The canine spleen in oxygen transport: gas exchange and hemodynamic responses to splenectomy.

In athletic animals the spleen induces acute polycythemia by dynamic contraction that releases red blood cells into the circulation in response to increased O(2) demand and metabolic stress; when energy demand is relieved, the polycythemia is rapidly reversed by splenic relaxation. We have shown in adult foxhounds that splenectomy eliminates exercise-induced polycythemia, thereby reducing peak O(2) uptake and lung diffusing capacity for carbon monoxide (DL(CO)) as well as exaggerating preexisting DL(CO) impairment imposed by pneumonectomy (Dane DM, Hsia CC, Wu EY, Hogg RT, Hogg DC, Estrera AS, Johnson RL Jr. J Appl Physiol 101: 289-297, 2006). To examine whether the postsplenectomy reduction in DL(CO) leads to abnormalities in O(2) diffusion, ventilation-perfusion inequality, or hemodynamic function, we studied these animals via the multiple inert gas elimination technique at rest and during exercise at a constant workload equivalent to 50% or 80% of peak O(2) uptake while breathing 21% and 14% O(2) in balanced order. From rest to exercise after splenectomy, minute ventilation was significantly elevated with respect to O(2) uptake compared with exercise before splenectomy; cardiac output, O(2) delivery, and mean pulmonary and systemic arterial blood pressures were 10-20% lower, while O(2) extraction was elevated with respect to O(2) uptake. Ventilation-perfusion inequality was unchanged, but O(2) diffusing capacities of lung (DL(O2)) and peripheral tissue during exercise were lower with respect to cardiac output postsplenectomy by 32% and 25%, respectively. The relationship between DL(O2) and DL(CO) was unchanged by splenectomy. We conclude that the canine spleen regulates both convective and diffusive O(2) transport during exercise to increase maximal O(2) uptake.     

Red cell distribution and the recruitment of pulmonary diffusing capacity.

The distribution of red blood cells in alveolar capillaries is typically nonuniform, as shown by intravital microscopy and in alveolar tissue fixed in situ. To determine the effects of red cell distribution on pulmonary diffusive gas transport, we computed the uptake of CO across a two-dimensional geometric capillary model containing a variable number of red blood cells. Red blood cells are spaced uniformly, randomly, or clustered without overlap within the capillary. Total CO diffusing capacity (DLCO) and membrane diffusing capacity (DmCO) are calculated by a finite-element method. Results show that distribution of red blood cells at a fixed hematocrit greatly affects capillary CO uptake. At any given average capillary red cell density, the uniform distribution of red blood cells yields the highest DmCO and DLCO, whereas the clustered distribution yields the lowest values. Random nonuniform distribution of red blood cells within a single capillary segment reduces diffusive CO uptake by up to 30%. Nonuniform distribution of red blood cells among separate capillary segments can reduce diffusive CO uptake by >50%. This analysis demonstrates that pulmonary microvascular recruitment for gas exchange does not depend solely on the number of patent capillaries or the hematocrit; simple redistribution of red blood cells within capillaries can potentially account for 50% of the observed physiological recruitment of DLCO from rest to exercise.     

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.     

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.     

Differential changes of lung diffusing capacity and tissue volume in hypergravity.

In normal gravity, lung diffusing capacity (DL(CO)) and lung tissue volume (LTV; including pulmonary capillary blood volume) change in concert, for example, during shifts between upright and supine. Accordingly, DL(CO) and LTV might be expected to decrease together in sitting subjects in hypergravity due to peripheral pooling of blood and reduced central blood volume. Nine sitting subjects in a human centrifuge were exposed to one, two, and three times increased gravity in the head-to-feet direction (G(z+)) and rebreathed a gas containing trace amounts of acetylene and carbon monoxide. DL(CO) was 25.2 +/- 2.6, 20.0 +/- 2.1, and 16.7 +/- 1.7 ml. min(-1). mbar(-1) (means +/- SE) at 1, 2, and 3 G(z+), respectively (ANOVA P < 0.001). Corresponding values for LTV increased from 541 +/- 34 to 677 +/- 43, and 756 +/- 71 ml (P < 0.001) at 2 and 3 G(z+). Results are compatible with sequestration of blood in the dependent part of the pulmonary circulation just as in the systemic counterpart. DL(CO,) which under normoxic conditions is mainly determined by its membrane component, decreased despite an increased pulmonary capillary blood volume, most likely as a consequence of a less homogenous distribution of alveolar volume with respect to pulmonary capillary blood volume.     

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.     

Effect of blood flow on gas transport in a pulmonary capillary

The effects of blood velocity on gas transport within the alveolar region of lungs, and on the lung diffusing capacity DL have for many years been regarded as negligible. The present work reports on a preliminary, two-dimensional investigation of CO convection-diffusion phenomenon within a pulmonary capillary. Numerical simulations were performed using realistic clinical and morphological parameter values, with discrete circular red blood cells (RBCs) moving with plasma in a single capillary. Steady-state simulations with stationary blood (RBCs and plasma) were performed to validate the model by comparison with published data. Results for RBCs moving at speeds varying from 1.0 mm/s to 10 mm/s, and for capillary hematocrit (Ht) from 5% to 55%, revealed an increase of up to 60% in DL, as compared to the stationary blood case. The increase in DL is more pronounced at low Ht (less than 25%) and high RBC speed and it seems to be caused primarily by the presence of plasma. The results also indicate that capillary blood convection affects DL not only by improving the plasma mixing in the capillary bed but also by replenishing the capillary with fresh (zero concentration) plasma, providing an additional reservoir for the consumption of CO. Our findings cast doubt on the current belief that an increase in the lung diffusing capacity of humans (for instance, during exercising), with fixed hematocrit, can only be accomplished by an increase in the lung volume effectively active in the respiration process.     

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.     

Diffusing Capacity,Specific Diffusing Capacity and Interpretation of Diffusion Defects

Six pathophysiologic mechanisms of a reduced single breath CO diffusing capacity are discussed and the usefulness of relating carbon monoxide (CO) uptake to the functioning alveolar volume (DL/VA, specific diffusing capacity) is illustrated for several pulmonary diseases. In patients with emphysema and pulmonary emboli (pulmonary vascular occlusive disease), reduced CO uptake is associated with significantly reduced DL/VA and is compatible with reduction of pulmonary capillary bed. In patients with pulmonary alveolar proteinosis, improvement in CO uptake and DL/VA follows lung lavage and suggests that lung units partially filled with proteinaceous material are responsible for hypoxemia, reduced CO uptake and reduced DL/VA. In most cases of radiation fibrosis, sarcoidosis and miscellaneous interstitial fibrosis, reduced CO uptake is associated with a normal DL/VA and suggests that loss of alveolar units, both capillaries and alveoli, has occurred. New regression equations for DL and DL/VA are established for children and adults. DL/VA is linearly related to height and independent of age and sex, while different predictive equations must be used for DL for the 5 through 17 and 18 through 76 age groups. The new regression equations for DL show better correlation in adults we studied over 50 years of age than previous regression equations which use a constant reduction of 2 to 3 ml CO per minute per mm of mercury for each 10 years of adult aging.     

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.     

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.     

Cardiopulmonary adaptations to pneumonectomy in dogs. I. Maximal exercise performance.

Maximal exercise performance was evaluated in four adult foxhounds after right pneumonectomy (removal of 58% of lung) and compared with that in seven sham-operated control dogs 6 mo after surgery. Maximal O2 uptake (ml O2.min-1.kg-1) was 142.9 +/- 1.9 in the sham group and 123.0 +/- 3.8 in the pneumonectomy group, a reduction of 14% (P less than 0.001). Maximal stroke volume (ml/kg) was 2.59 +/- 0.10 in the sham group and 1.99 +/- 0.05 in the pneumonectomy group, a reduction of 23% (P less than 0.005). Lung diffusing capacity (DL(CO)) (ml.min-1.Torr-1.kg-1) reached 2.27 +/- 0.08 in the combined lungs of the sham group and 1.67 +/- 0.07 in the remaining lung of the pneumonectomy group (P less than 0.001). In the pneumonectomy group, DL(CO) of the left lung was 76% greater than that in the left lung of controls. Blood lactate concentration and hematocrit were significantly higher at exercise in the pneumonectomy group. We conclude that, in dogs after resection of 58% of lung, O2 uptake, cardiac output, stroke volume, and DL(CO) at maximal exercise were restricted. However, the magnitude of overall impairment was surprisingly small, indicating a remarkable ability to compensate for the loss of one lung. This compensation was achieved through the recruitment of reserves in DL(CO) in the remaining lung, the development of exercise-induced polycythemia, and the maintenance of a relatively large stroke volume in the face of an increased pulmonary vascular resistance.     

Compensatory alveolar growth normalizes gas-exchange function in immature dogs after pneumonectomy.

To determine the extent and sources of adaptive response in gas-exchange to major lung resection during somatic maturation, immature male foxhounds underwent right pneumonectomy (R-Pnx, n = 5) or right thoracotomy without pneumonectomy (Sham, n = 6) at 2 mo of age. One year after surgery, exercise capacity and pulmonary gas-exchange were determined during treadmill exercise. Lung diffusing capacity (DL) and cardiac output were measured by a rebreathing technique. In animals after R-Pnx, maximal O2 uptake, lung volume, arterial blood gases, and DL during exercise were completely normal. Postmortem morphometric analysis 18 mo after R-Pnx (n = 3) showed a vigorous compensatory increase in alveolar septal tissue volume involving all cellular compartments of the septum compared with the control lung; as a result, alveolar-capillary surface areas and DL estimated by morphometry were restored to normal. In both groups, estimates of DL by the morphometric method agreed closely with estimates obtained by the physiological method during peak exercise. These data show that extensive lung resection in immature dogs stimulates a vigorous compensatory growth of alveolar tissue in excess of maturational lung growth, resulting in complete normalization of aerobic capacity and gas-exchange function at maturity.     

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.

     

Reducing lung strain after pneumonectomy impairs oxygen diffusing capacity but not ventilation-perfusion matching.

After pneumonectomy (Pnx), mechanical strain on the remaining lung is an important signal for adaptation. To examine how mechanical lung strain alters gas exchange adaptation after Pnx, we replaced the right lung of adult dogs with a custom-shaped inflatable silicone prosthesis. The prosthesis was kept 1) inflated (Inf) to reduce mechanical strain of the remaining lung and maintain the mediastinum in the midline, or 2) deflated (Def) to allow lung strain and mediastinal shift. Gas exchange was studied 4-7 mo later at rest and during treadmill exercise by the multiple inert gas elimination technique while animals breathed 21 and 14% O2 in balanced order. In the Inf group compared with Def group during hypoxic exercise, arterial O2 saturation was lower and alveolar-arterial O2 tension difference higher, whereas O2 diffusing capacity was lower at any given cardiac output. Dispersion of the perfusion distribution was similar between groups at rest and during exercise. Dispersion of the ventilation distribution was lower in the Inf group at rest, associated with a much higher respiratory rate, but rose to similar levels in both groups during hypoxic exercise. Mean pulmonary arterial pressure at a given cardiac output was higher in the Inf group, whereas peak cardiac output was similar between groups. Thus creating lung strain by post-Pnx mediastinal shift primarily enhances diffusive gas exchange with only minor effects on ventilation-perfusion matching, consistent with the generation of additional alveolar-capillary surfaces but not conducting airways and blood vessels.     

Three-dimensional,unsteady simulation of alveolar respiration

A novel macroscopic gas transport model, derived from fundamental engineering principles, is used to simulate the three-dimensional, unsteady respiration process within the alveolar region of the lungs. The simulations, mimicking the single-breath technique for measuring the lung diffusing capacity for carbon-monoxide (CO), allow the prediction of the red blood cell (RBC) distribution effects on the lung diffusing capacity. Results, obtained through numerical simulations, unveil a strong relationship between the type of distribution and the lung diffusing capacity. Several RBC distributions are considered, namely: normal (random), uniform, center-cluster, and corner-cluster red cell distributions. A nondimensional correlation is obtained in terms of a geometric parameter characterizing the RBC distribution, and presented as a useful tool for predicting the RBC distribution effect on the lung diffusing capacity. The effect of red cell movement is not considered in the present study because CO does not equilibrate with capillary blood within the time spent by blood in the capillary. Hence, blood flow effect on CO diffusion is expected to be only marginal.     

Effects of crocetin on pulmonary gas exchange in foxhounds during hypoxic exercise.

The carotenoid compound crocetin has been hypothesized to enhance the diffusion of O(2) through plasma, and observations in the rat and rabbit have revealed improvement in arterial PO(2) when crocetin is given. To determine whether crocetin enhances diffusion of O(2) between alveolar gas and the red blood cell in the pulmonary capillary in vivo, five foxhounds, two previously subjected to sham and three to actual lobectomy or pneumonectomy, were studied while breathing 14% O(2) at rest and during moderate and heavy exercise before and within 10 min after injection of a single dose of crocetin as the trans isomer of sodium crocetinate (TSC) at 100 microg/kg iv. This dose is equivalent to that used in previous studies and would yield an initial plasma concentration of 0.7-1.0 microg/ml. Ventilation-perfusion inequality and pulmonary diffusion limitation were assessed by the multiple inert gas elimination technique in concert with conventional measurements of arterial and mixed venous O(2) and CO(2). TSC had no effect on ventilation, cardiac output, O(2) consumption, arterial PO(2)/saturation, or pulmonary O(2) diffusing capacity. There were minor reductions in ventilation-perfusion mismatching (logarithm of the standard deviation of perfusion fell from 0.48 to 0.43, P = 0.001) and in CO(2) output and respiratory exchange ratio (P = 0.05), which may have been due to TSC or to persisting effects of the first exercise bout. Spectrophotometry revealed that TSC disappeared from plasma with a half time of approximately 10 min. We conclude that, in this model of extensive pulmonary O(2) diffusion limitation, TSC as given has no effect on O(2) exchange or transport. Whether the original hypothesis is invalid, the dose of TSC was too low, or plasma diffusion of O(2) is not rate limiting without TSC cannot be discerned from the present study.     

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.     

Application of carbon monoxide diffusing capacity in the mouse lung

In the past decade the mouse has become the primary animal model of a variety of lung diseases. To assess various mechanisms underlying such pathologies, it is essential to make functional measurements that can reflect the developing pathology. In this regard, the diffusing capacity for carbon monoxide is a variable that directly reflects structural changes in the lung. Although measurement of single-breath diffusing capacity of the lung for carbon monoxide (DL(CO)) has also been previously reported in mice by a number of investigators, a number of technical issues have precluded routine and widespread use of this metric in mouse models. In the present report, we describe a means to quickly and simply measure a dimensionless variable closely related to the DL(CO) in mice, termed a diffusion factor for carbon monoxide (DF(CO)). The DF(CO) procedure involves a 9-s lung inflation with tracer gases in an anesthetized mouse, followed by a 1-min gas analysis time. We have tested the approach with two common models of lung pathology, elastase-induced emphysema and bleomycin-induced fibrosis. Results show a significant 15% reduction in DF(CO) in emphysema, and a 41% reduction in the fibrosis model. Repeat measurements within a mouse were found to be highly reproducible. This pulmonary function test can thus be used to detect structural changes with these pathological models. The method can also be used to measure changes in pulmonary blood volume, since the uptake of CO is highly dependent on this variable in addition to the gas exchange surface area.     

Recruitment of lung diffusing capacity with exercise before and after pneumonectomy in dogs

Although the left lung constitutes 42% of the total by weight and volume in dogs, carbon monoxide diffusing capacity (DL) after left pneumonectomy in adults falls less than 30% at rest, indicating a significant increase of DL in the remaining lung. DL normally increases during exercise, presumably by recruitment of alveolar capillaries and surface area as lung volume (Vs) and pulmonary blood flow (Qc) increase. We asked whether the increase of DL in the remaining lung after pneumonectomy in adult dogs could be explained by this kind of passive recruitment by the increased volume and Qc in the remaining lung. We measured the relationship between DL and Qc with a rebreathing technique at increasing treadmill loads in adult foxhounds, before and 6 mo after left pneumonectomy, and the relationship between DL and Vs by the same technique under anesthesia as Vs was expanded. DL was reduced by 29.1% at rest and 26.5% with heavy exercise after left pneumonectomy, indicating either recruitment or new growth in the right lung. With the assumption that the right lung normally receives 58% of the Qc and contains 58% of the DL, DL of the right lung increased with Qc in accordance with the following relationships before and after left pneumonectomy: right lung DL (before pneumonectomy) = 6.44 + 2.40(Qc) (r = 0.963) and right lung DL (after pneumonectomy) = 7.51 + 1.75(Qc) (r = 0.958). Only approximately 7% of the increase in DL from rest to peak exercise could be attributed to the increase in Vs during exercise before pneumonectomy and approximately 15% after pneumonectomy.(ABSTRACT TRUNCATED AT 250 WORDS)