Effect of pancreatic and leukocyte elastase on hydraulic conductivity in lung interstitial segments.

Elastase-induced changes in flow were used to quantify the degradation of lung interstitial elastin. Degassed rabbit lungs were inflated with silicon rubber via airways and vessels. The lungs were cut into 1-cm-thick sections. Two chambers were bonded to each section to enclose the interstitium surrounding an arterial segment. Flow of albumin solution (0-5 g/dl) between the chambers was followed by that of the albumin solution with 0.25 g/dl pancreatic elastase solution. Driving pressure was 5 cmH(2)0, and mean interstitial pressure was either 0 or 10 cmH(2)O. Elastase caused an increase in flow in approximately 70% of the interstitial segments and a reduction in flow in the remaining segments. The elastase-induced response in flow was independent of both albumin concentration and mean interstitial pressure. Leukocyte elastase (5 units/dl) produced flow responses similar to those of 0.25 g/dl pancreatic elastase. The increased flow of leukocyte elastase was reduced by a subsequent flow with 0.25 g/dl pancreatic elastase but enhanced by a subsequent flow with a 10-fold lower concentration. A change in the order of the elastase flows reversed the concentration-dependent responses. This behavior suggests a complex interaction among the interstitial fibers after degradation by pancreatic and leukocyte elastase. Endogenous elastase-induced increases in interstitial permeability might affect blood-lymph barrier permeability, whereas elastase-induced cessation of flow might be related to the alveolar septal wall destruction observed in emphysema.

Effect of concentration and hyaluronidase on restriction of hetastarch flux through lung interstitial segments.

The transport properties of lung interstitium were studied by measuring the flow of hetastarch solution (2 and 6%) through 1-cm perivascular interstitial segments of rabbit lungs. Hetastarch (10(4)-10(7) Da) solution has a colloid osmotic pressure similar to that of albumin solution. Driving pressure was 5 cm H(2)O and mean interstitial pressure was 0 cm H(2)O. The flows of 2 and 6% hetastarch solutions were measured before (Q(1)) and after (Q(2)) the addition of 0.02% hyaluronidase. Hetastarch molecular distributions in effluent samples were measured by high-performance size-exclusion chromatography (HPSEC) to determine sieving ratio (C(out)/C(in), downstream-to-upstream concentration ratio). Hyaluronidase significantly (P < 0.0004) increased flow sixfold, but the increase in flow (Q(2)/Q(1)) was reduced through the interstitium around smaller vessels. A similar behavior was observed with the flow of albumin solution without and with hyaluronidase. C(out)/C(in) decreased monotonically with molecular weight, was greater with 6% than with 2% (low colloid osmotic pressure) hetastarch, and increased with hyaluronidase. Modeling the transport through uniform pores, equivalent pore radius was 10 and 15 nm with 2 and 6% hetastarch, respectively, and doubled with hyaluronidase. In conclusion, interstitial pores expand in response to an increase in colloid osmotic pressure both before and after tissue degradation by hyaluronidase.

Transport properties of alveolar epithelium measured by molecular hetastarch absorption in isolated rat lungs.

To evaluate the transport properties of the alveolar epithelium, we instilled hetastarch (Het; 6%, 10 ml, 1 - 1 x 10(4) kDa) into the trachea of isolated rat lungs and then measured the molecular distribution of Het that entered the lung perfusate from the air space over 6 h. Het transport was driven by either diffusion or an oncotic gradient. Perfusate Het had a unique, bimodal molecular weight distribution, consisting of a narrow low-molecular-weight peak at 10-15 kDa (range, 5-46 kDa) and a broad high-molecular-weight band (range 46-2,000 kDa; highest at 288 kDa). We modeled the low-molecular-weight transport as (passive) restricted diffusion or osmotic flow through a small-pore system and the high-molecular-weight transport as passive transport through a large-pore system. The equivalent small-pore radius was 5.0 nm, with a distribution of 150 pores per alveolus. The equivalent large-pore radius was 17.0 nm, with a distribution of one pore per seven alveoli. The small-pore fluid conductivity (2 x 10(-5) ml. h(-1). cm(-2). mmHg(-1)) was 10-fold larger than that of the large-pore conductivity.

Effects of age on elastic moduli of human lungs.

The model of the lung as an elastic continuum undergoing small distortions from a uniformly inflated state has been used to describe many lung deformation problems. Lung stress-strain material properties needed for this model are described by two elastic moduli: the bulk modulus, which describes a uniform inflation, and the shear modulus, which describes an isovolume deformation. In this study we measured the bulk modulus and shear modulus of human lungs obtained at autopsy at several fixed transpulmonary pressures (Ptp). The bulk modulus was obtained from small pressure-volume perturbations on different points of the deflation pressure-volume curve. The shear modulus was obtained from indentation tests on the lung surface. The results indicated that, at a constant Ptp, both bulk and shear moduli increased with age, and the increase was greater at higher Ptp values. The micromechanical basis for these changes remains to be elucidated.

Pleural tissue hyaluronan produced by postmortem ventilation in rabbits.

We developed a method that used Alcian blue bound to hyaluronan to measure pleural hyaluronan in rabbits postmortem. Rabbits were killed, then ventilated with 21% O2--5% CO2--74% N2 for 3 h. The pleural liquid was removed by suction and 5 ml Alcian blue stock solution (0.33 mg/ml, 3.3 pH) was injected into each chest cavity. After 10 min, the Alcian blue solution was removed and the unbound Alcian blue solution (supernatant) separated by centrifugation and filtration. The supernatant transmissibility (T) was measured spectrophotometrically at 613 nm. Supernatant Alcian blue concentration (Cab) was obtained from a calibration curve of T versus dilutions of stock solution Cab. Alcian blue bound to pleural tissue hyaluronan was obtained by subtracting supernatant Cab from stock solution Cab. Pleural tissue hyaluronan was obtained from a calibration curve of hyaluronan versus Alcian blue bound to hyaluronan. Compared with control rabbits, pleural tissue hyaluronan (0.21 +/- 0.04 mg/kg) increased twofold, whereas pleural liquid volume decreased by 30% after 3 h of ventilation. Pleural effusions present 3 h postmortem without ventilation did not change pleural tissue hyaluronan from control values. Thus ventilation-induced pleural liquid shear stress, not increased filtration, was the stimulus for the increased hyaluronan produced from pleural mesothelial cells.

Effect of hyaluronidase on albumin diffusion in lung interstitium.

Albumin diffusion measured in an isolated segment of rabbit lung interstitium with a radioactive tracer ((125)I-albumin) technique was independent of albumin concentration and similar to the free diffusion of albumin in water (Qiu et al, 1998. J Appl Physiol 85: 575-583). We studied the effect of hyaluronidase on the diffusion of albumin. Isolated rabbit lungs were inflated with silicon rubber by way of airways and blood vessels, and two chambers were bonded to the sides of a approximately 0.5-cm thick slab enclosing a vessel with an interstitial cuff. One chamber was filled with 2 g/dl albumin solution containing (125)I-albumin and 0.02 g/dl hyaluronidase. Unbound (125)I was removed from the tracer by dialysis before use. The other chamber filled with Ringer's solution was placed within a NaI(Tl) scintillation detector. Diffusion of tracer was measured continuously for 120 h. Albumin diffusion coefficient (D) and interstitial area (A) were obtained by fitting the tracer-time curve with the theoretical solution of the equation describing one-dimension diffusion of a solute across a membrane. D averaged 5.2 x 10(-7) cm(2)/s for albumin diffusion with hyaluronidase, 20% less than that measured previously without hyaluronidase. Hyaluronidase had no effect on A. Results indicated an interaction between albumin and interstitial hyaluronan that was the opposite of the steric effect on albumin excluded volume measured in solution.

Regional pleural filtration and absorption measured by fluorescent tracers in rabbits.

In prone anesthetized rabbits, we used Evans blue-dyed albumin (EBA) to study regional pleural filtration and FITC dextran to study regional pleural absorption. Evans blue was injected intravenously, and the animals were ventilated for 6 h at either of two levels of ventilation. Postmortem the right rib cage was frozen and thawed before study. EBA fluorescence emitted from the rib cage surface was measured along the cranial-caudal axis near the mid chest with fluorescence videomicroscopy. Fluorescent light intensity increased from the third to the eighth rib in a cyclic fashion, with peaks at the ribs and troughs at the intercostal spaces. This increase was greater at the higher ventilation. Fluorescent images of cross sections of a frozen rib cage verified a cranial-caudal gradient in filtration. Fluorescent images of FITC dextran absorbed from the pleural space into the rib cage surface indicated major areas of absorption at the ventral, caudal, and cranial regions adjacent to the lung margins and areas of absorption scattered in the intercostal spaces. Simultaneous measurements of EBA filtration and FITC absorption showed sites of maximal filtration that were different from sites of maximal absorption. Pleural uptake of fluorescent microspheres (2-microm diameter) located lymphatic stomata distributed randomly within clusters in the intercostal spaces and channels of lymphatic lacunae parallel to blood vessels. Diaphragmatic uptake of microspheres was confined mainly to the ventral surface of the central tendon. Visceral pleural absorption was minimal.

Effect of concentration and hyaluronidase on albumin diffusion across rabbit mesentery.

OBJECTIVE: To measure the diffusion coefficient of albumin through rabbit mesentery using the steady-state flux of radioactive tracer 125I-albumin. The effect of albumin concentration and testicular hyaluronidase were also studied. METHODS: Mesenteric tissue was bonded between two plates, exposing a 7 mm diameter surface, with two chambers on either side. One chamber was filled with a test solution of albumin containing the radioactive tracer and the other with lactated Ringer solution. The solutions in both chambers were stirred with small magnetic cylinders. The chamber filled with lactated Ringer solution was placed in a well-type NaI(Tl) detector, and the radiation emitted from the tracer that diffused across the mesentery was monitored continuously for 9 hours. The diffusion coefficient (D) was calculated using Fick's law of diffusion. The diffusion coefficient was measured at albumin concentration differences (delta C) between approximately 0 and 10 g/dL. The diffusion coefficient was also measured with testicular hyaluronidase at three different albumin-concentration differences. RESULTS: The diffusion coefficient increased significantly (P < 0.0001) approximately three-fold from a mean value of 2.2 x 10(-8) +/- 1.2 x 10(-8) (SD) cm2/s at 0-0.5 g/dL delta C to 5.9 x 10(-8) +/- 1.1 x 10(-8) (SD) cm2/s at 10 g/dL delta C. The values are much less than the free diffusion coefficient of albumin (6 x 10(-7) cm2/s). Testicular hyaluronidase added to the albumin solution decreased D by approximately 60%, but did not eliminate the increase in D with delta C. CONCLUSIONS: The increase in D with delta C and the reduced D with hyaluronidase were attributed to a reduced albumin-excluded volume caused by an interaction between albumin and hyaluronan. Further studies are required to define this interaction.

Hydraulic conductivity, albumin reflection and diffusion coefficients of pig mediastinal pleura.

Hydraulic conductivity (L), albumin reflection coefficient (sigma), and albumin diffusion coefficient (D) were measured across pig mediastinal pleura. The tissue (7 mm diameter) was bonded between two chambers. Flow (Q) of lactated Ringer solution between the chambers was measured in turn at driving pressures (DeltaP) of 2, 4, and 6 cm H(2)O. Value of L was proportional to the slope of the Q-DeltaP curve. Then Q was measured in turn at three albumin osmotic pressure differences (Deltapi equivalent to -1, -2, and -3 g/dl albumin concentration difference, DeltaC) with DeltaP constant at either 2, 3, 4, or 6 cm H(2)O. From Starling's equation, magnitude of sigma was the slope of the Q-Deltapi curve divided by the slope of the Q-DeltaP curve. We measured the diffusion of 0, 2, 5, and 10 g/dl albumin with tracer (125)I-albumin. Tracer mass (M) that diffused across the pleura was measured for 10 h using a well-type NaI(T1) detector. D was calculated from the slope of the M-time curve. Values of L averaged 2.0 x 10(-8) cm(3). s(-1). dyne(-1) (n = 23). Values of sigma were small (0.02-0.05) and sigma increased as flow increased 20-fold. D (n = 24) increased 3-fold from 2.7 x 10(-8) cm(2)/s as DeltaC increased from 0 to 10 g/dl. The small values of sigma indicated that mediastinal pleura provided little restriction to the passage of protein.

Effect of frequency and tidal volume on pleural pressure in rabbits during high frequency ventilation.

Regional effects of the chest wall on airway pressure transmission were studied during high frequency ventilation in anesthetized rabbits. We measured airway pressure (Paw), esophageal pressure (Pes), and costal pleural pressure (Ppl) by a rib capsule and flow and volume with a calibrated pneumotachograph. Using a closed circuit, pressures and flow were measured at varying frequencies (2-80 Hz) and tidal volumes (2-20 ml). Mean Pes and Ppl increased with flow amplitude above 100-250 ml/s, whereas mean Paw decreased, consistent with air trapping. Paw, Pes, and Ppl amplitudes increased monotonically with flow amplitude except above 400-500 ml/s, where the Ppl amplitude decreased suddenly. The latter occurring simultaneously with a sudden fall in mean Paw indicated airway flow limitation in costal regions. Flow instabilities during flow limitation were consistent with the large increase in the phase difference between Paw and Ppl and its variability, with frequency. By contrast, the phase difference between Paw and Pes and its variability were relatively small. These differences in Pes from Ppl responses might be caused by a difference in the impedance of the airway-mediastinum pathway or a direct transmission of tracheal pressure oscillations to the esophagus. The former suggests that constraints offered by the mediastinum and rib cage resulted in nonuniform ventilation during high frequency ventilation.

Effect of flow on hydraulic conductivity and reflection coefficient of rabbit mesentery.

OBJECTIVE: To measure the hydraulic conductivity and reflection coefficient for albumin, as defined by the Starling equation, in rabbit mesentery. METHODS: A section of rabbit mesentery was fixed between two chambers filled with lactated Ringer solution. Flow (Q) of Ringer solution was measured across the mesentery at driving pressures (delta P) between 1 and 6 cm H2O. Hydraulic conductivity was proportional to the slope of the Q-delta P curve. At constant delta P (approximately -2, -4, or -6 cm H2O), flow was measured at three different albumin concentration differences (0.5, 1, and 1.5 g/dl). Unstirred layer effects were minimized by magnetic stirrers. Reflection coefficient was the negative of the slope of the Q-delta pi curve divided by the slope of the Q-delta P curve, where delta pi was the albumin osmotic pressure difference. Hydraulic conductivity was measured before and after testicular hyaluronidase was added to the Ringer solution. RESULTS: There was no significant difference in conductivity per unit area (Lp) for the three different driving pressures. Hyaluronidase increased hydraulic conductivity significantly (p < 0.01) by 72 +/- 56%, indicating that hyaluronan and other glycosaminoglycans contributed to tissue fluid resistance. Reflection coefficient (sigma) increased from 0.02 to 0.14 as flow increased eightfold. CONCLUSIONS: The results suggest that the mesentery tissue provides little restriction to the passage of albumin. The increase in conductivity in the presence of hyaluronidase indicates that tissue hyaluronan and other glycosaminoglycans provide fluid resistance to bulk flow.

Effects of ventilation on hyaluronan and protein concentration in pleural liquid of anesthetized and conscious rabbits.

The hypothesis of this study is that pleural lubrication is enhanced by hyaluronan acting as a boundary lubricant in pleural liquid and by pleural filtration as reflected in changes in protein concentration with ventilation. Anesthetized rabbits were injected intravenously with Evans blue dye and ventilated with 100% O2 at either of two levels of ventilation for 6 h. Postmortem values of hyaluronan, total protein, and Evans blue-dyed albumin (EBA) concentrations in pleural liquid were greater at the higher ventilation, consistent with increases in boundary lubrication, pleural membrane permeability, and pleural filtration. To determine whether these effects were caused by hyperoxia or anesthesia, conscious rabbits were ventilated with either 3% CO2 or room air in a box for 6, 12, or 24 h. Similar to the anesthetized rabbits, pleural liquid hyaluronan concentration after 24 h was higher in the conscious rabbits with the hypercapnic-induced greater ventilation. By contrast, the time course of total protein and EBA in pleural liquid was similar in both groups of conscious rabbits, indicating no effect of ventilation on pleural permeability. The increase in pleural liquid hyaluronan concentration might be the result of mesothelial cell stimulation by a ventilation-induced increase in pleural liquid shear stress.

Effect of concentration on albumin diffusion in lung interstitium.

The transport of macromolecules through the lung interstitium depends on both bulk transport of fluid and diffusion. In the present study, we studied the diffusion of albumin. Isolated rabbit lungs were inflated with silicon rubber via airways and blood vessels, and two chambers were bonded to the sides of a 0.5-cm-thick slab that enclosed a vessel with an intersititial cuff. One chamber was filled with either albumin solution (2 or 5 g/dl) containing tracer 125I-albumin or with tracer 125I-albumin alone; the other was filled with Ringer solution. Unbound 125I was removed from the tracer by dialysis before use. The chamber with Ringer solution was placed in the well of a NaI(Tl) scintillation detector. Diffusion of tracer through the interstitium was measured continuously for 60 h. Tracer mass (M) showed a time (t) delay followed by an increase to a steady-state flow (dM/dt constant). Albumin diffusion coefficient (D) was given by L2/(6T), where T was the time intercept of the steady-state M-t line at zero M, and L was interstitial length. Interstitial cuff thickness-to-vessel radius ratio (Th0/R) was estimated by using Fick's law for steady-state diffusion. Both D and Th0/R were independent of albumin concentration. D averaged 6.6 x 10(-7) cm2/s, similar to the free D for albumin. Values of Th0/R averaged 0.047 +/- 0.024 (SD), near the values measured histologically. Thus pulmonary interstitial constituents offered no restriction to the diffusion of albumin.

Effects of hypoxia, blood P(CO2) and flow on O2 transport in excised rabbit lungs.

In previous studies using isolated perfused rabbit lungs, an O2 deficit measured by an alveolar gas-to-end capillary blood P(O2) difference (A-aD(O2)) was absent at blood flows (Q) consistent with severe exercise. Thus factors such as VA/Q heterogeneity, shunt and diffusion limitation that contribute to an O2 deficit in vivo were absent. Here we attempted to increase diffusion limitation to O2 transport by reducing the equilibration coefficient D/(betaQ), the ratio of the diffusing capacity (D) to the product of Q and the capacitance coefficient (beta, the slope of the blood O2 content-P(O2) curve). First, we used hypoxic (10% O2) ventilation in conjunction with a low PV(O2) (approximately 25 mmHg) because beta is largest in this region of the O2 dissociation curve. Second, we increased beta by decreasing blood P(CO2) which shifts the O2 dissociation curve to the left (Bohr effect). Third, we increased Q to three times control to reduce D/Q. CO diffusing capacity was measured as a function of blood flow and blood P(O2). A deficit in O2 transport as measured by a significant A-aD(O2) was measured only under conditions of hypoxia and high blood flow. The measured O2 deficit matched the predictions from the equilibration coefficients D/(betaQ) based on measurements of beta, D and Q.

Generation and detection of lung stress waves from the chest surface.

In anesthetized pigs, we generated stress' waves by imposing a distortion on the intercostal muscle between the 5th and 6th ribs. Stress waves were detected by two accelerometers, 5-7 cm apart, oriented in either the ventral-dorsal or cranial-caudal direction. Cross-spectral analysis was used to calculate transit time. Waves of velocities similar to those of lung shear waves were detected at transpulmonary pressures (Ptp) above 15 cmH2O in the nonedematous lung and above 25 cmH2O Ptp in the edematous lung. Waves were detected in the frequency range 9-40 Hz. Stress wave velocity increased from 287 +/- 24 (SD) cm/sec at 18 cmH2O Ptp to 342 +/- 41 cm/sec at 26 cmH2O Ptp, consistent with shear waves propagating in the lung having a shear modulus of 0.9 Ptp and lung density of 0.20 g/cm3. Stress wave velocities at 25 cmH2O Ptp decreased with the increases in lung density induced by alveolar edema, consistent with elasticity theory. An elasticity analysis showed the existence of lung-rib cage interfacial waves with properties similar to the measured stress waves.

Effect of hydration on lung interstitial conductivity response to electrically charged solutions.

In interstitial segments of rabbit lung, we compared the flow of a solution containing cationic protamine sulfate (0.08 mg/ml) or cationic dextran (0.1%) to that of Ringer or neutral dextran solution. Also compared, were the flow of solutions containing anionic dextran (0.1 or 1.5%) to those containing neutral dextran and the flow of hyaluronidase solution (0.02%) to that of Ringer solution, at mean interstitial pressures (Pm) between -5 and 15 cmH2O. Driving pressure was set at 5 cmH2O. Cationic protamine or cationic dextran-to-Ringer flow ratio increased with Pm (presumably as hydration increased) but in nonedematous interstitium (-5 cmH2O Pm), flow ratio was 1, indicating a viscosity-dependent flow. In contrast, the flow of anionic dextran solution decreased relative to that of neutral dextran; this decrease was constant with hydration, but was greater at the higher concentration of dextran. Interstitial conductivity to the flow of hyaluronidase increased with hydration. However, this behavior was absent after the flow of 1.5% anionic dextran, indicating an inhibitory effect of the higher concentration of anionic dextran on the hyaluronidase response. A negative charge in microvascular filtrate may control fluid clearance in normal interstitium, while a positive charge would enhance clearance only in edema formation.

Lung tissue resistance measured in saline-filled guinea pig lungs by micropuncture.

Lung tissue resistance (Rti) measured in air-filled guinea pig lungs by the alveolar capsule technique was a large part of total lung resistance (Rl), and we wondered whether similar results applied to saline-filled lungs. We used the micropuncture method to measure alveolar pressure (Palv) in saline-filled lungs of 21 guinea pigs. Palv and airway opening pressure (Pao) were measured before and after a sudden interruption of flow during an inflation or deflation maneuver. On stopping flow, there was an immediate large change in Pao followed by a smaller slower change in Pao. Palv was nearly constant immediately after flow interruption but followed the slower change in Pao. The initial change in Pao on flow interruption was interpreted as the resistive pressure loss in the airways. The small change in Pao and Palv was interpreted as the pressure loss caused by tissue stress adaptation. Airway resistance (R(aw)) and Rti were obtained by dividing the pressure losses by the flow before the interruption. Rl was the sum of R(aw) and Rti. The calcium blocker nifedipine reduced both R(aw) and Rti and abolished the difference in Rti between inflation and deflation. Values of Rti were 10-29% of Rl. However, with correction for viscosity, Rti predicted in air-filled lungs would dominate Rl.

Effect of mechanical ventilation on regional variation of pleural liquid thickness in rabbits.

We studied the effect of ventilation on the regional distribution of pleural liquid thickness in anesthetized rabbits. Three transparent pleural windows were made between the second and eight intercostal space along the midaxillary line of the right chest. Fluorescein isothiocyanate-labeled dextran (1 ml) was injected into the pleural space through a rib capsule and allowed to mix with the pleural liquid. The light emitted from the pleural space beneath the windows was measured by fluorescence videomicroscopy at a constant tidal volume (20 ml) and two ventilation frequencies (20 and 40 breaths/min). Pleural liquid thickness was determined from the light measurements after in vitro calibration of pleural liquid collected postmortem. At 20 breaths/min, pleural liquid thickness increased with a cranial-caudal distance from 5 microns at the second to third intercostal space to 30 microns at the sixth through eighth intercostal space. At 40 breaths/min, pleural space thickness was unchanged at the second to third intercostal space but increased to 46 microns at the sixth through eighth intercostal space. To determine this effect on pleural liquid shear stress, we measured relative lung velocity from videomicroscopic images of the lung surface through the windows. Lung velocity amplitude increased with cranial-caudal distance and with ventilation frequency. Calculated shear stress amplitude was constant with cranial-caudal distance but increased with ventilation frequency. Thus, pleural liquid thickness is matched to the relative lung motion so as to maintain a spatially uniform shear stress amplitude in pleural liquid during mechanical ventilation.

Effect of inflation on interstitial cuff and pressure in liquid-filled rabbit lung.

Degassed rabbit lungs were inflated to 15 cmH2O pressure with 3% albumin solution. To study cuff growth, lungs were frozen in liquid N2 at several (20-120 min) inflation times. Cuff-to-vessel area ratio measured from frozen lung pieces increased with time reaching a maximum value (0.5-0.9) by 1 h. Time constants (to) of cuff growth were similar to those (28 min) of the interstitial pressure (Pi) response measured by micropuncture at the lung hilum. Pi response was slower with saline (to = 84 min) than with albumin. Compared to saline, positively charged protamine sulphate increased the Pi response (to = 44 min). Time constants for cuff growth and Pi response were smaller at 15 cmH2O than at 5 cmH2O inflation pressure (30 vs. 60-120 min). Electrical analog models indicated a doubling of interstitial resistance with a four-to eight-fold decrease in interstitial specific compliance at the higher inflation pressure, the latter attributed to nonlinear elastic behavior of lung parenchyma.

Effect of blood flow on capillary transit time and oxygenation in excised rabbit lung.

We used an isolated perfused lung preparation of the rabbit to study the effect of increasing blood flow on pulmonary capillary transit time by two methods. In one method, capillary transit time was measured from fluorescent dye dilution curves from arterioles and venules of the subpleural microcirculation. Values of transit time were similar to those for the whole lung determined by dividing capillary blood volume by blood flow. Capillary transit times averaged 0.50-0.62 sec at a control blood flow of 80 ml min-1 kg-1 and decreased to 0.14-0.18 sec as blood flow increased to 6 times control. To determine whether the reduced transit time would limit O2 transport, we studied the effect of blood flow on oxygenation. Two isolated rabbit lungs were perfused in series. Blood from one lung deoxygenated by ventilation with a N2-CO2 mixture was oxygenated by the test lung ventilated with air. Ventilation was matched to blood flow. PO2 and PCO2 were measured in blood flowing into and out of the test lung. At all flows, no significant alveolar gas-to-end-capillary blood PO2 gradient (A-aDO2) was measured. The isolated perfused rabbit lung showed no transit time limitation to oxygenation for blood flows that are consistent with heavy exercise in vivo.