Vertical gradient of pulmonary capillary transit times

The key determinants of alveolar capillary perfusion are transit times and the extent of recruitment. Capillaries are known to be heavily recruited in the dependent lung, but there are no direct data that bear on how capillary transit times might be affected by gravity. We directly determined mean capillary transit times on the surface of the upper, middle, and lower lung by measuring the passage of fluorescent dye through the capillaries using in vivo television microscopy. In anesthetized dogs, mean capillary transit times averaged 12.3 s in the upper lung, 3.1 s in the midlung, and 1.6 s in the lower lung. This near order of magnitude variation in speed of blood transit establishes that there is a vertical gradient of capillary transit times in the lung. As expected, dependent capillary networks were nearly fully recruited, whereas relatively few capillaries were perfused in the upper lung. The lengthy transit times and sparsely perfused capillary beds in the upper lung combine to provide a substantial part of pulmonary gas exchange reserve.     

Distribution of pulmonary capillary transit times in recruited networks

When pulmonary blood flow is elevated, hypoxemia can occur in the fastest-moving erythrocytes if their transit times through the capillaries fall below the minimum time for complete oxygenation. This desaturation is more likely to occur if the distribution of capillary transit times about the mean is large. Increasing cardiac output is known to decrease mean pulmonary capillary transit time, but the effect on the distribution of transit times has not been reported. We measured the mean and variance of transit times in single pulmonary capillary networks in the dependent lung of anesthetized dogs by in vivo videofluorescence microscopy of a fluorescein dye bolus passing from an arteriole to a venule. When cardiac output increased from 2.9 to 9.9 l/min, mean capillary transit time decreased from 2.0 to 0.8 s. Because transit time variance decreased proportionately (relative dispersion remained constant), increasing cardiac output did not alter the heterogeneity of local capillary transit times in the lower lung where the capillary bed was nearly fully recruited.     

Oxygen transport during exercise in large mammals. II. Oxygen uptake by the pulmonary gas exchanger

Because the maximal rate of O2 consumption (VO2max) of the horse is 2.6 times larger than that of steers of equal size, we wondered whether their pulmonary gas exchanger is proportionately larger. Three Standardbred racehorses [body mass (Mb) = 447 kg] and three domestic steers (Mb = 474 kg) whose cardiovascular function at VO2max had been thoroughly studied (Jones et al. J. Appl. Physiol. 67: 862-870, 1989) were used to study their lungs by morphometry. The basic morphometric parameters were similar in both species. The nearly 2 times larger lung volumes of the horses caused the gas exchange surfaces and capillary blood volume to be 1.6 to 1.8 times larger. Morphometric pulmonary diffusing capacity was 2 times larger in the horse than in the steer; the 2.6-fold greater rate of O2 uptake thus required the alveolar-capillary PO2 difference to be 1.3 times larger in the horse than in the steer. Combining physiological and morphometric data, we calculated capillary transit time at VO2max to be 0.4-0.5 s. Bohr integration showed capillary blood to be equilibrated with alveolar air after 75 and 58% of transit time in horses and steers, respectively; horses maintain a smaller degree of redundancy in their pulmonary gas exchanger.     

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.     

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.     

Regional pulmonary transit times in humans

We measured the frequency distribution of erythrocyte (RBC) transit times in resected lobes of lungs in eight human subjects undergoing thoracotomy for peripheral lung tumors. RBC transit times were measured by the injection of radiolabeled blood flow and volume markers, which were counted in samples from the resected lung. In five of these subjects, the measurements from the resected lung were compared with preoperative measurements of the transit times of radiolabeled RBCs with a gamma camera-computer system. Time-activity curves from the cardiac chambers and the lung or its regions were obtained from which transit times were calculated by the centroid and deconvolution techniques. The reproducibility of transit times measured by this technique was assessed in another eight normal subjects, after sequential bolus injections of radiolabeled cells. The mean transit time of the upper lung region was longer (5.1 +/- 0.5 s) than that of the lower (4.1 +/- 0.6 s, P less than 0.05) in the preoperative study. Similarly, the mean transit time of the upper lung slice was longer (5.5 +/- 0.3 s) than that of the lower slice (3.8 +/- 0.3 s, P less than 0.05) in the resected lung specimens. We conclude that there was good agreement between these techniques and that there are long transit times in the upper regions of human lungs.     

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.     

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.     

Skeletal muscle capillary hemodynamics from rest to contractions: implications for oxygen transfer.

Muscle contractions evoke an immediate rise in blood flow. Distribution of this hyperemia within the capillary bed may be deterministic for muscle O(2) diffusing capacity and remains unresolved. We developed the exteriorized rat (n = 4) spinotrapezius muscle for evaluation of capillary hemodynamics before (rest), during, and immediately after (post) a bout of twitch contractions to resolve (second-by-second) alterations in red blood cell velocity (V(RBC)) and flux (f(RBC)). Contractions increased (all P < 0.05) capillary V(RBC) (rest: 270 +/- 62 microm/s; post: 428 +/- 47 microm/s), f(RBC) (rest: 22.4 +/- 5.5 cells/s; post: 44.3 +/- 5.5 cells/s), and hematocrit but not the percentage of capillaries supporting continuous RBC flow (rest: 84.0 +/- 0.7%; post: 89.5+/-1.4%; P > 0.05). V(RBC) peaked within the first one or two contractions, whereas f(RBC) increased to an initial short plateau (first 12-20 s) followed by a secondary rise to steady state. Hemodynamic temporal profiles were such that capillary hematocrit tended to decrease rather than increase over the first approximately 15 s of contractions. We conclude that contraction-induced alterations in capillary RBC flux and distribution augment both convective and diffusive mechanisms for blood-myocyte O(2) transfer. However, across the first 10-15 s of contractions, the immediate and precipitous rise in V(RBC) compared with the biphasic and prolonged increase of f(RBC) may act to lower O(2) diffusing capacity by not only reducing capillary transit time but by delaying the increase in the instantaneous RBC-to-capillary surface contact thought crucial for blood-myocyte O(2) flux.     

The lung diffusing capacity for nitric oxide in rats is increased during endotoxemia.

Rats, when injected with endotoxin, begin to exhale nitric oxide (NO) within 1 h. This study measured the diffusing capacity for NO in the lungs of rats (DL(NO)) under both control and endotoxemic conditions, and it also estimated the rate at which endogenous NO (VP(NO)) enters the distal compartment of the lung, both in control rats and during endotoxemia. DL(NO) increased from 0.68 +/- 0.12 (SE) ml. min(-1). mmHg(-1) in control rats to 1.17 +/- 0.25 ml. min(-1). mmHg(-1) in endotoxemic rats. VP(NO) was 2.6 +/- 0.5 nl/min in control rats and attained a value of 218.6 +/- 50.1 nl/min at the height of NO exhalation 3 h after the endotoxin. We suggest that increased DL(NO) reflects an increase in pulmonary membrane diffusing capacity, caused by a pulmonary hypertension that is due to neutrophil aggregation in the lung capillaries. DL(NO) may also be increased by an enlarged pulmonary capillary volume because of the vasodilatory effects of the endogenous NO that is produced by the lung in response to the endotoxin. NO production by the lungs in response to endotoxin is unique in that it is the only situation reported to date in which pathologically induced increases in NO exhalation originate from the alveolar compartment of the lung, as opposed to the small conducting airways.     

Effect of positive airway pressure on capillary transit time in rabbit lung

We used fluorescence videomicroscopy to measure the passage of fluorescent dye through the subpleural microcirculation of the lung. With the rabbit in the left lateral decubitus position, the subpleural microcirculation was viewed either through a transparent parietal pleural window located in the superior part of the chest or directly with the chest open. There was no physical contact with the chest or lung. The rabbit was anesthetized, paralyzed, and mechanically ventilated with 100% O2. The dye was injected into the right ventricle during a 2-min apneic period to eliminate lung movement due to ventilation. The video signal of the passage of the dye was analyzed frame by frame by use of digital image processing to compensate for cardiogenic oscillations of the lung surface. Gray scale levels of an arteriole and adjacent venule were measured every 1/30 s. Capillary transit time was determined from the difference between the concentration-weighted mean time values of the arteriolar and venular dye dilution curves. We studied the effect of airway pressure (0-20 cmH2O) on transit time. Cardiac output was measured at different airway pressures by the thermal dilution technique. Capillary transit time averaged 0.60 s at functional residual capacity. Right ventricular-to-arteriolar transit time was four times as large as the capillary transit time. An increase in airway pressure from 0-5 to 20 cmH2O resulted in a fourfold increase in both capillary and arterial transit times and a threefold decrease in cardiac output.     

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 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.     

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.     

Effect of epinephrine on neutrophil kinetics in rabbit lungs

The effect of epinephrine on neutrophil (PMN) kinetics in rabbit lungs was evaluated by measuring the retention of radiolabeled PMN's in the lung, the exchange rate between the marginated and circulating pools of PMN's, and the erythrocyte (RBC) transit time. Epinephrine treatment decreased RBC transit times and increased exchange rates in the regions with the shortest transit times but did not change the pulmonary recovery of radiolabeled PMN's. When regions of similar RBC transit time were compared, epinephrine did not affect PMN retention at short transit times but did produce greater retention at long transit times. These data suggest that the major effect of epinephrine was to increase the proportion of the lung having short RBC transit times and fast exchange rates between the marginated and circulating pools. However, this effect did not decrease the overall retention of PMN's most likely because it was balanced by recruitment of additional capillary segments, which increased PMN retention in regions with longer transit times.     

Effects of lung inflation and blood flow on capillary transit time in isolated rabbit lungs.

In a previous study, direct measurements of pulmonary capillary transit time by fluorescence video microscopy in anesthetized rabbits showed that chest inflation increased capillary transit time and decreased cardiac output. In isolated perfused rabbit lungs we measured the effect of lung volume, left atrial pressure (Pla), and blood flow on capillary transit time. At constant blood flow and constant transpulmonary pressure, a bolus of fluorescent dye was injected into the pulmonary artery and the passage of the dye through the subpleural microcirculation was recorded via the video microscope on videotape. During playback of the video signals, the light emitted from an arteriole and adjacent venule was measured using a video photoanalyzer. Capillary transit time was the difference between the mean time values of the arteriolar and venular dye dilution curves. We measured capillary transit time in three groups of lungs. In group 1, with airway pressure (Paw) at 5 cmH2O, transit time was measured at blood flow of approximately 80, approximately 40, and approximately 20 ml.min-1.kg-1. At each blood flow level, Pla was varied from 0 (Pla less than Paw, zone 2) to 11 cmH2O (Pla greater than Paw, zone 3). In group 2, at constant Paw of 15 cmH2O, Pla was varied from 0 (zone 2) to 22 cmH2O (zone 3) at the same three blood flow levels. In group 3, at each of the three blood flow levels, Paw was varied from 5 to 15 cmH2O while Pla was maintained at 0 cmH2O (zone 2).(ABSTRACT TRUNCATED AT 250 WORDS)     

An allometric study of pulmonary morphometric parameters in birds, with mammalian comparisons

Comprehensive pulmonary morphometric data from 42 species of birds representing ten orders were compared with those of other vertebrates, especially mammals, relating the comparisons to the varying biological needs of these avian taxa. The total lung volume was strongly correlated with body mass. The volume density of the exchange tissue was lowest in the charadriiform and anseriform species and highest in the piciform, cuculiform and passeriform species. The surface area of the blood-gas (tissue) barrier, the volume of the pulmonary capillary blood and the total morphometric pulmonary diffusing capacity were all strongly correlated with body mass. The harmonic mean thickness of both the blood-gas (tissue) barrier and the plasma layer were weakly correlated with body mass. The mass-specific surface area of the blood-gas (tissue) barrier (surface area per gram body mass) and the surface density of the blood-gas (tissue) barrier (i.e. its surface area per unit volume of exchange tissue) were inversely correlated (though weakly) with body mass. The passeriform species exhibited outstanding pulmonary morphometric adaptations leading to a high specific total diffusing capacity per gram body mass, consistent with the comparatively small size and energetic mode of life which typify passeriform birds. The relatively inactive, ground-dwelling domestic fowl (Gallus gallus) had the lowest pulmonary diffusing capacity per gram body mass. The specific total lung volume is about 27% smaller in birds than in mammals but the specific surface area of the blood-gas (tissue) barrier is about 15% greater in birds. The ratio of the surface area of the tissue barrier to the volume of the exchange tissue was also much greater in the birds (170-305%). The harmonic mean thickness of the tissue barrier was 56-67% less in the birds, but that of the plasma layer was about 66% greater in the birds. The pulmonary capillary blood volume was also greater (22%) in the birds. Except for the thickness of the plasma layer, these morphometric parameters all favour the gas exchange capacity of birds. Consequently, the total specific mean morphometric pulmonary diffusing capacity for oxygen was estimated to be about 22% greater in birds than in mammals of similar body mass. This estimate was obtained by employing oxygen permeation constants for mammalian tissue, plasma and erythrocytes, as avian constants were not then available.(ABSTRACT TRUNCATED AT 400 WORDS)     

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.     

Allometric analysis of the morphometric pulmonary diffusing capacity in dogs

The lung volume, the morphometrically determined alveolar and capillary surface area, and the capillary volume of 27 dogs (weight 2.65–57 kg) all were linearly correlated with body weight. The thickness of the air-blood barrier increased only slightly with increasing body size. The structural diffusing capacity, containing these parameters, was used to estimate the gas exchange capabilities of the lung and was also found to scale in direct proportion to body size. This coincides with reports on physiologically estimated diffusing capacity but is obviously different from the interspecies slope for metabolism which scales to the 3/4 power of body weight.     

Neutrophil transit times through pulmonary capillaries: the effects of capillary geometry and fMLP-stimulation

The deformations of neutrophils as they pass through the pulmonary microcirculation affect their transit time, their tendency to contact and interact with the endothelial surface, and potentially their degree of activation. Here we model the cell as a viscoelastic Maxwell material bounded by constant surface tension and simulate indentation experiments to quantify the effects of (N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLP)-stimulation on its mechanical properties (elastic shear modulus and viscosity). We then simulate neutrophil transit through individual pulmonary capillary segments to determine the relative effects of capillary geometry and fMLP-stimulation on transit time. Indentation results indicate that neutrophil viscosity and shear modulus increase by factors of 3.4, for 10(-9) M fMLP, and 7.3, for 10(-6) M fMLP, over nonstimulated cell values, determined to be 30.8 Pa.s and 185 Pa, respectively. Capillary flow results indicate that capillary entrance radius of curvature has a significant effect on cell transit time, in addition to minimum capillary radius and neutrophil stimulation level. The relative effects of capillary geometry and fMLP on neutrophil transit time are presented as a simple dimensionless expression and their physiological significance is discussed.