Effect of long-term anemia and retransfusion on central circulation during exercise

The bulk modulus and the shear modulus describe the capacity of material to resist a change in volume and a change of shape, respectively. The values of these elastic coefficients for air-filled lung parenchyma suggest that there is a qualitative difference between the mechanisms by which the parenchyma resists expansion and shear deformation; the bulk modulus changes roughly exponentially with the transpulmonary pressure, whereas the shear modulus is nearly a constant fraction of the transpulmonary pressure for a wide range of volumes. The bulk modulus is approximately 6.5 times as large as the shear modulus. In recent microstructural modeling of lung parenchyma, these mechanisms have been pictured as being similar to the mechanisms by which an open cell liquid foam resists deformations. In this paper, we report values for the bulk moduli and the shear moduli of normal air-filled rabbit lungs and of air-filled lungs in which alveolar surface tension is maintained constant at 16 dyn/cm. Elevating surface tension above normal physiological values causes the bulk modulus to decrease and the shear modulus to increase. Furthermore, the bulk modulus is found to be sensitive to a dependence of surface tension on surface area, but the shear modulus is not. These results agree qualitatively with the predictions of the model, but there are quantitative differences between the data and the model.     

Surface forces in lungs. I. Alveolar surface tension-lung volume relationships

Alveolar surface tension (gamma)-lung volume relationships were obtained for quasi-static and dynamic lung pressure-volume (PV) histories from measurements of PV curves of liquid- and air-filled excised rabbit lungs. PV relationships were measured at room temperature in lungs filled with test liquids with constant liquid-liquid interfacial tensions with alveolar surface-active materials; and air-filled lungs before and after the normal alveolar surface film was covered with test liquids with constant values of liquid- and air-liquid interfacial tensions. Interfacial tensions of test liquids were measured in a surface balance on monolayers of dipalmitoyl phosphatidylcholine. Values of gamma for the normal air-filled lung were obtained either from points of intersection between PV curves with the normal and test liquid interface or from a general relationship between gamma and the component of recoil pressure due to surface tension derived from the data. In contrast to previous analyses that have used PV measurements, this approach does not depend on assumptions about lung microstructural geometry. Surface tension-volume relationships for the normal air-filled lung show a prominent hysteresis with surface tension ranging from near 0 at low volumes during lung deflation to transiently high values near 40 dyn/cm during inflation; value of equilibrium surface tension (gamma EQ) near 28 dyn/cm; and characteristic transitions in surface film compressibility and associated transitions in film kinetic behavior in nonequilibrium film states where gamma deviates from gamma EQ. These features are consistent with the behavior predicted from current models of alveolar surface film behavior.     

Elastic properties of air- and liquid-filled lung parenchyma

Pressure-volume measurements and the punch indentation test are used to obtain the bulk modulus (kappa) and the shear modulus (mu) of lung parenchyma of air- and liquid-filled rabbit lungs. Plots of kappa and mu vs. transpulmonary pressure obtained from these measurements indicate that there is very little difference between the elastic behavior of the air- and liquid-filled lung, suggesting that the mechanism of resisting deformation in both cases is similar. On the other hand, from plots of kappa and mu vs. lung volume, it appears that the elastic moduli are higher in the air-filled lung than in the liquid-filled lung at the same volume. These differences, referred to as kappa gamma and mu gamma, as well as the difference in transpulmonary pressures (P gamma), are presumably due to the additional elastic recoil of the air-filled lung provided by alveolar surface tension (gamma). No conclusion could be reached about the shape of the kappa gamma vs. P gamma curve. However, the mu gamma vs. P gamma relationship appears to be approximately linear, with a slope of approximately 0.5. This result agrees qualitatively with the model (T. A. Wilson and H. Bachofen, J. Appl. Physiol. 52: 1064-1070, 1982) in which the part of the parenchyma that provides P gamma is pictured as mechanically analogous to an open cell liquid foam, having mu gamma = 0.4P gamma (J. Appl. Mech. Trans. ASME 51: 229-231, 1984), but it is statistically significant only at high lung volumes.     

Scintigraphic regional lung dimensions in upright and head-down men

Our purpose was to analyze regional intrapulmonary volumes and dimensions (especially heights) between total lung capacity and residual volume in upright and head-down healthy men. This analysis was based on the combination of previously obtained scintigraphic data of regional alveolar expansions and of lung shape. This analysis demonstrated that the changes in height were markedly smaller for the apical zones than for the diaphragmatic zones, especially in upright posture but to a smaller extent in head-down posture also. These changes in height in upright posture were attributable to the additive effects of changes in lung shape (which favored larger height changes in the more diaphragmatic zones) and the effects of the changes in regional alveolar expansion (which caused larger volume changes in the diaphragmatic zones). In head-down posture the effects of changes in lung shape (which again favored larger height changes in the diaphragmatic zones except at high volumes) were only partially counteracted by the now inverted changes in alveolar expansion. These height changes were qualitatively in agreement with the cephalad displacement of the minor fissure during lung inflation from residual volume to total lung capacity in both postures, measured previously on chest X-rays. In conclusion, this study shows that the gravitational distributions of alveolar expansion, as assessed by scintigraphy, go along with more complex shape-dependent distributions of regional dimensions and volumes as assessed, e.g., by radiological techniques.     

Retinoic acid-induced alveolar cellular growth does not improve function after right pneumonectomy.

To determine whether all-trans retinoic acid (RA) treatment enhances lung function during compensatory lung growth in fully mature animals, adult male dogs (n = 4) received 2 mg x kg(-1) x day(-1) po RA 4 days/wk beginning the day after right pneumonectomy (R-PNX, 55-58% resection). Litter-matched male R-PNX controls (n = 4) received placebo. After 3 mo, transpulmonary pressure (TPP)-lung volume relationship, diffusing capacities for carbon monoxide and nitric oxide, cardiac output, and septal volume (V(tiss-RB)) were measured under anesthesia by a rebreathing technique at two lung volumes. Lung air and tissue volumes (V(air-CT) and V(tiss-CT)) were also measured from high-resolution computerized tomographic (CT) scans at a constant TPP. In RA-treated dogs compared with controls, TPP-lung volume relationships were similar. Diffusing capacities for carbon monoxide and nitric oxide were significantly impaired at a lower lung volume but similar at a high lung volume. Whereas V(tiss-RB) was significantly lower at both lung volumes in RA-treated animals, V(air-CT) and V(tiss-CT) were not different between groups; results suggest uneven distribution of ventilation consistent with distortion of alveolar geometry and/or altered small airway function induced by RA. We conclude that RA does not improve resting pulmonary function during the early months after R-PNX despite histological evidence of its action in enhancing alveolar cellular growth in the remaining lung.     

Photographic measurement of pleural surface motion during lung oscillation

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.     

Mechanics of edematous lungs.

Using the parenchymal marker technique, we measured pressure (P)-volume (P-V) curves of regions with volumes of approximately 1 cm3 in the dependent caudal lobes of oleic acid-injured dog lungs, during a very slow inflation from P = 0 to P = 30 cmH2O. The regional P-V curves are strongly sigmoidal. Regional volume, as a fraction of volume at total lung capacity, remains constant at 0.4-0.5 for airway P values from 0 to approximately 20 cmH2O and then increases rapidly, but continuously, to 1 at P = approximately 25 cmH2O. A model of parenchymal mechanics was modified to include the effects of elevated surface tension and fluid in the alveolar spaces. P-V curves calculated from the model are similar to the measured P-V curves. At lower lung volumes, P increases rapidly with lung volume as the air-fluid interface penetrates the mouth of the alveolus. At a value of P = approximately 20 cmH2O, the air-fluid interface is inside the alveolus and the lung is compliant, like an air-filled lung with constant surface tension. We conclude that the properties of the P-V curve of edematous lungs, particularly the knee in the P-V curve, are the result of the mechanics of parenchyma with constant surface tension and partially fluid-filled alveoli, not the result of abrupt opening of airways or atelectatic parenchyma.     

Relations among alveolar surface tension, surface area, volume, and recoil pressure

For pulmonary structure-function analysis excised rabbit lungs were fixed by vascular perfusion at six points on the pressure-volume (P-V) curve, i.e. at 40, 80, and 100% of total lung capacity (TLC) on inflation, at 80 and 40% TLC on deflation, and at 80% TLC on reinflation. Before fixation alveolar surface tensions (gamma) were measured in individual alveoli over the entire P-V loop, using an improved microdroplet method. A maximal gamma of approximately 30 mN/m was measured at TLC, which decreased during lung deflation to about 1 mN/m at 40% TLC. Surface tensions were considerably higher on the inflation limb starting from zero pressure than on the deflation limb (gamma-V hysteresis). In contrast, the corresponding alveolar surface area-volume (SA-V) relationship did not form a complete hysteresis over the entire volume range. There was a considerable difference in SA between lungs inflated to 40% TLC (1.49 +/- 0.11 m2) and lungs deflated to 40% TLC (2.19 +/- 0.21 m2), but at 80% TLC the values of SA were essentially the same regardless of the volume history. The data indicate that the gamma-SA hysteresis is only in part accountable for the P-V hysteresis and that the determinative factors of alveolar geometry change with lung volume. At low lung volumes airspace dimensions appear to be governed by an interplay between surface and tissue forces. At higher lung volumes the tissue forces become predominant.     

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).     

Pulmonary NO and CO2 uptake during pressure-induced lung expansion in rabbits

In artificially ventilated animals we investigated the dependence of the pulmonary diffusing capacities of nitric oxide (NO) and doubly 18O-labeled carbon dioxide (DLNO, DLC18O2) on lung expansion with respect to ventilator-driven increases in intrapulmonary pressure. For this purpose we applied computerized single-breath experiments to 11 anesthetized paralyzed rabbits (weight 2.8-3.8 kg) at various alveolar volumes (45-72 ml) by studying the almost entire inspiratory limb of the respective pressure/volume curves (intrapulmonary pressure: 6-27 cmH2O). The animals were ventilated with room air, employing a computerized ventilatory servo-system that we designed to maintain mechanical ventilation and to execute the particular lung function tests automatically. Each single-breath maneuver was started from residual volume (13.5+/-2 ml, mean+/-SD) by inflating the rabbit lungs with 35-55 ml indicator gas mixture containing 0.05% NO in N2 or 0.9% C18O2 in N2. Alveolar partial pressures of NO and C18O2 were measured by respiratory mass spectrometry. Values of DLNO and DLC18O2 ranged between 1.55 and 2.49 ml/(mmHg min) and 11.7 and 16.6 ml/(mmHg min), respectively. Linear regression analyses yielded a significant increase in DLNO with simultaneous increase in alveolar volume (P<0.005) and intrapulmonary pressure (P<0.023) whereas DLC18O2 was not improved. Our results suggest that the ventilator-driven lung expansion impaired the C18O2 blood uptake conductance, finally compensating for the beneficial effect of the increase in alveolar volume on DLC18O2 values.     

Alveoli increase in number but not size from birth to adulthood in rhesus monkeys

Postnatal developmental stages of lung parenchyma in rhesus monkeys is about one-third that of humans. Alveoli in humans are reported to be formed up to 8 yr of age. We used design-based stereological methods to estimate the number of alveoli (N(alv)) in male and female rhesus monkeys over the first 7 yr of life. Twenty-six rhesus monkeys (13 males ranging in age from 4 to 1,920 days and lung volumes from 41.7 to 602 cm(3), 13 females ranging in age from 22 to 2,675 days and lung volumes from 43.5 to 380 cm(3)) were necropsied and lungs fixed, isotropically oriented, fractionated, sampled, embedded, and sectioned for alveolar counting. Parenchymal, alveolar, alveolar duct core air, and interalveolar septal tissue volumes increased rapidly during the first 2 yr with slowed growth from 2 to 7 yr. The rate of change was greater in males than females. N(alv) also showed consistent growth throughout the study, with increases in N(alv) best predicted by increases in lung volume. However, mean alveolar volume showed little relationship with age, lung volume, or body weight but was larger in females and showed a greater size distribution than in males. Alveoli increase in number but not volume throughout postnatal development in rhesus monkeys.     

CO2 relaxes parenchyma in the liquid-filled rat lung.

CO(2) regulation of lung compliance is currently explained by pH- and CO(2)-dependent changes in alveolar surface forces and bronchomotor tone. We hypothesized that in addition to, but independently of, those mechanisms, the parenchyma tissue responds to hypercapnia and hypocapnia by relaxing and contracting, respectively, thereby improving local matching of ventilation (Va) to perfusion (Q). Twenty adult rats were slowly ventilated with modified Krebs solution (rate = 3 min(-1), 37 degrees C, open chest) to produce unperfused living lung preparations free of intra-airway surface forces. The solution was gassed with 21% O(2), balance N(2), and CO(2) varied to produce alveolar hypocapnia (Pco(2) = 26.1 +/- 2.4 mmHg, pH = 7.56 +/- 0.04) or hypercapnia (Pco(2) = 55.0 +/- 2.3 mmHg, pH = 7.23 +/- 0.02). The results show that lung recoil, as indicated from airway pressure measured during a breathhold following a large volume inspiration, is reduced approximately 30% when exposed to hypercapnia vs. hypocapnia (P < 0.0001, paired t-test), but stress relaxation and flow-dependent airway resistance were unaltered. Increasing CO(2) from hypo- to hypercapnic levels caused a substantial, significant decrease in the quasi-static pressure-volume relationship, as measured after inspiration and expiration of several tidal volumes, but hysteresis was unaltered. Furthermore, addition of the glycolytic inhibitor NaF abolished CO(2) effects on lung recoil. The results suggest that lung parenchyma tissue relaxation, arising from active elements in response to increasing alveolar CO(2), is independent of (and apparently in parallel with) passive tissue elements and may actively contribute to Va/Q matching.     

Relationship of tracheal size to maximal expiratory airflow and density dependence

Wave-speed theory predicts that maximal expiratory flow (MEF) at high lung volumes depends strongly on size of central airways. We tested this prediction by correlating MEF and tracheal cross-section area (T-XSA) in 15 (11 males, 4 females) healthy never-smoking volunteers. T-XSA was determined by planimetric analysis of contiguous 1-cm computerized tomographic scans of the intrathoracic trachea. We found a significant correlation between T-XSA at total lung capacity (TLC) and flow at 75% of vital capacity (V75) (r = 0.88, P less than 0.001). This contrasted to the correlation found between lung volume at TLC and V75 (r = 0.60). Density dependence of airflow (percent increase in V75 in air) was 35 +/- 17% and showed a significant inverse relationship to T-XSA (r = 0.70). These results confirm predictions of wave-speed theory and demonstrate the importance of cross-sectional area of central airways in determining MEF at high lung volumes. The large variability of MEF in normal individuals partly represents variations in tracheal size. Poor correlation between lung size and airway size suggests only a loose coupling between airways and lung parenchyma consistent with dysanaptic growth. Our findings indicate that changes in density dependence of airflow are not solely determined by the status of small airways and that differences in tracheal size contribute to its variability.     

Microscopic vs. macroscopic deformation of the pulmonary alveolar duct.

The stretch of the perimeters of alveolar ducts was measured at the surface of saline-filled specimens of human and dog lung parenchyma that were stretched biaxially. The microscopic stretch of these ducts was measured at several levels of isotropic biaxial macroscopic stretch of the parenchyma with stretch ratio (lambda x = lambda y) in the range of 1.20-1.40, which roughly corresponds to tidal breathing in humans and dogs. Alveolar walls were found to be load-carrying elements in the saline-filled lung, as seen by their straightness at all levels of stretch. Quantitatively, let l, A, L, and S denote, respectively, the duct perimeter length and area and the parenchymal target perimeter and area in the deformed state and lo, Ao, Lo, and So the corresponding variables in the undeformed state. The microscopic stretch ratio of the ducts (l/lo) was found to be approximately 4% larger than the macroscopic stretch ratio (L/Lo) in human lung and approximately 10% larger in dog lung. The microscopic area ratio of the ducts (A/Ao) was found to be approximately 10% larger than the macroscopic area ratio (S/So) in human lung and approximately 22% larger in dog lung. Ducts within human parenchyma were seen to be about twice as stiff as ducts within dog parenchyma over the range of macroscopic stretch studied. This correlates with the volume fractions of collagen and elastin being higher in the human lung than in dog lung. The observed nonuniformity in strain field at the microstructural level suggests the need to include a force balance between alveolar ducts and septal walls when modeling the mechanics of saline-filled parenchyma.     

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.     

Morphometric analyses of the effects of thyrotrophin releasing hormone and cortisol on the lungs of fetal sheep

Morphometric analyses of ovine fetal lung parenchyma were undertaken in order to elucidate the roles of pituitary, thyroid and adrenocortical hormones in promoting the structural changes underlying the increased distensibility and stability present in mature fetal lungs. Twenty-six Romney fetuses were treated with either cortisol for 84 h from 125 days (4), pulsatile TRH for 6.5 days from 122 days (4), cortisol and TRH (12), or 0.9% NaCl solution (6). The left lungs were used for physiological studies (distensibility, V40) and the right lungs were prepared for electron microscopy. Using 32 regions of lung parenchyma per fetus, volume density, surface density and arithmetic mean thickness of the alveolar walls were calculated using point and intersection counts. Of the three regimens, treatment with TRH + cortisol (exposure to raised concentrations of cortisol, T3 and prolactin) induced significantly greater lung distensibility, the largest potential alveolar air space (62% of the parenchyma), the greatest alveolar surface area (113.7 mm2/mm3 x 10(-3)) and the thinnest alveolar walls (6.7 microns). We conclude that cortisol, T3 and prolactin act synergistically to promote maturational changes in the alveolar wall. While cortisol plays the major role, T3 and prolactin enhance the ability of the immature lung to respond to the cortisol.     

Impact of postnatal glucocorticoids on early lung development.

Inhaled glucocorticoid treatment during the first 2 yr of life is controversial because this is a period of major structural remodeling of the lung. Rabbits received aerosolized budesonide (Bud; 250 microg/ml) or injected dexamethasone (Dex; 0.05 mg.ml(-1).kg(-1)) between 1 and 5 wk of age. Treatment with Bud caused specific growth retardation of the lung. Dex but not Bud affected the mechanical properties of the lung parenchyma, when corrected for lung volume. Small peripheral airway walls in both glucocorticoid groups were thinner and had fewer alveolar attachment points with greater distance between attachments than controls, but collagen content was not affected by glucocorticoids. Dex led to reduced body weight, lung volume, alveolar number, and surface area. The alveolar size and number and elastin content, when related to lung volume, was not affected by Bud, suggesting normal structural development but inhibition of total growth. Arterial wall thickness and diameter were affected by Bud. This study demonstrates that developing lungs are sensitive to inhaled glucocorticoids. As such, the use of glucocorticoids in young infants and children should be monitored with caution and only the lowest doses that yield significant clinical improvement should be used.     

Analysis of stress distribution in the alveolar septa of normal and simulated emphysematic lungs.

The alveolar septum consists of a skeleton of fine collagen and elastin fibers, which are interlaced with a capillary network. Its mechanical characteristics play an important role in the overall performance of the lung. An alveolar sac model was developed for numerical analysis of the internal stress distribution and septal displacements within the alveoli of both normal and emphysematic saline-filled lungs. A scanning electron micrograph of the parenchyma was digitized to yield a geometric replica of a typical two-dimensional alveolar sac. The stress-strain relationship of the alveolar tissue was adopted from experimental data. The model was solved by using commercial finite-element software for quasi-static loading of alveolar pressure. Investigation of the state of stresses and displacements in a healthy lung simulation yielded values that compared well with experimentally reported data. Alteration of the mechanical characteristics of the alveolar septa to simulate elastin destruction in the emphysematic model induced significant stress concentrations (e.g., at a lung volume of 60% total capacity, tensions at certain parts in an emphysematic lung were up to 6 times higher than those in a normal lung). The combination of highly elevated stress sites together with the cyclic loading of breathing may explain the observed progressive damage to elastin fibers in emphysematic patients.     

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.     

Flow and volume dependence of expiratory resistance in anesthetized cats

In five anesthetized paralyzed cats, mechanically ventilated with tidal volumes of 36-48 ml, the isovolume pressure-flow relationships of the lung and respiratory system were studied. The expiratory pressure was altered between 3 and -12 cmH2O for single tidal expirations. Isovolume pressure-flow plots for three lung volumes showed that the resistive pressure-flow relationships were curvilinear in all cases, fitting Rohrer's equation: P = K1V + K2V2, where P is the resistive pressure loss, K1 and K2 are Rohrer's coefficients, and V is flow. Values of K1 and K2 declined with lung inflation, consistent with the volume dependence of pulmonary (RL) and respiratory system resistances (Rrs). During lung deflation against atmospheric pressure, RL and Rrs tended to remain constant through most of expiration, resulting in a nearly linear volume-flow relationship. In the presence of a fixed respiratory system elastance, the shape of the volume-flow profile depended on the balance between the volume and the flow dependence of RL and Rrs. However, the flow dependence of RL and Rrs indicates that their measured values will be affected by all factors that modify expiratory flow, e.g., respiratory system elastance, equipment resistance, and the presence of respiratory muscle activity.