Assessing recruitment of lung diffusing capacity in exercising guinea pigs with a rebreathing technique.

Noninvasive techniques for assessing cardiopulmonary function in small animals are limited. We previously developed a rebreathing technique for measuring lung volume, pulmonary blood flow, diffusing capacity for carbon monoxide (Dl(CO)) and its components, membrane diffusing capacity (Dm(CO)) and pulmonary capillary blood volume (Vc), and septal volume, in conscious nonsedated guinea pigs at rest. Now we have extended this technique to study guinea pigs during voluntary treadmill exercise with a sealed respiratory mask attached to a body vest and a test gas mixture containing 0.5% SF(6) or Ne, 0.3% CO, and 0.8% C(2)H(2) in 40% or 98% O(2). From rest to exercise, O(2) uptake increased from 12.7 to 25.5 ml x min(-1) x kg(-1) while pulmonary blood flow increased from 123 to 239 ml/kg. The measured Dl(CO), Dm(CO), and Vc increased linearly with respect to pulmonary blood flow as expected from alveolar microvascular recruitment; body mass-specific relationships were consistent with those in healthy human subjects and dogs studied with a similar technique. The results show that 1) cardiopulmonary interactions from rest to exercise can be measured noninvasively in guinea pigs, 2) guinea pigs exhibit patterns of exercise response and alveolar microvascular recruitment similar to those of larger species, and 3) the rebreathing technique is widely applicable to human ( approximately 70 kg), dog (20-30 kg), and guinea pig (1-1.5 kg). In theory, this technique can be extended to even smaller animals provided that species-specific technical hurdles can be overcome.     

Preventing mediastinal shift after pneumonectomy does not abolish physiological compensation.

To determine the role of mediastinal shift after pneumonectomy (PNX) on compensatory responses, we performed right PNX in adult dogs and replaced the resected lung with a custom-shaped inflatable silicone prosthesis. Prosthesis was inflated (Inf) to prevent mediastinal shift, or deflated (Def), allowing mediastinal shift to occur. Thoracic, lung air, and tissue volumes were measured by computerized tomography scan. Lung diffusing capacities for carbon monoxide (DL(CO)) and its components, membrane diffusing capacity for carbon monoxide (Dm(CO)) and capillary blood volume (Vc), were measured at rest and during exercise by a rebreathing technique. In the Inf group, lung air volume was significantly smaller than in Def group; however, the lung became elongated and expanded by 20% via caudal displacement of the left hemidiaphragm. Consequently, rib cage volume was similar, but total thoracic volume was higher in the Inf group. Extravascular septal tissue volume was not different between groups. At a given pulmonary blood flow, DL(CO) and Dm(CO) were significantly lower in the Inf group, but Vc was similar. In one dog, delayed mediastinal shift occurred 9 mo after PNX; both lung volume and DL(CO) progressively increased over the subsequent 3 mo. We conclude that preventing mediastinal shift after PNX impairs recruitment of diffusing capacity but does not abolish expansion of the remaining lung or the compensatory increase in extravascular septal tissue volume.     

Lower pulmonary diffusing capacity in the prone vs. supine posture.

We evaluated the effect of prone positioning on gas-transfer characteristics in normal human subjects. Single-breath (SB) and rebreathing (RB) maneuvers were employed to assess carbon monoxide diffusing capacity (DlCO), its components related to capillary blood volume (Vc) and membrane diffusing capacity (Dm), pulmonary tissue volume (Vti), and cardiac output (Qc). Alveolar volume (Va) was significantly greater prone than supine, irrespective of the test maneuver used. Nevertheless, Dl(CO) was consistently lower prone than supine, a difference that was enhanced when appropriately corrected for the higher Va prone. When adequately corrected for Va, diffusing capacity significantly decreased by 8% from supine to prone [SB: Dl(CO,corr) supine vs. prone: 32.6 +/- 2.3 (SE) vs. 30.0 +/- 2 ml x min(-1) x mmHg(-1) stpd; RB: Dl(CO,corr) supine vs. prone: 30.2 +/- 2.2 (SE) vs. 27.8 +/- 2.0 ml x min(-1) x mmHg(-1) stpd]. Both Vc and Dm showed a tendency to decrease from supine to prone, but neither reached significance. Finally, there were no significant differences in Vti or Qc between supine and prone. We interpret the lower diffusing capacity of the healthy lung in the prone posture based on the relatively larger space occupied by the heart in the dependent lung zones, leaving less space for zone 3 capillaries, and on the relatively lower position of the heart, leaving the zone 3 capillaries less engorged.     

Evaluation of lung diffusing capacity by physiological and morphometric techniques

Determinations of pulmonary diffusing capacity for CO (DLCO) by physiological and morphometric techniques have resulted in substantially different values for both DLCO and its major components. To evaluate the differences in these methods of measurement of DLCO, measurements were made under controlled conditions on isolated perfused dog lungs. Multiple gas-rebreathing techniques were used to measure DLCO, the membrane component of the diffusing capacity for CO (DmCO), and pulmonary capillary blood volume (Vc) in both anesthetized dogs and after isolation and perfusion of their lungs. The isolated perfused lungs were than perfusion fixed for morphometric analysis of the components of DLCO. The values obtained morphometrically for Vc were similar to those measured by physiological techniques. Perfusion fixation did not substantially alter the morphometric estimate of DmCO when compared with previous values obtained on inflation fixed lungs. However, the morphometric estimate of DmCO was over 10 times higher than that estimated physiologically. Analysis of the potential errors in the techniques suggests that the correct value for DmCO is substantially higher than that commonly estimated by use of physiological techniques and that the explanation for the difference is due to a number of factors that can influence the binding of CO to hemoglobin under in vivo conditions. The net effect of these factors can be represented by an unknown in each component of the Roughton-Forster relationship so that 1/DL = 1/(U1.Dm) + 1/(U2.theta Vc), where theta is the binding rate for CO to hemoglobin. Because the magnitudes of the unknown terms (U1 and U2) in the Roughton-Forster relationship are likely to be large, this relationship cannot be reliably used to determine Dm and Vc.     

Improvement in lung diffusion by endothelin A receptor blockade at high altitude

Lung diffusing capacity has been reported variably in high-altitude newcomers and may be in relation to different pulmonary vascular resistance (PVR). Twenty-two healthy volunteers were investigated at sea level and at 5,050 m before and after random double-blind intake of the endothelin A receptor blocker sitaxsentan (100 mg/day) vs. a placebo during 1 wk. PVR was estimated by Doppler echocardiography, and exercise capacity by maximal oxygen uptake (Vo(2 max)). The diffusing capacities for nitric oxide (DL(NO)) and carbon monoxide (DL(CO)) were measured using a single-breath method before and 30 min after maximal exercise. The membrane component of DL(CO) (Dm) and capillary volume (Vc) was calculated with corrections for hemoglobin, alveolar volume, and barometric pressure. Altitude exposure was associated with unchanged DL(CO), DL(NO), and Dm but a slight decrease in Vc. Exercise at altitude decreased DL(NO) and Dm. Sitaxsentan intake improved Vo(2 max) together with an increase in resting and postexercise DL(NO) and Dm. Sitaxsentan-induced decrease in PVR was inversely correlated to DL(NO). Both DL(CO) and DL(NO) were correlated to Vo(2 max) at sea level (r = 0.41-0.42, P < 0.1) and more so at altitude (r = 0.56-0.59, P < 0.05). Pharmacological pulmonary vasodilation improves the membrane component of lung diffusion in high-altitude newcomers, which may contribute to exercise capacity.     

Alveolar diffusion-perfusion interactions during high-altitude residence in guinea pigs.

We previously reported in weanling guinea pigs raised at high altitude (HA; 3,800 m) an elevated lung diffusing capacity estimated by morphometry from alveolar-capillary surface area, harmonic mean blood-gas barrier thickness, and pulmonary capillary blood volume (Vc) compared with litter-matched control animals raised at an intermediate altitude (IA; 1,200 m) (Hsia CCW, Polo Carbayo JJ, Yan X, Bellotto DJ. Respir Physiol Neurobiol 147: 105-115, 2005). To determine if HA-induced alveolar ultrastructural changes are associated with improved alveolar function, we measured lung diffusing capacity for carbon monoxide (DLCO), membrane diffusing capacity for carbon monoxide (DMCO), Vc, pulmonary blood flow, and lung volume by a rebreathing technique in litter-matched male weanling Hartley guinea pigs raised at HA or IA for 4 or 12 mo. Separate control animals were also raised and studied at sea level (SL). Resting measurements were obtained in the conscious nonsedated state. In HA animals compared with corresponding IA or SL controls, lung volume and hematocrit were significantly higher while pulmonary blood flow was lower. At a given pulmonary blood flow, DLCO and DMCO were higher in HA-raised animals than in control animals without a significant change in Vc. We conclude that 1) HA residence enhanced physiological diffusing capacity corresponding to that previously estimated on the basis of structural adaptation, 2) adaptation in diffusing capacity and its components should be interpreted with respect to pulmonary blood flow, and 3) this noninvasive rebreathing technique could be used to follow adaptive responses in small animals.     

Effect of ventilation and perfusion imbalance on inert gas rebreathing variables

The effects of ventilation-to-perfusion (VA/Qc) maldistribution within the lungs on measured multiple gas rebreathing variables were studied in 14 dogs. The rebreathing method (using He, C18O, and C2H2) allows for measurements of pulmonary capillary blood flow (Qc), diffusing capacity (DLco), lung gas volume, and the combined pulmonary tissue and capillary blood volume (VTPC). VA/Qc imbalance was created by reversibly occluding the right main pulmonary artery or by reversibly obstructing the left main bronchus in eight dogs. Six additional dogs were ventilated with 10 cmH2O positive end-expiratory pressure (PEEP) to create a bimodal distribution of VA/Qc within the lungs. No significant alterations in computed rebreathing variables, except for a small (14%) decrease in DLco, occurred during right main pulmonary artery occlusion, whereas obstruction of the left main bronchus caused parallel decreases (mean of 46%) in all rebreathing variables. Ventilation with 10 cmH2O PEEP for 3 h caused no alterations in VTPC when compared with postmortem determinations of total lung water. Thus marked alterations in distribution of Qc or creation of VA/Qc maldistributions with PEEP caused no significant changes in rebreathing parameters, whereas obstruction of the left main bronchus resulted in decreases in all rebreathing values consistent with the presumed size of the ventilation defect. Thus it appears that rebreathing estimates of VTPC and other rebreathing parameters are accurate in states of moderate VA/Qc maldistribution within the lung.     

The Single-Breath Diffusing Capacity of CO and NO in Healthy Children of European Descent

Rationale

The diffusing capacity (D_L) of the lung can be divided into two components: the diffusing capacity of the alveolar membrane (Dm) and the pulmonary capillary volume (Vc). D_L is traditionally measured using a single-breath method, involving inhalation of carbon monoxide, and a breath hold of 8–10 seconds (D_L,CO). This method does not easily allow calculation of Dm and Vc. An alternative single-breath method (D_L,CO,NO), involving simultaneous inhalation of carbon monoxide and nitric oxide, and traditionally a shorter breath hold, allows calculation of Dm and Vc and the D_L,NO/D_L,CO ratio in a single respiratory maneuver. The clinical utility of Dm, Vc, and D_L,NO/D_L,CO in the pediatric age range is currently unknown but also restricted by lack of reference values.

Objectives

The aim of this study was to establish reference ranges for the outcomes of D_L,CO,NO with a 5 second breath hold, including the calculated outcomes Dm, Vc, and the D_L,NO/D_L,CO ratio, as well as to establish reference values for the outcomes of the traditional D_L,CO method, with a 10 second breath hold in children.

Methods

D_L,CO,NO and D_L,CO were measured in healthy children, of European descent, aged 5–17 years using a Jaeger Masterscreen PFT. The data were analyzed using the Generalized Additive Models for Location Scale and Shape (GAMLSS) statistical method.

Measurements and Main Results

A total of 326 children were eligible for diffusing capacity measurements, resulting in 312 measurements of D_L,CO,NO and 297 of D_L,CO, respectively. Reference equations were established for the outcomes of D_L,CO,NO and D_L,CO, including the calculated values: Vc, Dm, and the D_L,NO/D_L,CO ratio.

Conclusion

These reference values are based on the largest sample of children to date and may provide a basis for future studies of their clinical utility in differentiating between alterations in the pulmonary circulation and changes in the alveolar membrane in pediatric patients.     

Short-term hypoxic exposure at rest and during exercise reduces lung water in healthy humans.

Hypoxia and hypoxic exercise increase pulmonary arterial pressure, cause pulmonary capillary recruitment, and may influence the ability of the lungs to regulate fluid. To examine the influence of hypoxia, alone and combined with exercise, on lung fluid balance, we studied 25 healthy subjects after 17-h exposure to 12.5% inspired oxygen (barometric pressure = 732 mmHg) and sequentially after exercise to exhaustion on a cycle ergometer with 12.5% inspired oxygen. We also studied subjects after a rapid saline infusion (30 ml/kg over 15 min) to demonstrate the sensitivity of our techniques to detect changes in lung water. Pulmonary capillary blood volume (Vc) and alveolar-capillary conductance (D(M)) were determined by measuring the diffusing capacity of the lungs for carbon monoxide and nitric oxide. Lung tissue volume and density were assessed using computed tomography. Lung water was estimated by subtracting measures of Vc from computed tomography lung tissue volume. Pulmonary function [forced vital capacity (FVC), forced expiratory volume after 1 s (FEV(1)), and forced expiratory flow at 50% of vital capacity (FEF(50))] was also assessed. Saline infusion caused an increase in Vc (42%), tissue volume (9%), and lung water (11%), and a decrease in D(M) (11%) and pulmonary function (FVC = -12 +/- 9%, FEV(1) = -17 +/- 10%, FEF(50) = -20 +/- 13%). Hypoxia and hypoxic exercise resulted in increases in Vc (43 +/- 19 and 51 +/- 16%), D(M) (7 +/- 4 and 19 +/- 6%), and pulmonary function (FVC = 9 +/- 6 and 4 +/- 3%, FEV(1) = 5 +/- 2 and 4 +/- 3%, FEF(50) = 4 +/- 2 and 12 +/- 5%) and decreases in lung density and lung water (-84 +/- 24 and -103 +/- 20 ml vs. baseline). These data suggest that 17 h of hypoxic exposure at rest or with exercise resulted in a decrease in lung water in healthy humans.     

Characteristics of pulmonary diffusing capacity for CO at rest and during exercise

Characteristic patterns of changes in pulmonary diffusing capacity (DL) at rest and during exercise were investigated and characteristics of normal DL values concerned on sex, age, and ethnic groups were examined by viewing our studies and other reports. The relation of DL and pulmonary capillary blood volume (Vc) was represented as a logarithmic regression at rest and as a linear regression during exercise. The curve relation at rest is considered to show that the increase in Vc mainly reflects the process of transport from pulmonary capillary recruitment to pulmonary capillary dilation. The increasing rate of DL was not decreased during exercise, which seemed to be due to an increase in pulmonary blood flow accompanying exercise. The linear regression was also found between DL and oxygen intake during exercise and the slope was always constant among individuals and among subject groups. The general results concerned with sex difference in Japanese or ethnic difference between Japanese and Caucasians in both sexes could show that DL per stature was greater in males or Caucasians than in females or Japanese in young adults, however, the sex or ethnic difference disappeared in middle or old aged group. DL per alveolar volume which showed no sex or ethnic difference in young adults, was greater in middle or old aged group of females or Japanese than in that of males or Caucasians.     

Effect of lung volume and positional changes on pulmonary diffusing capacity and its components.

Normal subjects have a larger diffusing capacity normalized per liter alveolar volume (DL/VA) in the supine than in the sitting position. Body position changes total lung diffusing capacity (DL), DL/VA, membrane conductance (Dm), and effective pulmonary capillary blood volume (Qc) as a function of alveolar volume (VA). These functions were studied in 37 healthy volunteers. DL/VA vs. VA yields a linear relationship in sitting as well as in supine position. Both have a negative slope but usually do not run parallel. In normal subjects up to 50 yr old DL/VA and DL increased significantly when subjects moved from a sitting to a supine posture at volumes between 50 and 100% of total lung capacity (TLC). In subjects greater than 50 yr old the responses of DL/VA and DL to change in body position were not significant at TLC. Functional residual capacity (FRC) decreases and DL/VA increases in all normal subjects when they change position from sitting to supine. When DL/VA increases more than predicted from the DL/VA vs. VA relationship in a sitting position, we may infer an increase in effective Qc in the supine position. In 56% of the volunteers, supine DL was smaller than sitting DL despite a higher DL/VA at FRC in the supine position because of the relatively larger decrease in FRC. When the positional response at TLC is studied, an estimation obtained accidentally at a volume lower than TLC may influence results. Above 80% of TLC, Dm decreased significantly from sitting to supine. Below this lung volume the decrease was not significant. The relationship between Qc and VA was best described by a second-order polynomial characterized by a maximum Qc at a VA greater than 60% of TLC. Qc was significantly higher in the supine position than in the sitting position, but the difference became smaller with increasing age. In observing the sitting and supine positions, we saw a decrease in maximum Qc normalized per square meter of body surface area with age.     

Estimation of amount of stationary pulmonary blood from carbon monoxide uptake measurements

A mathematical model of CO uptake from a single alveolus is modified to include stationary pulmonary blood arising from a pulmonary vascular obstruction. From this model an estimator model is developed that produces simultaneous estimations of the diffusing capacity of the lung for CO and the fraction of the pulmonary capillary blood that is stationary. The estimator model was tested using simulated data from uniform and non-uniform simulators and found to be only mildly sensitive to noise and incorrect values for the pulmonary capillary blood volume. Both the estimator model and breath-to-breath changes in the diffusing capacity of the lung for CO (exhaled) were found to be greatly affected by inhomogeneity of diffusing capacity and ventilation. At times both returned false positive results that limit their use as a screening test for stationary pulmonary blood. Although changes in CO uptake may at times indicate the presence of stationary pulmonary blood, the confounding effects of inhomogeneity of ventilation and diffusing capacity make the use of such changes impractical under most circumstances.     

Pulmonary vascular changes following air embolism in the dog.

The effect of an intravenous injection of air in a dose of 1 ml/kg body weight was determined in 15 healthy mongrel dogs. In 4 control dogs the mean pulmonary artery pressure rose to 2-3 times the resting values at 30 seconds, and carbon monoxide diffusing capacity and pulmonary capillary blood volume decreased by half. In the animals pretreated either with heparin or with methysergide (antiserotonin group) the results were the same as in the control animals. In the vagotomized dogs, the rise in pulmonary artery pressure was not significant, and the decrease in pulmonary capillary blood volume was of lesser magnitude and shorter duration than in the control and the antiserotonin dogs. It is concluded that the intravenous injection of air in supine dogs causes a transient obstruction of small pulmonary arteries. Evidence is presented to implicate a vagal mechanism in both main aspects of the response, namely the pulmonary artery pressure rise, and the partial obstruction of the pulmonary capillary bed. These studies offer additional explanation of the symptoms of respiratory distress observed in rapid decompression.     

Ventilatory changes of pulmonary capillary blood volume assessed by arterial density

By use of an improved density measuring system, we found that the gravimetric density of arterial blood of dogs fluctuates at the same frequency as the spontaneous or mechanical ventilation. Similar density fluctuations were observed in the blood leaving isolated, perfused lobes of dogs that were ventilated cyclicly. Employing an analysis that balanced the erythrocyte and plasma flows through distensible capillaries containing blood with a tube hematocrit lower than the hematocrit in large blood vessels, we derived a relationship to estimate from the density fluctuation the change in pulmonary capillary blood volume (Vc). For mechanical ventilation, the maximum change in density over one ventilation cycle increased from 0.084 +/- 0.01 to 0.47 +/- 0.05 (SE) g/l as the frequency decreased from 29 to 6 cycles/min. These density changes were estimated to be the result of an 1-16% change in Vc. A larger tidal volume for the mechanical ventilation led to a larger density fluctuation. The maximum density change of spontaneous respiration of 6 cycles/min was one-sixth of the mechanical case, indicating a much smaller change in Vc during spontaneous respiration. When the airway flow resistance was increased for spontaneous respiration, larger density fluctuations were observed.     

Long-term enhancement of pulmonary gas exchange after high-altitude residence during maturation.

In a previous study, our laboratory showed that young dogs born at sea level (SL) and raised from 2.5 mo of age to beyond somatic maturity at a high altitude (HA) of 3,100 m show enhanced resting lung function (Johnson RL Jr, Cassidy SS, Grover RF, Schutte JE, and Epstein RH. J Appl Physiol 59: 1773-1782, 1985). To examine whether HA-induced adaptation improves pulmonary gas exchange during exercise and whether adaptation is reversible when animals return to SL before somatic maturity, we raised 2.5-mo-old foxhounds at HA (3,800 m) for 5 mo (to age 7.5 mo) before returning them to SL. Lung function was measured under anesthesia 1 mo and 2 yr after return to SL and during exercise approximately 1 yr after return. In animals exposed to HA relative to simultaneous litter-matched SL controls, resting circulating blood and erythrocyte volumes, lung volumes, septal volume estimated by a rebreathing technique, and lung tissue volume estimated by high-resolution computed tomography scan were persistently higher. Lung diffusing capacity, membrane diffusing capacity, and pulmonary capillary blood volume estimated at a given cardiac output were significantly higher in animals exposed to HA, whereas maximal oxygen uptake and hematocrit were similar between groups. We conclude that relatively short exposure to HA during somatic maturation improves long-term lung function into adulthood.     

Steady-state measurement of NO and CO lung diffusing capacity on moderate exercise in men.

Using a rapidly responding nitric oxide (NO) analyzer, we measured the steady-state NO diffusing capacity (DL(NO)) from end-tidal NO. The diffusing capacity of the alveolar capillary membrane and pulmonary capillary blood volume were calculated from the steady-state diffusing capacity for CO (measured simultaneously) and the specific transfer conductance of blood per milliliter for NO and for CO. Nine men were studied bicycling at an average O(2) consumption of 1.3 +/- 0.2 l/min (mean +/- SD). DL(NO) was 202.7 +/- 71.2 ml. min(-1). Torr(-1) and steady-state diffusing capacity for CO, calculated from end-tidal (assumed alveolar) CO(2), mixed expired CO(2), and mixed expired CO, was 46.9 +/- 12.8 ml. min(-1). Torr(-1). NO dead space = (VT x FE(NO) - VT x FA(NO))/(FI(NO) - FA(NO)) = 209 +/- 88 ml, where VT is tidal volume and FE(NO), FI(NO), and FA(NO) are mixed exhaled, inhaled, and alveolar NO concentrations, respectively. We used the Bohr equation to estimate CO(2) dead space from mixed exhaled and end-tidal (assumed alveolar) CO(2) = 430 +/- 136 ml. Predicted anatomic dead space = 199 +/- 22 ml. Membrane diffusing capacity was 333 and 166 ml. min(-1). Torr(-1) for NO and CO, respectively, and pulmonary capillary blood volume was 140 ml. Inhalation of repeated breaths of NO over 80 s did not alter DL(NO) at the concentrations used.     

Pulmonary diffusing capacity and pulmonary capillary blood volume during parabolic flights

Vaïda, Pierre, Christian Kays, Daniel Rivière,Pierre Téchoueyres, and Jean-Luc Lachaud.Pulmonary diffusing capacity and pulmonary capillary blood volumeduring parabolic flights. J. Appl.Physiol. 82(4): 1091-1097, 1997.Data from theSpacelab Life Sciences-1 (SLS-1) mission have shown sustained butmoderate increase in pulmonary diffusing capacity(DL). Because of the occupational constraints of the mission, data were only obtained after24 h of exposure to microgravity. Parabolic flights are often used tostudy some effects of microgravity, and we measured changes inDL occurring at the very onsetof weightlessness. Measurements ofDL, membrane diffusing capacity,and pulmonary capillary blood volume were made in 10 male subjectsduring the 20-s 0-G phases of parabolic flights performed by the"zero-G" Caravelle aircraft. Using the standardized single-breathtechnique, we measuredDL for CO andnitric oxide simultaneously. We found significant increases inDL for CO (62%),in membrane diffusing capacity for CO (47%), inDL for nitric oxide (47%), andin pulmonary capillary blood volume (71%). We conclude that majorchanges in the alveolar membrane gas transfers and in the pulmonarycapillary bed occur at the very onset of microgravity. Because thesechanges are much greater than those reported during sustainedmicrogravity, the effects of rapid transition from hypergravity tomicrogravity during parabolic flights remain questionable.

     

Comparison of direct and indirect measurements of pulmonary capillary transit times

Using in vivo microscopy, we made direct measurements of pulmonary capillary transit time by determining the time required for fluorescent dye to pass from an arteriole to a venule on the dependent surface of the dog lung. Concurrently, in the same animals, pulmonary capillary transit time was measured indirectly in the entire lung using the diffusing capacity method (capillary blood volume divided by cardiac output). Transit times by each method were the same in a group of five dogs [direct: 1.75 +/- 0.27 (SE) s; indirect: 1.85 +/- 0.33 s; P = 0.7]. The similarity of these transit times is important, because the widely used indirect determinations based on diffusing capacity are now shown to coincide with direct measurements and also because it demonstrates that measurements of capillary transit times on the surface of the dependent lung bear a useful relationship to measurements on the capillaries in the rest of the lung.     

Pulmonary gas transfer related to markers of angiogenesis during the menstrual cycle.

Gas transfer in the female lung varies over the menstrual cycle in parallel with the cyclic angiogenesis that occurs in the uterine endometrium. Given that vessels form and regress in the uterus under the control of hormones, angiogenic factors, and proangiogenic circulating bone marrow-derived progenitor cells, we tested the possibility that variation in pulmonary gas transfer over the menstrual cycle is related to a systemic cyclic proangiogenic state that influences lung vascularity. Women were evaluated over the menstrual cycle with weekly measures of lung diffusing capacity and its components, the pulmonary vascular capillary bed and membrane diffusing capacity, and their relation to circulating CD34(+)CD133(+) progenitor cells, hemoglobin, factors affecting hemoglobin binding affinity, and proangiogenic factors. Lung diffusing capacity varied over the menstrual cycle, reaching a nadir during the follicular phase following menses. The decline in lung diffusing capacity was accounted for by approximately 25% decrease in pulmonary capillary blood volume. In parallel, circulating CD34(+)CD133(+) progenitor cells decreased by approximately 24% and were directly related to angiogenic factors and to lung diffusing capacity and pulmonary capillary blood volume. The finding of a greater number of lung microvessels in ovariectomized female mice receiving estrogen compared with placebo verified that pulmonary vascularity is influenced by hormonal changes. These findings suggest that angiogenesis in the lungs may participate in the cyclic changes in gas transfer that occur over the menstrual cycle.     

Effect of pneumonectomy on the remaining lung in dogs

To determine the magnitude of functional compensation after pneumonectomy and whether compensation is related to maturity of the animal at the time of resection, we performed left pneumonectomy in either adult or 10-wk-old beagles. Studies were performed in adults 7-9 mo after surgery and in puppies 18-23 mo after surgery when the dogs reached full maturity. Results were compared with those in age- and sex-matched unoperated controls. Measurements included pressure-volume relationships, pulmonary hemodynamics, rebreathing studies of lung volume, diffusing capacity and its components, lung tissue volume, and pulmonary blood flow. Computerized-tomographic scans were performed in the puppy groups to determine changes in thoracic shape and size. Morphometric analysis of the lungs was performed under light microscopy. There was partial compensation for loss of one lung by functional improvement in the remaining lung. Compensation was greater in those pneumonectomized as puppies than as adults. Volume of the remaining lung was larger than predicted for a given transpulmonary pressure in both groups. Diffusing capacity, pulmonary capillary blood volume, and lung tissue volume were larger than expected for the normal right lung. After pneumonectomy, compliance of the rib cage was greater in puppies than in adults. Weight of the costal diaphragm was reduced in pneumonectomized puppies. Pulmonary hypertension at rest did not develop, and pulmonary vascular reactivity to hypoxia was unchanged after pneumonectomy in both groups. Significant correlations were obtained between physiological and morphometric measurements.