Promethazine or DPPD pretreatment attenuates oleic acid-induced injury in isolated canine lungs

Oleic acid causes pulmonary edema by increasing capillary endothelial permeability, although the mechanism of this action is uncertain. We tested the hypothesis that the damage is an oxidant injury initiated by oleic acid, using isolated blood-perfused canine lung lobes. The lobes were dilated with papaverine and perfused in zone III with a constant airway pressure of 3 cmH2O. Changes in isogravimetric capillary pressure (Pc,i) and capillary filtration coefficient (Kf,C) were used as indices of alterations in microvascular permeability in lungs treated with silicone fluid (n = 3), oleic acid (n = 11), oleic acid after pretreatment with the antioxidants promethazine HCl (n = 11) or N,N'-diphenyl-p-phenylenediamine (DPPD; n = 4), or oleic acid following pretreatment with methylprednisolone (n = 4). Kf,C averaged 0.21 +/- 0.02 ml X min-1 X cmH2O-1 X 100 g-1 in control and increased to 0.55 +/- 0.05 and 0.47 +/- 0.05 when measured 20 and 180 min after the administration of oleic acid. When oleic acid was infused into lungs pretreated with promethazine, Kf,C increased to only 0.38 +/- 0.05 ml X min-1 X cmH2O-1 X 100 g-1 after 20 min and had returned to control levels by 180 min. Pretreatment with DPPD, but not methylprednisolone, similarly attenuated the increase in Kf,C following oleic acid. Silicone fluid had no effect on Kf,C. That oleic acid increases vascular permeability was also evidenced by a fall (P less than 0.05) in Pc,i from control when measured at 180 min in every group.(ABSTRACT TRUNCATED AT 250 WORDS)     

Extra-alveolar vessel fluid filtration coefficients in excised and in situ canine lobes

We continuously weighed fully distended excised or in situ canine lobes to estimate the fluid filtration coefficient (Kf) of the arterial and venous extra-alveolar vessels compared with that of the entire pulmonary circulation. Alveolar pressure was held constant at 25 cmH2O after full inflation. In the in situ lobes, the bronchial circulation was interrupted by embolization. Kf was estimated by two methods (Drake and Goldberg). Extra-alveolar vessels were isolated from alveolar vessels by embolizing enough 37- to 74-micron polystyrene beads into the lobar artery or vein to completely stop flow. In excised lobes, Kf's of the entire pulmonary circulation by the Drake and Goldberg methods were 0.122 +/- 0.041 (mean +/- SD) and 0.210 +/- 0.080 ml X min-1 X mmHg-1 X 100 g lung-1, respectively. Embolization was not found to increase the Kf's. The mean Kf's of the arterial extra-alveolar vessels were 0.068 +/- 0.014 (Drake) and 0.069 +/- 0.014 (Goldberg) (24 and 33% of the Kf's for the total pulmonary circulation). The mean Kf's of the venous extra-alveolar vessels were similar [0.046 +/- 0.020 (Drake) and 0.065 +/- 0.036 (Goldberg) or 33 and 35% of the Kf's for the total circulation]. No significant difference was found between the extra-alveolar vessel Kf's of in situ vs. excised lobes. These results suggest that when alveolar pressure, lung volume, and pulmonary vascular pressures are high, approximately one-third of the total fluid filtration comes from each of the three compartments.     

Venous occlusion pressure and vascular permeability in the dog lung after air embolization

Pulmonary edema has frequently been associated with air embolization of the lung. In the present study the hemodynamic effects of air emboli (AE) were studied in the isolated mechanically ventilated canine right lower lung lobe (RLL), pump perfused at a constant blood flow. Air was infused via the pulmonary artery (n = 7) at 0.6 ml/min until pulmonary arterial pressure (Pa) rose 250%. While Pa rose from 12.4 +/- 0.6 to 44.6 +/- 2.0 (SE) cmH2O (P less than 0.05), venous occlusion pressure remained constant (7.0 +/- 0.5 to 6.8 +/- 0.6 cmH2O; P greater than 0.05). Lobar vascular resistance (RT) increased from 2.8 +/- 0.3 to 12.1 +/- 0.2 Torr.ml-1.min.10(-2) (P less than 0.05), whereas the venous occlusion technique used to determine the segmental distribution of vascular resistance indicated the increase in RT was confined to vessels upstream to the veins. Control lobes (n = 7) administered saline at a similar rate showed no significant hemodynamic changes. As an index of microvascular injury the pulmonary filtration coefficient (Kf) was obtained by sequential elevations of lobar vascular pressures. The Kf was 0.11 +/- 0.01 and 0.07 +/- 0.01 ml.min-1.Torr-1.100 g RLL-1 in AE and control lobes, respectively (P less than 0.05). Despite a higher Kf in AE lobes, total lobe weight gains did not differ and airway fluid was not seen in the AE group. Although air embolization caused an increase in upstream resistance and vascular permeability, venous occlusion pressure did not increase, and marked edema did not occur.     

Osmotic reflection coefficient for total plasma protein in lung microvessels

The osmotic reflection coefficient (sigma) for total plasma proteins was estimated in 11 isolated blood-perfused canine lungs. Sigma's were determined by first measuring the capillary filtration coefficient (Kf,C in ml X min-1 X 100g-1 X cmH2O-1) using increased hydrostatic pressures and time 0 extrapolation of the slope of the weight gain curve. Kf,C averaged 0.19 +/- 0.05 (mean +/- SD) for 14 separate determinations in the 11 lungs. Following a Kf,C determination, the isogravimetric capillary pressure (Pc,i) was determined and averaged 9.9 +/- 0.5 cmH2O for all controls reported in this study. Then the blood colloids in the perfusate were either diluted or concentrated. The lung either gained or lost weight, respectively, and an initial slope of the weight gain curve (delta W/delta t)0 was estimated. The change in plasma protein colloid osmotic pressure (delta IIP) was measured using a membrane osmometer. The measured delta IIP was related to the effective colloid osmotic pressure (delta IIM) by delta IIM = (delta W/delta t)0/Kf,C = sigma delta IIP. Using this relationship, sigma averaged 0.65 +/- 0.06, and the least-squares linear regression equation relating Pc,i and the measured IIP was Pc,i = -3.1 + 0.67 IIP. The mean estimate of sigma (0.65) for total plasma proteins is similar to that reported for dog lung using lymphatic protein flux analyses, although lower than estimates made in skeletal muscle using the present methods (approximately 0.95).     

Effects of arachidonate on permeability and resistance distribution in canine lungs

In this study, 14 canine lung lobes were isolated and perfused with autologous blood at constant pressure (CP) or constant flow (CF). Pulmonary capillary pressure (Pc) was measured via venous occlusion or simultaneous arterial and venous occlusions. Arterial and venous pressures and blood flow were measured concurrently so that total pulmonary vascular resistance (RT) as well as pre- (Ra) and post- (Rv) capillary resistances could be calculated. In both CP and CF perfused lobes, 5-min arachidonic acid (AA) infusions (0.085 +/- 0.005 to 2.80 +/- 0.16 mg X min-1 X 100 g lung-1) increased RT, Rv, and Pc (P less than 0.05 at the highest dose), while Ra was not significantly altered and Ra/Rv fell (P less than 0.05 at the highest AA dose). In five CP-perfused lobes, the effect of AA infusion on the pulmonary capillary filtration coefficient (Kf,C) was also determined. Neither low-dose AA (0.167 +/- 0.033 mg X min-1 X 100 g-1) nor high-dose AA (1.35 +/- 0.39 mg X min-1 X 100 g-1) altered Kf,C from control values (0.19 +/- 0.02 ml X min-1 X cmH2O-1 X 100 g-1). The hemodynamic response to AA was attenuated by prior administration of indomethacin (n = 2). We conclude that AA infusion in blood-perfused canine lung lobes increased RT and Pc by increasing Rv and that microvascular permeability is unaltered by AA infusion.     

Interaction of chemical and high vascular pressure injury in isolated canine lung

Because both chemical and mechanical insults to the lung may occur concomitantly with trauma, we hypothesized that the pressure threshold for vascular pressure-induced (mechanical) injury would be decreased after a chemical insult to the lung. Normal isolated canine lung lobes (N, n = 14) and those injured with either airway acid instillation (AAI, n = 18) or intravascular oleic acid (OA, n = 25) were exposed to short (5-min) periods of elevated venous pressure (HiPv) ranging from 19 to 130 cmH2O. Before the HiPv stress, the capillary filtration coefficient (Kf,c) was 0.12 +/- 0.01, 0.27 +/- 0.03, and 0.31 +/- 0.02 ml.min-1.cmH2O-1 x 100 g-1 and the isogravimetric capillary pressure (Pc,i) was 9.2 +/- 0.3, 6.8 +/- 0.5, and 6.5 +/- 0.3 cmH2O in N, AAI, and OA lungs, respectively. However, the pattern of response to HiPv was similar in all groups: Kf,c was no different from the pre-HiPv value when the peak venous pressure (Pv) remained less than 55 cmH2O, but it increased reversibly when peak Pv exceeded 55 cmH2O (P less than 0.05). The reflection coefficient (sigma) for total proteins measured after pressure exposure averaged 0.60 +/- 0.03, 0.32 +/- 0.04, and 0.37 +/- 0.09 for N, AAI, and OA lobes respectively. However, in contrast to the result expected if pore stretching had occurred at high pressure, in all groups the sigma measured during the HiPv stress when Pv exceeded 55 cmH2O was significantly larger than that measured during the recovery period.(ABSTRACT TRUNCATED AT 250 WORDS)     

Canine pulmonary filtration coefficient calculated from optical, radioisotope, and weight measurements.

Three independent methods were used to estimate filtration coefficient (Kf) in isolated dog lungs perfused with low-hematocrit (Hct) blood. Pulmonary vascular pressure was increased by 12-23 cmH2O to induce fluid filtration. Average Kf (ml.min-1 x cmH2O-1 x 100 g dry wt-1) for six lungs was 0.26 +/- 0.05 (SE) with use of equations describing conservation of optically measured protein labeled with indocyanine green. Good agreement was found when a simplified version of the multiequation theory was applied to the data (0.24 +/- 0.05). Both optical estimates were lower than those predicted by constant slope (0.55 +/- 0.07) or extrapolation (1.20 +/- 0.15) techniques, which are based on changes in total lung weight. Subsequent studies in five dog lungs investigated whether the higher Kf from weight analyses could be caused by prolonged pulmonary vascular filling. We found that 51Cr-labeled red blood cells (RBCs), monitored over the lung, continued to accumulate for 30 min after vascular pressure elevations of 9-16 cmH2O.Kf was determined by subtracting computed vascular filling from total weight change (0.28 +/- 0.06) and by perfusate Hct changes determined from radiolabeled RBCs (0.23 +/- 0.04). These values were similar to those obtained from analysis of optical data with the complete model (0.30 +/- 0.06), the simplified version (0.26 +/- 0.05), and from optically determined perfusate Hct (0.16 +/- 0.03). However, constant slope (0.47 +/- 0.04) and extrapolation (0.57 +/- 0.07) computations of Kf were higher than estimates from the other methods. Our studies indicate that prolonged blood volume changes may accompany vascular pressure elevations and produce overestimates of Kf with standard weight measurement techniques. However, Kf computed from optical measurements is independent of pulmonary blood volume changes.     

Vascular pressure effects on lung edema formation after glass bead embolism

The canine lung lobe was embolized with 100-micron glass beads before lobectomy and blood anticoagulation. The lobe was isolated, ventilated, and pump-perfused with blood at an arterial pressure (Pa) of about 50 (high pressure, HP, n = 9) or 25 Torr (low pressure, LP, n = 9). Rus/PVR, the ratio of upstream (Rus) to total lobar vascular resistance (PVR), was determined by venous occlusion and the isogravimetric capillary pressure technique. The capillary filtration coefficient (Kf), an index of vascular permeability, was obtained from rate of lobe weight gain during stepwise capillary pressure (Pc) elevation. The embolized lobes became more edematous than nonembolized controls, (C, n = 11), (P less than 0.05), with Kf values of 0.20 +/- 0.04, 0.25 +/- 0.06, and 0.07 +/- 0.01 ml X min-1 X Torr-1 X 100 X g-1 in LP, HP, and C, respectively (P less than 0.05). The greater Rus/PVR in embolized lobes (P less than 0.05) protected the microvessels and, although Pc was greater in HP than in controls (P less than 0.05), Pc did not differ between HP and LP (P greater than 0.05). Although indexes of permeability did not differ between embolized groups (P greater than 0.05), HP became more edematous than LP (P less than 0.05). The greater edema in HP did not appear due to a greater imbalance of Starling forces across the microvessel wall or to vascular recruitment. At constant Pc and venous pressure, elevating Pa from 25 to 50 Torr in embolized lobes resulted in greater edema to suggest fluid filtration from precapillary vessels.     

Phorbol myristate acetate-induced injury of isolated perfused rat lungs: neutrophil dependence

The effect of leukocyte depletion on acute lung injury produced by intravenous or intratracheal phorbol myristate acetate (PMA) administration was studied in isolated perfused rat lungs. Vascular endothelial permeability was assessed by use of the capillary filtration coefficient (Kf,c). A predicted pulmonary capillary pressure (Ppc,p) was calculated from measurements of postcapillary resistances. These parameters were measured before and 90 min after the administration of PMA, either intratracheally or intravascularly. When blood elements were present both intratracheal and intravascular PMA caused an increased Kf,c [0.27 +/- 0.02 vs. 0.99 +/- 0.22 and 0.25 +/- 0.05 vs. 0.64 +/- 0.15 (SE) ml.min-1.cmH2O-1.100 g-1, respectively; P less than 0.05] and an increased Ppc,p (8.3 +/- 0.4 vs. 74.7 +/- 18.3 and 8.7 +/- 0.8 vs. 74.2 +/- 25.1 cmH2O, respectively; P less than 0.05). Removal of circulating leukocytes abolished the increased Kf,c when PMA was given intratracheally (0.35 +/- 0.06 vs. 0.23 +/- 0.07 ml.min-1.cmH2O-1.100 g-1) or intravascularly (0.39 +/- 0.07 vs. 0.33 +/- 0.07 ml.min-1.cmH2O-1.100 g-1). In the absence of neutrophils, Ppc,p slightly increased with intratracheal PMA, from 6.9 +/- 0.5 to 10.5 +/- 1.1 cmH2O (P less than 0.05), but was unchanged at 90 min with intravascular PMA. Depletion of circulating neutrophils with an antineutrophil serum failed to block the Kf,c change with intratracheal PMA (from 0.24 +/- 0.03 to 0.42 +/- 0.09 ml.min-1.cmH2O-1.100 g-1; P less than 0.05). Ppc,p also increased from 6.9 +/- 0.6 to 19.8 +/- 6.7 cmH2O (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Filtration coefficient obtained by stepwise pressure elevation in isolated dog lung

The base-line capillary filtration coefficient (Kf) obtained from rates of lobe weight gain during stepwise vascular pressure elevation is reported to be threefold greater in isolated than in intact dog lung. To further evaluate the stepwise pressure elevation technique, we obtained Kf in control and oleic acid-injured isolated lung. The left lower lung lobe was removed, placed on a balance, ventilated, and pump perfused with autogenous blood. Saline (n = 6) or oleic acid (n = 6) was infused, and rate of lobe weight gain was obtained during stepwise pressure elevation. Kf averaged 0.071 +/- 0.012 and 0.243 +/- 0.027 ml X min-1 X Torr-1 X 100 g-1 in the control and injured lobes, respectively. Stepwise pressure elevation can yield a base-line Kf in isolated lung similar to Kf's obtained from this and other gravimetric methods in intact and isolated lung. Furthermore, Kf increased severalfold following lung injury with oleic acid. The stepwise pressure elevation technique for Kf determination in isolated lung can be a useful tool for quantitating changes in vascular permeability.     

Lung endothelial and epithelial permeability after platelet-activating factor

We investigated whether platelet-activating factor (PAF) increased epithelial or endothelial permeability in isolated-perfused rabbit lungs. PAF was either injected into the pulmonary artery or instilled into the airway of lungs perfused with Tyrode's solution containing 1% bovine serum albumin. The effect of adding neutrophils or platelets to the perfusate was also tested. Perfusion was maintained 20-40 min after adding PAF and then a fluid filtration coefficient (Kf) was determined to assess vascular permeability. At the end of each experiment, one lung was lavaged, and the lavagate protein concentration (BALP) was determined. Wet weight-to-dry weight ratios (W/D) were determined on the other lung. PAF added to the vascular space increased peak pulmonary arterial pressure (Ppa) from 13.5 +/- 3.1 (mean +/- SE) to 24.2 +/- 3.3 cmH2O (P less than 0.05). The effect was amplified by platelets [Ppa to 70.8 +/- 8.0 cmH2O (P less than 0.05)] but not by neutrophils [Ppa to 22.0 +/- 1.4 cmH2O (P less than 0.05)]. Minimal changes in Ppa were observed after instilling PAF into the airway. The Kf, W/D, and BALP of untreated lungs were not increased by injecting PAF into the vasculature or into the air space. The effect of PAF on Kf, W/D, and BALP was unaltered by adding platelets or neutrophils to the perfusate. PAF increases intravascular pressure (at a constant rate of perfusion) but does not increase epithelial or endothelial permeability in isolated-perfused rabbit lungs.     

Slow phase of transvascular fluid flux reviewed

In six circuit experiments using a clinical hemofiltration device, we validated a colorimetric technique to measure transvascular volume exchange (VE). In 12 isolated excised canine left lower lobes, continuous colorimetric measurements of VE correlated well with calculations of VE from changes in microhematocrit obtained simultaneously. We introduced step increases in microvascular hydrostatic pressure (Pc) of 9 +/- 4.8 (SD) cmH2O and followed the time course of weight and continuous hematocrit changes measured colorimetrically for 40 min, after which Pc was returned to base line, while measurements were continuously obtained. This procedure was repeated for an additional 30 min. VE was calculated from the hematocrit signals and compared with the time course of the weight signal. After increases in Pc, followed by a rapid weight gain, weight signals followed a slow exponential time course, whereas the calculated VE changed linearly. VE reflected approximately 60% of the slow weight gain. When Pc was decreased, weight signals decreased exponentially, whereas VE continued to increase linearly at a slower rate. These results suggest that a significant component of the slow weight signal represents slow vascular volume changes. Contrary to what the weight signal suggested, edema was never reabsorbed over the range of Pc measured.     

Lung edema increases transvascular filtration rate but not filtration coefficient

To determine whether the accelerated rate of lobe weight gain during severe pulmonary edema is attributed to increased permeability of the microvascular barrier or a loss of tissue forces opposing filtration, the effect of edema on capillary filtration coefficient (Kf,C), interstitial compliance (Ci), and the volume of fluid filtered after a step increase in microvascular pressure (delta Vi) were determined in eight isolated left lower lobes of dog lungs perfused at 37 degrees C with autologous blood. After attaining a base-line isogravimetric state, the capillary pressure (Pc) was increased in successive steps of 2, 5, and 10 cmH2O. This sequence of vascular pressure increases was repeated three times. Edema accumulation was expressed as weight gained as a percent of initial lobe weight (% delta Wt), and Kf,C was measured by time 0 extrapolation of the weight gain curve. An exponential rate constant for the decrease in the rate of weight gain with time (K) was calculated for each curve. Ci was then calculated by assuming that the capillary wall and interstitium constitute a resistance-capacitance network. Kf,C was not increased by edema formation in any group. Between mild (% delta Wt less than 30%) and severe edema states (% delta Wt greater than 50%) respective mean Ci increased significantly from 3.54 to 9.12 ml.cmH2O-1.100 g-1, K decreased from 0.089 to 0.036 min-1, and delta Vi increased from 1.28 to 2.4 ml.cmH2O-1.100 g-1. The delta Vi during each Pc increase was highly correlated with Kf,C and Ci when used together as independent variables (r = 0.99) but less well correlated when used separately.(ABSTRACT TRUNCATED AT 250 WORDS)     

Interstitial fluid pressure gradient measured by micropuncture in excised dog lung

We have directly measured lung interstitial fluid pressure at sites of fluid filtration by micropuncturing excised left lower lobes of dog lung. We blood-perfused each lobe after cannulating its artery, vein, and bronchus to produce a desired amount of edema. Then, to stop further edema, we air-embolized the lobe. Holding the lobe at a constant airway pressure of 5 cmH2O, we measured interstitial fluid pressure using beveled glass micropipettes and the servo-null method. In 31 lobes, divided into 6 groups according to severity of edema, we micropunctured the subpleural interstitium in alveolar wall junctions, in adventitia around 50-micron venules, and in the hilum. In all groups an interstitial fluid pressure gradient existed from the junctions to the hilum. Junctional, adventitial, and hilar pressures, which were (relative to pleural pressure) 1.3 +/- 0.2, 0.3 +/- 0.5, and -1.8 +/- 0.2 cmH2O, respectively, in nonedematous lobes, rose with edema to plateau at 4.1 +/- 0.4, 2.0 +/- 0.2, and 0.4 +/- 0.3 cmH2O, respectively. We also measured junctional and adventitial pressures near the base and apex in each of 10 lobes. The pressures were identical, indicating no vertical interstitial fluid pressure gradient in uniformly expanded nonedematous lobes which lack a vertical pleural pressure gradient. In edematous lobes basal pressure exceeded apical but the pressure difference was entirely attributable to greater basal edema. We conclude that the presence of an alveolohilar gradient of lung interstitial fluid pressure, without a base-apex gradient, represents the mechanism for driving fluid flow from alveoli toward the hilum.     

Pressure-dependent increase in lung vascular permeability to water but not protein.

Simultaneous measures of vascular permeability to fluid (capillary filtration coefficient, Kf) and to plasma proteins (solvent drag reflection coefficient, sigma) were obtained over venous pressures (Pv) from 14 to 105 Torr in the isolated ventilated canine lung lobe (n = 70) pump perfused with autologous blood. The sigma was obtained from the relative increase in the concentration of plasma proteins vs. erythrocytes during fluid filtration. Kf's were obtained from two gravimetric methods as well as from change in hematocrit. All Kf's increased (P less than 0.05) as Pv was increased. However, sigma averaged 0.59 +/- 0.01 (range 0.54-0.67) and was unchanged (P greater than 0.05) by elevation of Pv over 20-105 Torr. In 44 lobes where all three Kf measures were obtained, gravimetric measures of Kf did not differ (P greater than 0.05) and were highly correlated with Kf obtained from hematocrit change, Vf Kf (P less than 0.001). However, both weight-based Kf's exceeded Vf Kf (P less than 0.05), suggesting that fluid filtration was overestimated by rate of lung weight gain or underestimated by hematocrit change. Increased permeability to water but not to protein over Pv from 20 to 105 Torr indicates that permeability to both can change independently and is counter to the theory that elevated vascular pressure "stretches" vascular pores.     

Role of xanthine oxidase and neutrophils in ischemia-reperfusion injury in rabbit lung

This study evaluated the effect of ischemia-reperfusion (I-R) on pulmonary capillary permeability in isolated rabbit lungs and the roles of xanthine oxidase (XO), aldehyde oxidase (AO), and neutrophils (PMN) in producing this lung injury. Effects of XO and AO were studied by inactivation with a tungsten-enriched diet (0.7 g/kg) and inhibition of XO by allopurinol (100 microM) or AO by menadione (3.5 microM). PMN effects were studied by preventing endothelial adhesion with the monoclonal antibody IB4 (10 microM). Vascular permeability was evaluated by determining the capillary filtration coefficient (Kf,c) measured before and after I-R in all experimental conditions. Reperfusion after 2 h of ischemia significantly increased pulmonary capillary permeability (Kf,c changed from 0.096 +/- 0.014 to 0.213 +/- 0.025 ml.min-1. cmH2O-1.100 g-1), and this increase was blocked by the addition of catalase (50,000 U) at reperfusion (baseline Kf,c was 0.125 +/- 0.023 and 0.116 +/- 0.014 ml.min-1.cmH2O-1.100 g-1). XO inactivation with the tungsten-supplemented diet and XO inhibition with allopurinol prevented the Kf,c increase observed after I-R (0.183 +/- 0.030 to 0.185 +/- 0.033 and 0.126 +/- 0.018 to 0.103 +/- 0.005 ml.min-1.cmH2O-1.100 g-1). Inhibition of AO had no effect on I-R injury (Kf,c 0.108 +/- 0.011 to 0.167 +/- 0.014 ml.min-1.cmH2O-1.100 g-1). Preventing PMN adhesion resulted in significant attenuation of the change in Kf,c associated with I-R (0.112 +/- 0.032 to 0.090 +/- 0.065 ml.min-1.cmH2O-1.100 g-1). We conclude that XO and PMN adherence, but not AO, are involved in the increased capillary permeability associated with I-R.     

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.     

Indirect estimate of perimicrovascular pressure rise in edema in isolated zone 1 lung

To determine how liquid accumulation affects extra-alveolar perimicrovascular interstitial pressure, we measured filtration rate under zone 1 conditions (25 cmH2O alveolar pressure, 20 or 10 cmH2O vascular pressure) in isolated dog lung lobes in which all vessels were filled with autologous plasma. In the base-line condition, starting with normal extra-alveolar water content, filtration rate decreased by about one-half over 1 h as edema liquid slowly accumulated. We repeated each experiment after inducing edema (up to 100% lung weight gain). The absolute values and time course of filtration in the edema condition did not differ from base-line, i.e., the edema did not affect the time course of filtration. To compute the maximal initial and maximal change in extra-alveolar perimicrovascular pressure that occurred over each 1-h filtration study, we first assumed that the reflection coefficient is 0 in the Starling equation, then calculated perimicrovascular pressure and filtration coefficient from two equations with two unknowns. The mean filtration coefficient in 10 lobes is 0.063 g/(min X cmH2O X 100 g wet wt), and the initial perimicrovascular pressure is 3.9 cmH2O, rising by 4-7 cmH2O at 1 h. Finally we tested low protein perfusates and found the filtration rate was higher. We calculated an overall reflection coefficient = 0.44, a decrease in the initial perimicrovascular pressure to 1.9 cmH2O and a slightly lower increase after 1 h of edema formation, 2.2-6.6 cmH2O.     

Fluid filtration coefficient of isolated goat lungs was unchanged by endotoxin

The Starling fluid filtration coefficient (Kf) of blood-perfused excised goat lungs was examined before and after infusion of Escherichia coli endotoxin. Kf was calculated from rate of weight gain as described by Drake et al. [Am. J. Physiol. 234 (Heart Circ. Physiol. 3): H266-H274, 1978]. These calculations were made twice during base line and then at hourly intervals for 5 h after infusion of 5 mg (approximately 250 micrograms/kg) of E. coli endotoxin or after injection of oleic acid (47 microliter/kg). All lungs were perfused at constant arterial and venous pressure under zone 3 conditions. Base-line Kf averaged 27 +/- 10 and 20 +/- 4 (SD) microliter.min-1.cmH2O-1.g dry wt-1 for endotoxin and oleic acid groups, respectively. It was unchanged in the endotoxin group throughout the experiment but approximately doubled in the oleic acid lungs. Pulmonary arterial and venous pressures were not changed significantly during the course of these experiments in either group. Lung wet-to-dry weight ratios of these lungs were 5.6 +/- 0.6 and 6.1 +/- 0.5 ml/g for the endotoxin and oleic acid groups, respectively. This compares with 4.6 +/- 0.5 ml/g for normal, freshly excised but not perfused goat lungs. The small change in lung water and unchanged pulmonary pressures after both endotoxin and oleic acid suggest that lung injury was minimal. We conclude that 1) endotoxin does not cause a direct injury to the endothelium of isolated lungs during the first 5 h of perfusion, and 2) neutrophils are not sufficient to cause increased Kf after endotoxin infusion in this preparation.     

Leukotrienes C4 and D4 do not increase filtration coefficient of excised perfused guinea pig lungs

We tested the direct effects of leukotriene (LT) C4 or D4 on the pulmonary vascular fluid filtration coefficient (Kf) by adding these LT's to the cell-depleted perfusate of excised guinea pig lungs. Pulmonary arterial (Ppa) and airway (Paw) pressures were monitored, and left atrial pressure was kept constant during 10 min of constant-flow perfusion. Kf's were then calculated by two methods [Drake and colleagues (KfD), Am. J. Physiol. 234 (Heart Circ. Physiol. 3): H266-H274, 1978; and Goldberg (KfG), Am. J. Physiol. 239 (Heart Circ. Physiol. 8): H189-H198, 1980] from the change in lung weight resulting from a no-flow zone 3 hydrostatic stress applied for 20 min. With no LT's (Tyrode's buffer alone), the mean +/- SE Paw was 9.0 +/- 0.7 cmH2O and the Ppa was 14.2 +/- 1.1 cmH2O throughout the 10-min perfusion. The KfD and KfG were 1.239 +/- 0.169 and 1.586 +/- 0.223 ml X min-1 X mmHg-1 X 100 g lung-1, respectively. The mean +/- SE lung wet-to-dry ratio (W/D) after the 20-min hydrostatic stress was 16.7 +/- 1.6. Within 30-45 s of adding 4 micrograms of LTC4 or LTD4, Paw and Ppa both increased and remained elevated throughout the perfusion period. The KfD and KfG were 1.586 +/- 0.223 and 2.071 +/- 0.234 ml X min-1 X mmHg-1 X 100 g lung-1, respectively, and the W/D was 18.1 +/- 1.7 after LTC4 (all P greater than 0.4 compared with Tyrode's buffer alone) and 1.417 +/- 0.200 and 1.851 +/- 0.244 ml X min-1 X mmHg-1 X 100 g lung-1, respectively, with a W/D of 20.5 +/- 1.3 after LTD4 (all P greater than 0.4 compared with Tyrode's buffer alone).(ABSTRACT TRUNCATED AT 250 WORDS)