Regional lung density and blood volume in nonsmoking and smoking subjects measured by PET

Regional lung density (DL) and regional fractional pulmonary blood volume (VB) were measured quantitatively during tidal breathing in 30 healthy supine subjects (15 smokers and 15 nonsmokers) in a 1.7-cm-thick midthoracic cross section using positron emission tomography (PET) and 11CO (inhaled)-labeled erythrocytes. Regional alveolar volume (VA), extravascular lung density (DEV), and relative alveolar size (Valv = VA/DEV) were calculated. For the nonsmokers, mean values (+/- SD between subjects) for the right lung were as follows: DL, 0.28 +/- 0.03 g/cm3; DEV, 0.10 +/- 0.02 g/cm3; and Valv, 7.1 +/- 1.9 ml/g lung tissue. In the smoking subjects DEV (right plus left lung) was 16% higher. No significant difference in VB between smokers and nonsmokers was found. The differences in DEV and VB between right and left lung were not significant. Mean values (+/- SD) of the dorsal-to-ventral ratios calculated for the right lung in the nonsmokers were as follows: DL, 1.34 +/- 0.16; VA, 0.90 +/- 0.05; VB, 1.52 +/- 0.26; DEV, 1.10 +/- 0.17; and Valv, 0.85 +/- 0.19. Almost identical ratios were found in the smokers. The influence of overall thoracic expansion was investigated in one subject restudied during voluntary hyperinflation and during positive end-expiratory pressure.     

Pulmonary blood volume and edema in postpneumonectomy lung growth in rats

After pneumonectomy in young animals, the contralateral lung undergoes compensatory growth and generally attains the same weight and air space volume as both lungs in age-matched controls. In this study, we determined the contribution of lung edema and increased blood volume to the weight gain in rats. Three weeks after pneumonectomy (n = 18) or sham pneumonectomy (n = 17), the pulmonary blood volume and the extravascular water and albumin were evaluated by use of 51Cr-labeled erythrocytes and 125I-labeled albumin. The air space volume, blood-free lung weights, and DNA and protein content were also compared. The data show that the total pulmonary blood volumes and the blood volume per gram of blood-free dry lung were similar in pneumonectomized and age-matched sham controls. The total extravascular albumin and the extravascular albumin per gram of blood-free dry lung were also similar as well as the extravascular lung water, wet-to-dry weight ratios, DNA and protein content, and air space volumes. These data indicate that the increased weight of the postpneumonectomy lung was due to cellular and stromal proliferation. The blood volume and interstitial fluid increased in proportion to the increase in lung parenchyma. Neither vascular congestion nor increased extravascular protein and water contributed to the observed weight gain.     

实验性高原肺水肿发病机制的初步研究

本研究用Ｗｉｓｔａｒ大鼠在模拟海拔６０００ｍ高度停留４８ｈ,对实验性高原肺水肿的发病机制进行了初步观察,结果表明：（１）大鼠肺血管外含水量明显增多;（２）肺泡隔增宽,肺泡隔内血管口径大小不一,有的扩张,有的狭窄甚至闭锁,硝酸镧示踪电镜术发现肺泡上皮、血管内皮和肺泡隔内有数量不等的镧颗粒;（３）硝苯啶或地塞米松均可使肺血管外含水量明显降低,二者联合作用效果更佳;（４）血浆内心钠素（ＡＮＰ）含量明显增多,伴有体重和血液含水量明显减少。从而表明,低氧性肺动脉压升高和肺泡壁微血管壁通透性增强在高原肺水肿的发生中有重要作用。血浆ＡＮＰ增加和伴随的血液浓缩是对抗血浆进一步外渗的因素之一。     

Effect of alveolar liquid on distribution of blood flow in dog lungs.

Previous studies have shown that a shift in blood flow away from edematous regions does not occur until the alveoli contain liquid. The present experiments were designed to examine the separate effect of air space liquid, air space plus interstitial liquid, and reduced lung volume on blood flow. We found that reduced lung volume was not associated with significant changes in blood flow and that no systematic change in blood flow occurred when alveoli were filled with isosmotic liquid (autologous plasma). However, when hyposmotic liquid (dilute plasma) was instilled so that both the air space and the alveolar wall interstitial space were filled, blood flow was systematically reduced. This suggested that interstitial liquid was responsible raising vascular resistance in these experiments and that it might also be important in raising local vascular resistance in pulmonary edema. This latter hypothesis was tested in isolated perfused lobes where rapid freezing and quantitative histology showed that the number of open capillaries was significantly reduced in the liquid-filled alveoli (P less than 0.001). These observations suggest that interstitial pressure rises in pulmonary edema with the result that the transmural pressure of the alveolar vessels falls and vascular resistance is increased.     

Protective effect of endogenous beta-adrenergic tone on lung fluid balance in acute bacterial pneumonia in mice

Some investigators have reported that endogenous beta-adrenoceptor tone can provide protection against acute lung injury. Therefore, we tested the effects of beta-adrenoceptor inhibition in mice with acute Escherichia coli pneumonia. Mice were pretreated with propranolol or saline and then intratracheally instilled with live E. coli (10(7) colony-forming units). Hemodynamics, arterial blood gases, plasma catecholamines, extravascular lung water, lung permeability to protein, bacterial counts, and alveolar fluid clearance were measured. Acute E. coli pneumonia was established after 4 h with histological evidence of acute pulmonary inflammation, arterial hypoxemia, a threefold increase in lung vascular permeability, and a 30% increase in extravascular lung water as an increase in plasma catecholamine levels. beta-Adrenoceptor inhibition resulted in a marked increase in extravascular lung water that was explained by both an increase in lung vascular permeability and a reduction in net alveolar fluid clearance. The increase in extravascular lung water with propranolol pretreatment was not explained by an increase in systemic or vascular pressures. The increase in lung vascular permeability was explained in part by anti-inflammatory effects of beta-adrenoceptor stimulation because plasma macrophage inflammatory protein-2 levels were higher in the propranolol pretreatment group compared with controls. The decrease in alveolar fluid clearance with propranolol was explained by a decrease in catecholamine-stimulated fluid clearance. Together, these results indicate that endogenous beta-adrenoceptor tone has a protective effect in limiting accumulation of extravascular lung water in acute severe E. coli pneumonia in mice by two mechanisms: 1) reducing lung vascular injury and 2) upregulating the resolution of alveolar edema.     

Regional extravascular and interstitial lung water in normal dogs

We measured the regional distribution of pulmonary extravascular and interstitial water to examine the possibility that regional differences in microvascular pressure or tissue stress may cause regional differences in lung water. We placed chloralose-anesthetized dogs in an upright (n = 6) or supine (n = 7) position for 180 min. We injected 51Cr-labeled EDTA to equilibrate to the extracellular space and 125I-labeled albumin to equilibrate with plasma. At the end of the experiment, the lungs were removed, passively drained of blood, and inflated before rapid freezing. Lungs were divided into horizontal slices, and extravascular, interstitial, and plasma water, red cell volume, and dry lung weight were determined for each slice. We found that regional extravascular and interstitial water were constant throughout the lungs in both groups and that there were no significant differences between upright and supine dogs. There were no significant differences in hematocrit between slices. We conclude that gravity and body position have no measurable effect on either the total size of the extravascular and interstitial compartments or their regional distribution.     

Electron microscopic pathological patterns of alveolar septum in acute dextran-induced and alloxan-induced pulmonary edema in dogs

We studied the incidence of electron microscopic pathological patterns of the alveolar septum observed 30 min after induction of pulmonary edema by dextran-70 infusion (6 dogs, dextran group) and by alloxan injection (6 dogs, alloxan group). For comparable amounts of extravascular lung water in both dextran and alloxan groups, which were twice as much as control group (6 dogs), we characterized the pathological changes. The incidence of the electron microscopic pathological patterns that appeared in dextran group compared with that in control group was significantly high in terms of the widening of the interstitial space, dispersion and disarray of collagen fibrils, and erythrocytes in the interstitial space. The incidence in alloxan group compared with that in control group was significantly high in terms of the swelling of epithelial cells and endothelial cells as well as the widening of the interstitial space, and dispersion and disarray of collagen fibrils. We conclude that dextran causes interstitial changes exclusively and alloxan causes cellular changes primarily coupled with secondary interstitial changes in acute pulmonary edema.     

Direct injury to the bronchial vasculature in anesthetized sheep.

Injury to the bronchial vasculature may contribute to liquid and solute leakage into the lung during noncardiac pulmonary edema. The purpose of this study was to measure changes in hemodynamics, pulmonary mechanics, extravascular lung water, and lung morphometry after selectively injuring the bronchial vasculature in anesthetized sheep. In two groups of seven sheep, we injected oleic acid (0.1 ml/kg) or normal saline directly into the bronchoesophageal artery. We measured systemic and pulmonary arterial pressures, cardiac output, oxygen saturation, pulmonary resistance and compliance, and lung volumes before and 1 and 4 h after injection. The lungs were removed for measurement of extravascular water, histology, and morphometry. Four hours after injection of oleic acid, cardiac output decreased but pulmonary arterial pressure did not change. In addition, pulmonary resistance increased and dynamic compliance and vital capacity decreased. Extravascular lung water was slightly but significantly greater in the oleic acid group. Histological examination showed interstitial edema and leukocytes in airway walls and sloughing of bronchial epithelium but little or no alveolar edema. Morphometric analysis showed significant thickening of airway walls. We conclude that direct injury to the bronchial vasculature increases lung resistance, decreases dynamic compliance, and increases extravascular lung water by the accumulation of an inflammatory infiltrate in airway walls.     

Respiratory failure after endotoxin infusion in sheep: lung mechanics and lung fluid balance

Infusion of Escherichia coli endotoxin (0.12-1.5 micrograms/kg) into unanesthetized sheep causes transient pulmonary hypertension and several hours of increased lung vascular permeability, after which sheep recover. To produce enough lung injury to result in pulmonary edema with respiratory failure, we infused larger doses of E. coli endotoxin (2.0-5.0 micrograms/kg) into 11 chronically instrumented unanesthetized sheep and continuously measured pulmonary arterial, left atrial and aortic pressures, dynamic lung compliance, lung resistance, and lung lymph flow. We intermittently measured arterial blood gas tensions and pH, made interval chest radiographs, and calculated postmortem extravascular bloodless lung water-to-dry lung weight ratio (EVLW/DLW). Of 11 sheep 8 developed respiratory failure; 7 died spontaneously 6.3 +/- 1.1 h, and one was killed 10 h after endotoxin infusion. All sheep that had a premortem room air alveolar-arterial gradient in partial pressure of O2 (PAo2-Pao2) greater than 42 Torr (58 +/- 5 (SE) Torr) died. Of eight sheep that had radiographs made, six developed radiographically evident interstitial or interstitial and alveolar edema. Pulmonary artery pressure rose from base line 22 +/- 2 to 73 +/- 3 cmH2O and remained elevated above baseline levels until death. There was an initial fourfold decrease in dynamic compliance and sixfold increase in pulmonary resistance; both variables remained abnormal until death. EVLW/DLW increased with increasing survival time after endotoxin infusion, suggesting that pulmonary edema accumulated at the same rate in all fatally injured sheep, regardless of other variables. The best predictor of death was a high PAo2-Pao2. The marked increase in pulmonary resistance and decrease in dynamic compliance occurred too early after endotoxin infusion (15-30 min) to be due to pulmonary edema. The response to high-dose endotoxin in sheep closely resembles acute respiratory failure in humans following gram-negative septicemia. Respiratory failure and death in this model were not due to pulmonary edema alone.     

Regional lung hematocrit in humans using positron emission tomography

Regional lung hematocrit ratio (R) was measured in five normal subjects and five patients (2 with pneumonia, 2 with nephrotic syndrome with anemia, and 1 with pancreatitis) using positron emission tomography, a red cell marker 11CO, and a plasma marker [methyl-11C]albumin). The measurements were made in a transaxial thoracic section at midheart level with the subject in supine posture and with a spatial resolution of 1.7 cm. The normal regional hematocrit ratio (means +/- SE) calculated for the lung was 0.90 +/- 0.014, 0.94 +/- 0.023 for the thoracic wall, and 1.00 +/- 0.003 for the heart chambers. The regional lung hematocrit ratio in the patients ranged between 0.81 and 0.86. No correlation was found among the regional lung hematocrit ratio and regional blood volume, lung extravascular density, and the peripheral hematocrit (obtained from venous blood samples). To the extent that 70% of the pulmonary blood in the field of view is in larger vessels with normal hematocrit, the hematocrit in the capillary bed is approximately two-thirds that of the peripheral venous value. Blood volume measurements on the basis of single vascular tracers need to take account of these results.     

Lung mechanics in hypervolemic pulmonary edema.

Extravascular thermal volume of the lung (ETVL) is a double indicator dilution technique of use in measuring pulmonary edema. ETVL and lung mechanics measurements were followed to find a less invasive monitor of pulmonary edema than the double indicator dilution technique. Pulmonary edema was induced by overloading the dogs' circulation with dextran. Phases of overload were defined on the basis of a previous electron microscopic study (Noble et al., Can. Anesthetists Soc. J. 21:275, 1974) of lung biopsies relating anatomic changes to physiologic measurements of ETVL and central blood volume (CBV). Congestion occurred when CBV was elevated and ETVL was not, interstitial edema when ETVL was elevated but smaller than 60% above control and alveolar edema when ETVL greater than 85% above control. Once the dogs were in alveolar edema, they were mechanically ventilated with 4, 8, 12, and 16 cmH2O end-tidal pressure (CPPV). Mean functional residual capacity (FRC) for all 15 dogs did not change up to the time CPPV was applied. Pulmonary resistance did not rise until alveolar edema was present. Once in pulmonary edema, lung compliance always fell as lung water increased. In individual dogs, the compliance fall was directly proportional to the rising lung water. However, the variations in slope and beginning point among dogs made it difficult to predict the amount of lung water from dynamic compliance values. PaO2 fell markedly in alveolar edema as a result of a widened A-a gradient. CPPV did not decrease lung water but did increase FRC and PaO2.     

Evaluating flux of labeled albumin into the pulmonary interstitium of sheep lungs.

A noninvasive method was used to measure the movement of 131I-labeled albumin across the pulmonary microvascular barrier of a blood-perfused in situ sheep lung lymph preparation. After injection of labeled albumin into the blood, external measurements of gamma activity were taken for 2 h. The interstitial concentrations were calculated by applying the external activities and sampled lung lymph concentrations to a mass transport model. For the external activities and lymph activities to yield the same quantitative results, two modifications were necessary. First, lymph concentrations were corrected for transport delay from the lymphatic system. Second, externally detected radioactivity had to be corrected for the contribution of unbound nuclide. Application of a mathematical model to the data indicated the extravascular distribution volume for albumin was 79% of the pulmonary blood volume, and the extravascular distribution volume for radiolabeled iodide was 4.42 times greater than the pulmonary blood volume. The permeability-surface area product for iodide in the lung was estimated to be 0.274 ml.min-1.g blood-free dry lung wt-1. The transport delay in the lymphatic system was approximately 30-45 min and represented a volume of 1.44-2.80 ml.     

Effect of interstitial edema on lung lymph flow in goats in the absence of filtration.

We tested the effect of interstitial edema on lung lymph flow when no filtration occurred. In 16 anesthetized open-thorax ventilated supine goats, we set pulmonary arterial and left atrial pressures to nearly zero and measured lymph flow for 3 h from six lungs without edema and ten with edema. Lymph flow decreased exponentially in all experiments as soon as filtration ceased. In the normal lungs the mean half time of the lymph flow decrease was 12.7 +/- 4.8 (SD) min, which was significantly shorter (P less than 0.05) than the 29.1 +/- 14.8 min half time in the edematous lungs. When ventilation was stopped, lymph flow in the edematous lungs decreased as rapidly as in the normal lungs. The total quantity of lymph after filtration ceased was 2.7 +/- 0.8 ml in normal lungs and 9.5 +/- 6.3 ml in edematous lungs, even though extravascular lung water was doubled in the latter (8.4 +/- 2.4 vs. 3.3 +/- 0.4 g/g dry lung, P less than 0.01). Thus the maximum possible clearance of the interstitial edema liquid by the lymphatics was 6.3 +/- 4.8%. When we restarted pulmonary blood flow after 1-2 h in four additional goats, lymph flow recovered within 30 min to the baseline level. These findings support the hypothesis that lung lymph flow originates mainly from alveolar wall perimicrovascular interstitial liquid and that the contribution of the lung lymphatic system to the clearance of interstitial edema (bronchovascular cuffs, interlobular septa) is small.     

Lung expansion and the perialveolar interstitial pressure gradient

We have determined the combined effects of lung expansion and increased extravascular lung water (EVLW) on the perialveolar interstitial pressure gradient. In the isolated perfused lobe of dog lung, we measured interstitial pressures by micropuncture at alveolar junctions (Pjct) and in adventitia of 30- to 50-microns microvessels (Padv) with stopped blood flow at vascular pressure of 3-5 cmH2O. We induced edema by raising vascular pressures. In nonedematous lobes (n = 6, EVLW = 3.1 +/- 0.3 g/g dry wt) at alveolar pressure of 7 cmH2O, Pjct averaged 0.5 +/- 0.8 (SD) cmH2O and the Pjct-Padv gradient averaged 0.9 +/- 0.5 cmH2O. After increase of alveolar pressure to 23 cmH2O the gradient was abolished in nonedematous lobes, did not change in moderately edematous lobes (n = 9, EVLW = 4.9 +/- 0.6 g/g dry wt), and increased in severely edematous lobes (n = 6, EVLW = 7.6 +/- 1.4 g/g dry wt). Perialveolar interstitial compliance decreased with increase of alveolar pressure. We conclude that increase of lung volume may reduce perialveolar interstitial liquid clearance by abolishing the Pjct-Padv gradient in nonedematous lungs and by compressing interstitial liquid channels in edematous lungs.     

Proportional analysis of respiratory cells obtained by bronchoalveolar lavage.

Bronchoalveolar lavage was performed during fibreoptic bronchoscopy in 17 patients with biopsy-proven interstitial lung disease and in 12 control subjects who had focal lesions in the lung. The volume of fluid recovered was unrelated to disease activity or diagnosis. In the control subjects alveolar macrophages represented over 95% of the lavaged cells. The proportion of lymphocytes in the lavaged cells enabled a natural division of the diffuse interstitial lung diseases into two categories: active sarcoidosis, indicated by a large proportion of lymphocytes but a normal proportion of polymorphonuclear leukocytes; and idiopathic pulmonary fibrosis and asbestosis, indicated by a normal proportion of lymphocytes but a variable proportion of polymorphonuclear leukocytes. Bronchoalveolar lavage is a safe and well tolerated method for evaluating the role of alveolitis in diffuse interstitial lung disease through the sampling of respiratory alveolar cells.     

Pulmonary blood flow distribution measured by radionuclide-computed tomography

Distributions of pulmonary blood flow per unit lung volume were measured with subjects in the prone, supine, and sitting positions by means of radionuclide-computed tomography of intravenously administered 99mTc-labeled macroaggregates of human serum albumin. The blood flow was greater in the direction of gravity in all 31 subjects except one with severe mitral valve stenosis. With the subject in a sitting position, four different types of distribution were distinguished. One type had a three-zonal blood flow distribution as previously reported by West and co-workers (J. Appl. Physiol. 19: 713-724, 1964). Pulmonary arterial pressure and venous pressure estimated from this model showed reasonable agreement with pulmonary arterial pressure and capillary wedge pressure measured by Swan-Ganz catheter in 17 supine patients and in 2 sitting patients. The method makes possible noninvasive assessment of pulmonary vascular pressures.     

Spontaneous resolution of pulmonary edema caused by short periods of cyclic overinflation.

Mechanical ventilation with high or even moderate peak inspiratory pressure produces pulmonary permeability edema. Besides the level of overinflation, duration may affect both severity and type of edema. We studied the effect of 2 min of 35-mmHg peak pressure mechanical ventilation (HV) on microvascular permeability and deep lung fluid balance in rats. It resulted in increased extravascular lung water (+50%), bloodless dry lung weight (+25%), and albumin uptake in lungs (+450%). The increase in dry lung weight and albumin uptake compared with that of lung water suggested major permeability alterations. Ultrastructural examination showed the presence of numerous endothelial blebs. Epithelial lining fluid (ELF) volume, its potassium and protein concentrations, and cellular composition were assessed by bronchoalveolar lavage. There was an increase in ELF volume (+180%), a decrease in ELF potassium concentration (-50%), and an increase in ELF protein content (+76%). A few blood cells were recovered, suggesting the presence of a few large epithelial breaks. Some animals were allowed to recover for periods less than or equal to 180 min after HV. Extravascular lung water, dry lung weight, and albumin distribution space returned to control levels within 45 min. ELF volume diminished but remained larger than in controls, and ELF protein concentration increased probably because of alveolar fluid resorption. No further hemorrhage was observed. These results indicate that periods of HV as short as 2 min transiently alter microvascular permeability in rats.     

High surface tension pulmonary edema induced by detergent aerosol

The effect of the detergent dioctyl sodium sulfosuccinate on pulmonary extravascular water volume (PEWV) was studied in adult anesthetized mongrel dogs. The detergent was dissolved as a 1% solution in a vehicle of equal volumes of 95% ethanol and normal saline and administered by ultrasonic nebulizer attached to the inspiratory tubing of a piston ventilator. Two hours following detergent aerosol PEWV measured gravimetrically was increased compared with either animals receiving no aerosol or those receiving an aerosol of vehicle alone. Loss of surfactant activity and increased alveolar surface tension were demonstrated by Wilhelmy balance studies of minced lung extracts, by a fall in static compliance, and by evidence of atelectasis and instability noted by gross observation and by in vivo microscopy. No significant changes in colloid oncotic pressure or pulmonary microvascular hydrostatic pressure were observed. These data suggest that pulmonary edema can be induced by increased alveolar surface tension and support the concept that one of the major roles of pulmonary surfactant is to prevent pulmonary edema.     

Marked differences between prone and supine sheep in effect of PEEP on perfusion distribution in zone II lung.

The classic four-zone model of lung blood flow distribution has been questioned. We asked whether the effect of positive end-expiratory pressure (PEEP) is different between the prone and supine position for lung tissue in the same zonal condition. Anesthetized and mechanically ventilated prone (n = 6) and supine (n = 5) sheep were studied at 0, 10, and 20 cm H2O PEEP. Perfusion was measured with intravenous infusion of radiolabeled 15-microm microspheres. The right lung was dried at total lung capacity and diced into pieces (approximately 1.5 cm3), keeping track of the spatial location of each piece. Radioactivity per unit weight was determined and normalized to the mean value for each condition and animal. In the supine posture, perfusion to nondependent lung regions decreased with little relative perfusion in nondependent horizontal lung planes at 10 and 20 cm H2O PEEP. In the prone position, the effect of PEEP was markedly different with substantial perfusion remaining in nondependent lung regions and even increasing in these regions with 20 cm H2O PEEP. Vertical blood flow gradients in zone II lung were large in supine, but surprisingly absent in prone, animals. Isogravitational perfusion heterogeneity was smaller in prone than in supine animals at all PEEP levels. Redistribution of pulmonary perfusion by PEEP ventilation in supine was largely as predicted by the zonal model in marked contrast to the findings in prone. The differences between postures in blood flow distribution within zone II strongly indicate that factors in addition to pulmonary arterial, venous, and alveolar pressure play important roles in determining perfusion distribution in the in situ lung. We suggest that regional variation in lung volume through the effect on vascular resistance is one such factor and that chest wall conformation and thoracic contents determine regional lung volume.     

Growth rate of perivascular cuffs in liquid-inflated dog lung lobes

In the early stages of pulmonary edema, excess liquid leaving the pulmonary exchange vessels accumulates in the peribronchovascular interstitium where it forms large peribronchovascular cuffs. The peribronchovascular interstitium therefore acts as a reservoir to protect the air spaces from alveolar flooding. The rate of liquid accumulation and the liquid storage capacity of the cuffs determine how quickly alveolar flooding is likely to follow once edema formation has begun. To measure the rate and capacity of interstitial filling we inflated 11 isolated degassed dog lung lobes with liquid to an inflation pressure of 14 cmH2O (total lung capacity) for 1-300 min, then froze the lobes in liquid N2. We made photographs of 20 randomly selected 12 X 8-mm cross sections from each lobe and measured cuff volume from the photographs by point-counting. We found that cuff volume increased from 2.2% of air-space volume after 1 min of inflation to 9.3% after 300 min. To measure the driving pressure responsible for cuff formation we used micropipettes to measure subpleural interstitial liquid pressure at the hilum of three additional lobes. With liquid inflation pressure set to 14 cmH2O interstitial pressure rose exponentially to 11.5 cmH2O. Interstitial compliance calculated from our volume and pressure measurements equaled 0.09 ml X cmH2O-1 X g wet wt-1, a value similar to that measured in air-inflated lungs. Goldberg [Am. J. Physiol. 239 (Heart Circ. Physiol. 8): H189-H198, 1980] has likened interstitial filling to the charging of a capacitor, a process that follows a monoexponential time course.(ABSTRACT TRUNCATED AT 250 WORDS)