersley parameter from 2 to 30. The steady-state component (time averaged) of the pressure measured at the terminal with the smaller branching angle was found to be consistently higher than that at the other terminal. This steady-state pressure difference scaled approximately as a fixed fraction of the parent duct dynamic head. Guided by the results of flow-visualization studies, we modeled such behavior based on the temporal and spatial differences of head loss between the two branches of the bifurcation. Our results suggest that interlobar heterogeneity of mean alveolar-pressure observed in excised canine lungs during high frequency oscillation (Allen et al., J. Appl. Physiol. 62: 223-228, 1987) arises solely from fluid dynamic origins: differential head loss due to asymmetry of central airway branching structure.