A hemodynamic model representation of the dog lung.

The published morphometric data from human, cat, and dog lungs suggest that the power-law relationships between the numbers (Na and Nv) and diameters (Da and Dv) of arteries and veins and between the lengths (La and Lv) and diameters of the arteries and veins could be used as scaling rules for assigning dimensions and numbers to the intrapulmonary vessels of the arterial and venous trees of the dog lung. These rules, along with the dimensions of the extrapulmonary arteries and capillary sheet and the distensibility coefficients of the vessels obtained from the literature, were used to construct a steady-state hemodynamic model of the dog lung vascular bed. The model can be characterized approximately by 15 orders of arteries with Na approximately 2.07 Da-2.58 and 13 orders of veins with Nv approximately 2.53 Dv-2.61. For the intrapulmonary vessels (orders 1-12), La approximately 4.85 Da1.01, and Lv approximately 6.02 Da1.07. The average ratio of the numbers of vessels in consecutive orders is approximately 3.2 for the arteries and veins. These arterial and venous trees are connected by the capillary sheet with an undistended thickness of approximately 3.5 microns and an area of 33 m2. The average distensibility (% increase in diameter over the undistended diameter/Torr increase in transmural pressure) for the model arteries and veins is approximately 2.4%/Torr, and the distensibility of the capillary sheet (% increase in thickness over the undistended thickness/Torr increase in transmural pressure) is approximately 3.6%/Torr. The calculated arterial-capillary-venous volumes and compliances of the model agree well with experimental estimates of these variables in dogs. In addition, the model appears consistent with certain aspects of the pressure-flow relationships measured in dog lungs. The model appears to be a useful summary of some of the available data on pulmonary morphometry and vessel properties. It is anticipated that the model will provide the basis for dynamic modeling of the dog lung in the future.

A simple distensible vessel model for interpreting pulmonary vascular pressure-flow curves.

A simple distensible vessel model was developed for the purpose of interpreting the vascular pressure-flow curve in the zone 3 lung. The model-governing equation has two parameters: R0, representing the hemodynamic resistance of the undistended pulmonary vascular bed, and alpha, representing the distensibility of the resistance vessels. To evaluate the model, the governing equation was used in a nonlinear regression analysis of the pressure-flow data from isolated dog lung lobes. The dependency of the estimates of the model parameters in response to changes in perfusate viscosity (hematocrit) was determined. The distensible vessel model provided reasonable fits to the data, and, as predicted, R0, but not alpha, was hematocrit dependent. On the other hand, the traditional linear ohmic-Starling resistor model fit to the same pressure-flow data generally provided fits approaching those of the distensibility model only if the pressure intercept (the mean "critical closing pressure") was allowed to increase with hematocrit. Because the ohmic-Starling resistor concept does not predict a hematocrit dependence of the critical closing pressure, this latter observation is evidence that the distensible vessel model offers an alternative conceptualization of the pulmonary circulation worthy of additional study with respect to the interpretation of experimental pressure-flow data.

Pulmonary arterial dilation by inhaled NO: arterial diameter, NO concentration relationship.

The objective of this study was to determine the nitric oxide (NO) concentration and vessel diameter dependence of the pulmonary arterial dilation induced by inhaled NO. Isolated dog lung lobes were situated between a microfocal X-ray source and X-ray detector and perfused with either blood or plasma. Boluses of radiopaque contrast medium were injected into the lobar artery under control conditions, when the pulmonary arteries were constricted by infusion of serotonin and when the serotonin infusion was accompanied by inhalation of from 30 to 960 parts/million NO. Arterial diameter measurements were obtained from X-ray images of vessels having control diameters in the 300- to 3,400-microm range. Serotonin constricted the vessels throughout the size range studied, with an average decrease in diameter of approximately 20%. The fractional reversal of the serotonin-induced constriction by inhaled NO was directly proportional to inhaled NO concentration, inversely proportional to vessel size, and greater with plasma than with blood perfusion in vessels as large as 3 mm in diameter. The latter indicates that intravascular hemoglobin affected the bronchoalveolar-to-arterial luminal NO concentration gradient in fairly large pulmonary arteries. The data provide information regarding pulmonary arterial smooth muscle accessibility to intrapulmonary gas that should be useful as part of the database for modeling the communication between intrapulmonary gas and pulmonary arterial smooth muscle cells in future studies.

Subpleural pulmonary microvascular pressures in the dog lung.

The reported values for the pressure difference between lobar artery and subpleural arteriole and between subpleural venule and lobar vein as a fraction of the total arterial-to-venous pressure drop across the dog lung have varied considerably. We carried out the present study to provide an additional set of measurements and to determine whether it is likely that differences in venous pressure or transpulmonary pressure between studies might make a substantial contribution to variations between studies. We measured the lobar arterial pressure (Pa) to subpleural arteriole (22-60 microns diam) pressure (Pma) to subpleural venule (30-80 microns diam) pressure (Pmv) to lobar venous pressure (Pv) distribution over a range of alveolar pressures (PA; 2.5-13.1 mmHg) and venous pressures (0-24.2 mmHg) in isolated dog lung lobes using the micropuncture servo-null technique. On average, near functional residual capacity (PA = 3 mmHg) and venous pressure equal to PA, (Pa-Pma)/(Pma-Pmv)/(Pmv-Pv) was 37:30:33%. Under zone 3 conditions, there was a small positive correlation between the fractional Pa-to-Pma pressure difference and PA and Pv, but dependence of the Pmv-to-Pv fraction on PA and Pv was not consistent. The overall effects of PA and Pv on the fractional pressure drops were not sufficient to account for differences between previous studies. Under zone 2 conditions as the venous pressure was varied, the changes in Pmv were nearly equal to the changes in Pv, whereas Pma was relatively insensitive to Pv. Thus, the zone 2 results were consistent with a capillary location for the flow-limiting segment under zone 2 conditions.

Angiotensin-converting enzyme preferentially hydrolyzes trans isomer of proline-containing substrate.

An analysis of the hydrolysis kinetics of the synthetic angiotensin-converting enzyme (ACE) substrate benzoyl-phenylalanyl-alanyl-proline (BPAP) in the intact lung suggested that 12-15% of the BPAP was in a form that could not be hydrolyzed by ACE in the time course of a single pass through the lungs [C. A. Dawson et al. Am. J. Physiol. 257 (Heart Circ. Physiol. 26): H853-H865, 1989]. BPAP has been found to exist as a mixture of cis and trans isomers in a ratio of approximately 14:86 in aqueous solution at equilibrium. Thus, one possible explanation for the incomplete hydrolysis of BPAP on passage through the intact lung is that the trans form is the preferred substrate for ACE. To examine this hypothesis, we measured BPAP hydrolysis by ACE in vitro over a range of ACE concentrations and in the presence and absence of the peptidyl-prolyl cis-trans isomerase cyclophilin. In the presence of a sufficient concentration of ACE and in the absence of cyclophilin, hydrolysis of [3H]BPAP by ACE followed biexponential progress curves, consistent with the hypothesis that the rate of hydrolysis of the majority (approximately 87%) of the substrate is proportional to ACE concentration, whereas the hydrolysis rate of the remaining substrate fraction is independent of enzyme concentration. The addition of cyclophilin resulted in an increase in the ACE-independent rate constant, an effect that was reversed by the cyclophilin inhibitor cyclosporin A. These results suggest that the enzyme-independent rate constant represents the rate of cis-trans isomerization and that the enzyme-dependent rate constant represents the hydrolysis of the trans isomer.(ABSTRACT TRUNCATED AT 250 WORDS)

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

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

Transit time dispersion in the pulmonary arterial tree.

Knowledge of the contributions of arterial and venous transit time dispersion to the pulmonary vascular transit time distribution is important for understanding lung function and for interpreting various kinds of data containing information about pulmonary function. Thus, to determine the dispersion of blood transit times occurring within the pulmonary arterial and venous trees, images of a bolus of contrast medium passing through the vasculature of pump-perfused dog lung lobes were acquired by using an X-ray microfocal angiography system. Time-absorbance curves from the lobar artery and vein and from selected locations within the intrapulmonary arterial tree were measured from the images. Overall dispersion within the lung lobe was determined from the difference in the first and second moments (mean transit time and variance, respectively) of the inlet arterial and outlet venous time-absorbance curves. Moments at selected locations within the arterial tree were also calculated and compared with those of the lobar artery curve. Transit times for the arterial pathways upstream from the smallest measured arteries (200-micron diameter) were less than approximately 20% of the total lung lobe mean transit time. Transit time variance among these arterial pathways (interpathway dispersion) was less than approximately 5% of the total variance imparted on the bolus as it passed through the lung lobe. On average, the dispersion that occurred along a given pathway (intrapathway dispersion) was negligible. Similar results were obtained for the venous tree. Taken together, the results suggest that most of the variation in transit time in the intrapulmonary vasculature occurs within the pulmonary capillary bed rather than in conducting arteries or veins.

Structure-function relationships in the pulmonary arterial tree.

Knowledge of the relationship between structure and function of the normal pulmonary arterial tree is necessary for understanding normal pulmonary hemodynamics and the functional consequences of the vascular remodeling that accompanies pulmonary vascular diseases. In an effort to provide a means for relating the measurable vascular geometry and vessel mechanics data to the mean pressure-flow relationship and longitudinal pressure profile, we present a mathematical model of the pulmonary arterial tree. The model is based on the observation that the normal pulmonary arterial tree is a bifurcating tree in which the parent-to-daughter diameter ratios at a bifurcation and vessel distensibility are independent of vessel diameter, and although the actual arterial tree is quite heterogeneous, the diameter of each route, through which the blood flows, tapers from the arterial inlet to essentially the same terminal arteriolar diameter. In the model the average route is represented as a tapered tube through which the blood flow decreases with distance from the inlet because of the diversion of flow at the many bifurcations along the route. The taper and flow diversion are expressed in terms of morphometric parameters obtained using various methods for summarizing morphometric data. To help put the model parameter values in perspective, we applied one such method to morphometric data obtained from perfused dog lungs. Model simulations demonstrate the sensitivity of model pressure-flow relationships to variations in the morphometric parameters. Comparisons of simulations with experimental data also raise questions as to the "hemodynamically" appropriate ways to summarize morphometric data.

Feldkamp and circle-and-line cone-beam reconstruction for 3D micro-CT of vascular networks.

Detailed morphometric knowledge of the microvascular network is needed for studies relating structure to haemodynamic function in organs like the lung. Clinical volumetric CT is limited to millimetre-order spatial resolution. Since evidence suggests that small arterioles (50 to 300 micrometres) dominate pulmonary haemodynamics, we built a micro-CT scanner, capable of imaging excised lungs in 3D with 100 microm resolution, for basic physiology research. The scanner incorporates a micro-focal (3 microm) x-ray source, an xyz theta stage and a CCD-coupled image intensifier detector. We imaged phantoms and contrast-enhanced rat lungs, reconstructing the data with either the Feldkamp or the circle-and-line cone-beam reconstruction algorithm. We present reconstructions using 180 views over 360 degrees for the circular trajectory, augmented with views from a linear scan for the circle-and-line algorithm. Especially for platelike features perpendicular to the rotation axis and remote from the midplane, the circle-and-line algorithm produces superior reconstructions compared with Feldkamp's algorithm. We conclude that the use of nonplanar source trajectories to perform micro-CT on contrast-enhanced, excised lungs can provide data useful for morphometric analysis of vascular trees, currently down to the 130 microm level.

Novel Flurometric Tool to Assess Mitochondrial Redox State of Isolated Perfused Rat Lungs after Exposure to Hyperoxia.

Recently we demonstrated the utility of optical fluorometry to detect a change in the redox status of mitochondrial autofluorescent coenzymes NADH (Nicotinamide Adenine Dinucleotide) and FAD (oxidized form of Flavin Adenine Dinucleotide (FADH2,)) as a measure of mitochondrial function in isolated perfused rat lungs (IPL). The objective of this study was to utilize optical fluorometry to evaluate the effect of rat exposure to hyperoxia (>95% O2 for 48 hours) on lung tissue mitochondrial redox status of NADH and FAD in a nondestructive manner in IPL. Surface NADH and FAD signals were measured before and after lung perfusion with perfusate containing rotenone (ROT, complex I inhibitor), potassium cyanide (KCN, complex IV inhibitor), and/or pentachlorophenol (PCP, uncoupler). ROT- or KCN-induced increase in NADH signal is considered a measure of complex I activity, and KCN-induced decrease in FAD signal is considered a measure of complex II activity. The results show that hyperoxia decreased complex I and II activities by 63% and 55%, respectively, as compared to lungs of rats exposed to room air (normoxic rats). Mitochondrial complex I and II activities in lung homogenates were also lower (77% and 63%, respectively) for hyperoxic than for normoxic lungs. These results suggest that the mitochondrial matrix is more reduced in hyperoxic lungs than in normoxic lungs, and demonstrate the ability of optical fluorometry to detect a change in mitochondrial redox state of hyperoxic lungs prior to histological changes characteristic of hyperoxia.

Effects of hypoxia on pulmonary microvascular volume.

To determine the effects of alveolar hypoxia on pulmonary microvascular volume, X-ray microfocal angiographic images of isolated perfused dog lung lobes were obtained during passage of a bolus of radiopaque contrast medium during both normoxic (alveolar gas, 15% O(2), 6% CO(2), and 79% N(2)) and hypoxic (3% O(2), 6% CO(2), and 91% N(2)) conditions. Regions of interest (ROIs) over the lobar artery and vein at low magnification and a feeding artery ( approximately 500 microm diameter) and the nearby microvasculature (vessels smaller than approximately 50 microm) at high magnification were identified, and X-ray absorbance vs. time curves were acquired under both conditions from the same ROIs. The total pulmonary vascular volume was calculated from the flow and the mean transit time for the contrast medium passage from the lobar artery to lobar vein. The fractional changes in microvascular volume were determined from the areas under the high-magnification X-ray absorbance curves. Hypoxia decreased lobar volume by 13 +/- 3% (SE) and regional microvascular volume by 26 +/- 4% (SE). Given the morphometry of the lung vasculature, these results suggest that capillary volume was decreased by hypoxia.

On the estimation of pulmonary capillary pressure from arterial occlusion.

We have attempted to evaluate some approaches for estimating pulmonary capillary pressure from the transient pressure data obtained from the tip of the Swanz-Ganz catheter after inflation of the balloon. To this end experiments were carried out in anesthetized dogs in which pulmonary vasoconstriction was induced by infusion of histamine, serotonin, or norepinephrine or by hypoxia. In a group of closed chest dogs, the time course for the fall in the catheter tip pressure toward the wedge pressure was different for the different vasoconstrictors. For example, during histamine infusion the fall in pressure was slow, whereas during serotonin infusion it was rapid. To evaluate the information in the decay curves, a group of dogs was studied with open thorax to permit the simultaneous occlusion of both the artery and vein of one lung lobe (double occlusion) as well as occlusion of the lobar artery alone (arterial occlusion). The pattern of response to the various vasoconstrictors observed with lobar arterial occlusion was similar in these animals to the closed chest animals. The equilibrium pressure after double occlusion (the double occlusion pressure), expressed as a fraction of the mean arterial-venous pressure difference before occlusion, was correlated with the mean decay time of the arterial pressure curve after arterial occlusion. We also found significant correlations between the double occlusion pressure and the estimates of capillary pressure based on model interpretations of the pressure decay curve after arterial occlusion. However, there was wide scatter in the individual comparisons.(ABSTRACT TRUNCATED AT 250 WORDS)

Microfocal X-ray CT imaging and pulmonary arterial distensibility in excised rat lungs.

The objective of this study was to develop an X-ray computed tomographic method for measuring pulmonary arterial dimensions and locations within the intact rat lung. Lungs were removed from rats and their pulmonary arterial trees were filled with perfluorooctyl bromide to enhance X-ray absorbance. The lungs were rotated within the cone of the X-ray beam projected from a microfocal X-ray source onto an image intensifier, and 360 images were obtained at 1 degrees increments. The three-dimensional image volumes were reconstructed with isotropic resolution using a cone beam reconstruction algorithm. The vessel diameters were obtained by fitting a functional form to the image of the vessel circular cross section. The functional form was chosen to take into account the point spread function of the image acquisition and reconstruction system. The diameter measurements obtained over a range of vascular pressures were used to characterize the distensibility of the rat pulmonary arteries. The distensibility coefficient alpha [defined by D(P) = D(0)(1 + alphaP), where D(P) is the diameter at intravascular pressure (P)] was approximately 2.8% mmHg and independent of vessel diameter in the diameter range (about 100 to 2,000 mm) studied.

Pulmonary arterial morphometry from microfocal X-ray computed tomography.

The objective of this study was to develop an X-ray computed tomographic method for pulmonary arterial morphometry. The lungs were removed from a rat, and the pulmonary arterial tree was filled with perfluorooctyl bromide to enhance X-ray absorbance. At each of four pulmonary arterial pressures (30, 21, 12, and 5.4 mmHg), the lungs were rotated within the cone of the X-ray beam that was projected from a microfocal X-ray source onto an image intensifier, and 360 images were obtained at 1 degrees increments. The three-dimensional image volumes were reconstructed with isotropic resolution with the use of a cone beam reconstruction algorithm. The luminal diameter and distance from the inlet artery were measured for the main trunk, its immediate branches, and several minor trunks. These data revealed a self-consistent tree structure wherein the portion of the tree downstream from any vessel of a given diameter has a similar structure. Self-consistency allows the entire tree structure to be characterized by measuring the dimensions of only the vessels comprising the main trunk of the tree and its immediate branches. An approach for taking advantage of this property to parameterize the morphometry and distensibility of the pulmonary arterial tree is developed.