Eicosanoid balance and perfusion redistribution of oleic acid-induced acute lung injury.

We have proposed that endogenous prostacyclin opposes the vasoconstriction responsible for redistribution of regional pulmonary blood flow (rPBF) away from areas of increased regional lung water concentration (rLWC) in canine oleic acid- (OA) induced acute lung injury (D. P. Schuster and J. Haller. J. Appl. Physiol. 69: 353-361, 1990). To test this hypothesis, we related regional lung tissue concentrations of 6-ketoprostaglandin (PG) F1 alpha and thromboxane (Tx) B2 in tissue samples obtained 2.5 h after administration of OA (0.08 ml/kg iv) to rPBF and rLWC measured by positron emission tomography. After OA only (n = 16), rLWC increased in dependent lung regions. Some animals responded to increased rLWC by redistribution of rPBF away from the most edematous regions (OA-R, n = 6), whereas others did not (OA-NR, n = 10). In another six animals, meclofenamate was administered after OA (OA-meclo). After OA, tissue concentrations of 6-keto-PGF1 alpha were greater than TxB2 in all groups, but concentrations of 6-keto-PGF1 alpha were not different between OA-R and OA-NR animals. TxB2 was increased in the dependent regions of animals in both OA-R and OA-NR groups compared with controls (no OA, n = 4, P < 0.05). The tissue TxB2/6-keto-PGF1 alpha ratio was smaller in controls and OA-NR in which no perfusion redistribution occurred than in OA-R and OA-meclo in which it did occur. This TxB2/6-keto-PGF1 alpha ratio correlated significantly with the magnitude of perfusion redistribution.(ABSTRACT TRUNCATED AT 250 WORDS)     

Assessment of temporal changes in pulmonary edema with NMR imaging

Nuclear magnetic resonance imaging (NMRI) parameters [longitudinal relaxation time (T1), transverse relaxation time (T2), and signal intensity] acquired at a magnetic field of 2.35 T were validated with a study of nine different phantom gel solutions. This technique was then applied to study 13 anesthetized supine cats, among which 10 had lung edema induced by oleic acid (0.075 ml/kg); the result was compared with postmortem analyses of lung water. Three animals (series A) were imaged until the edema was first visualized in NMRI, usually 15-20 min after oleic acid infusion. Another seven animals (series B) were imaged over 4-5 h. As lung water increased, so did the signal intensity. When edema first appeared, T1, T2, and the volume of the edematous region within the slice in the upper lobes showed no gravity-dependent differences; this was confirmed by postmortem measurements (series A) of lung water. With time, gravity-dependent regions displayed greater volumes of edematous regions and greater T1 values (P less than 0.01), suggesting a continued accumulation of lung water. In comparison, nondependent regions displayed constant volumes of edematous region and lesser T1 values (P less than 0.01), suggesting an increased protein concentration but no change in lung water. This study suggests the potential applicability of NMRI parameters in the assessment of pulmonary edema.     

Relationship between regional pulmonary edema and blood flow

We studied the effect of edema on the regional distribution of pulmonary blood flow in 12 anesthetized dogs. Two were controls, six had low-pressure pulmonary edema, and four had high-pressure pulmonary edema. All were ventilated with 100% O2. The physiological shunt fraction (Qs/QT), as an indicator of the degree of venous admixture, was determined by measuring the arterial and venous blood gases and the hemoglobin at different times during the experiment. Cardiac output (QT) was modestly increased by opening the femoral arteriovenous shunts. The initial regional blood flow (Qi) and final regional blood flow (Qf) were marked before and after the shunts were opened, using two differently labeled macroaggregates. The dogs were then killed, and the lungs were removed and sampled completely so that Qi and Qf and the amount of regional extravascular lung water (Wdl) in each regional sample could be measured (sample size: wet wt = 5.9 +/- 2.9 g, n = 833; Wdl ranged from 5.15 +/- 1.18 to 14.42 +/- 2.34 g). The data show that QS/QT increased as QT increased in the three conditions studied. However, there was no correlation between Wdl and Qi, Qf, or the relative change in regional blood flow. The data also show that gravity affects regional blood flow more than it affects regional edema. We conclude that the increased Qs/QT seen with increased pulmonary blood flow cannot be explained by a preferential increase of blood flow to the more edematous regions.     

Hypoxic pulmonary vasoconstriction does not affect hydrostatic pulmonary edema formation

We studied the effects of regional hypoxic pulmonary vasoconstriction (HPV) on lobar flow diversion in the presence of hydrostatic pulmonary edema. Ten anesthetized dogs with the left lower lobe (LLL) suspended in a net for continuous weighing were ventilated with a bronchial divider so the LLL could be ventilated with either 100% O2 or a hypoxic gas mixture (90% N2-5% CO2-5% O2). A balloon was inflated in the left atrium until hydrostatic pulmonary edema occurred, as evidenced by a continuous increase in LLL weight. Left lower lobe flow (QLLL) was measured by electromagnetic flow meter and cardiac output (QT) by thermal dilution. At a left atrial pressure of 30 +/- 5 mmHg, ventilation of the LLL with the hypoxic gas mixture caused QLLL/QT to decrease from 17 +/- 4 to 11 +/- 3% (P less than 0.05), pulmonary arterial pressure to increase from 35 +/- 5 to 37 +/- 6 mmHg (P less than 0.05), and no significant change in rate of LLL weight gain. Gravimetric confirmation of our results was provided by experiments in four animals where the LLL was ventilated with an hypoxic gas mixture for 2 h while the right lung was ventilated with 100% O2. In these animals there was no difference in bloodless lung water between the LLL and right lower lobe. We conclude that in the presence of left atrial pressures high enough to cause hydrostatic pulmonary edema, HPV causes significant flow diversion from an hypoxic lobe but the decrease in flow does not affect edema formation.     

Does indomethacin affect shunt and its response to PEEP in oleic acid pulmonary edema?

We assessed hemodynamics, lobar perfusion, and shunts at base line 1.5 h after unilobar oleic acid edema, 15 min after indomethacin (10 mg/kg iv), and 15 min after positive end-expiratory pressure (PEEP) (10 cm) in 10 dogs. In 10 additional dogs (control) the same measurements were made but no indomethacin was administered. Shunts of the edematous lobe were: 10.6 +/- 6.3, 54.1 +/- 22.8, 30.8 +/- 16.6, and 12.4 +/- 6.3% for dogs administered indomethacin and 10.9 +/- 4.2, 53.8 +/- 13.1, 72.3 +/- 14.6, and 11.5 +/- 4.1% for the controls. Perfusions (% cardiac output) to the edematous lobe were 27.6 +/- 3.6, 14.6 +/- 2.0, 9.9 +/- 1.5, and 27.9 +/- 2.9% in the dogs administered indomethacin and 27.3 +/- 3.1, 14.0 +/- 1.7, 13.2 +/- 1.3, and 26.9 +/- 2.8% in controls. The decrease in lobar perfusion was similar before indomethacin with a further decrease in lobar perfusion and an increase in lobar vascular resistance 15 min after indomethacin. The increase in vascular resistance of the edematous lobe was three times that of nonedematous lobes after indomethacin (149.6 +/- 76% vs. 58.0 +/- 43%). Indomethacin, therefore, decreases shunt possibly by enhancing alveolar hypoxic vasoconstriction and does not block the improvement in shunt with PEEP.     

Effect of PEEP and type of injury on thermal-dye estimation of pulmonary edema

We investigated the effect of positive end-expiratory pressure (PEEP) on the extravascular thermal volume of the lung (ETV) determined by the thermal-dye technique in three canine models of pulmonary edema created by injection of alpha-naphthylthiourea (ANTU) or oleic acid (OA) into the pulmonary circulation or intrabronchial instillation of hydrochloric acid (HCl). ETV was determined before, during, and after ventilation with 14 cmH2O PEEP, and final ETV was compared with the extravascular lung mass (ELM) determined postmortem. Final ETV correctly estimated ELM in 12 animals with ANTU injury, ETV/ELM = 1.04 +/- 0.13, but underestimated after HCl injury (n = 5), ETV/ELM = 0.61 +/- 0.23, and OA injury (n = 6), ETV/ELM = 0.73 +/- 0.19. Whereas PEEP had no consistent effect on extravascular thermal volume in ANTU edema, there was a reversible increase in ETV during PEEP in animals with HCl or OA injury and underestimation of ELM. The increase in ETV during PEEP averaged 9.3 +/- 3.8 ml/kg (62 +/- 42%) over the mean of the pre- and post-PEEP values after HCl injury (P less than 0.01) and 6.7 +/- 4.4 ml/kg (47 +/- 35%) after OA injury (P less than 0.02). There was an inverse correlation between the change in ETV during PEEP and the ETV/ELM ratio for animals with HCl and OA injury (r = -0.94). We conclude that PEEP produces a reversible increase in ETV in some models of lung injury by allowing for distribution of thermal indicator through a larger fraction of the lung water and that this response may be useful to detect underestimation when gravimetric measurements are not available.     

Endothelial injury and pulmonary congestion characterize neurogenic pulmonary edema in rabbits

The objectives of the present study were to determine whether an intracisternal injection of fibrinogen-sodium citrate, a model of neurogenic pulmonary edema (NPE), produces protein-rich or protein-poor pulmonary edema, and to determine whether the edema is associated with pulmonary vascular hypertension and pulmonary congestion. Fibrinogen (6-10 mg/ml) dissolved in 0.055 M sodium citrate was injected into the cisterna magna of six New Zealand White rabbits. Six additional rabbits were injected with saline to control for the effects of intracranial hypertension and pulmonary vascular hypertension. The fibrinogen-sodium citrate solution or sodium citrate alone, as opposed to saline, produced systemic and pulmonary vascular hypertension, pulmonary edema, hypoxemia, hypercapnia, and acidosis. The lungs from fibrinogen-injected rabbits were edematous, congested, and liverlike in appearance. Tracheal froth that was blood tinged and protein rich was present in five of the six rabbits. Microscopic examination of lung biopsies revealed erythrocytes and plasma in the alveoli and focal injury to the pulmonary microvascular endothelium. Fibrinogen-sodium citrate increased (P less than 0.05) the extravascular lung water (EVLW) (10.3 +/- 2.0 vs. 5.5 +/- 0.6 g, means +/- SE), lung blood weight (9.7 +/- 1.3 vs. 3.8 +/- 0.6 g), total dry lung weight (3.2 +/- 0.4 vs. 2.0 +/- 0.1 g), and the EVLW-to-blood-free dry lung weight ratio (7.0 +/- 0.8 vs. 4.0 +/- 0.3 g) from saline-control values. There was no difference in the blood-fre dry lung weight (1.4 +/- 0.1 vs. 1.3 +/- 0.1 g) between the two groups. These findings demonstrate that pulmonary congestion, pulmonary vascular hypertension, and focal endothelial injury contribute to the development of NPE.     

Effects of PEEP on pulmonary hemodynamics in intact dogs with oleic acid pulmonary edema

The effects of positive end-expiratory pressure (PEEP) on the pulmonary circulation were studied in 14 intact anesthetized dogs with oleic acid (OA) lung injury. Transmural (tm) mean pulmonary arterial pressure (Ppa)/cardiac index (Q) plots with transmural left atrial pressure (Pla) kept constant were constructed in seven dogs, and Ppa(tm)/PEEP plots with Q and Pla(tm) kept constant were constructed in seven other dogs. Q was manipulated by using a femoral arteriovenous bypass and a balloon catheter inserted in the inferior vena cava. Pla was manipulated using a balloon catheter placed by thoracotomy in the left atrium. Ppa(tm)/Q plots were essentially linear. Before OA, the linearly extrapolated pressure intercept of the Ppa(tm)/Q relationship approximated Pla(tm). OA (0.09 ml/kg into the right atrium) produced a parallel shift of the Ppa(tm)/Q relationship to higher pressures; i.e., the extrapolated pressure intercept increased while the slope was not modified. After OA, 4 Torr PEEP (5.4 cmH2O) had no effect on the Ppa(tm)/Q relationship and 10 Torr PEEP (13.6 cmH2O) produced a slight, not significant, upward shift of this relationship. Changing PEEP from 0 to 12 Torr (16.3 cmH2O) at constant Q before OA led to an almost linear increase of Ppa(tm) from 14 +/- 1 to 19 +/- 1 mmHg. After OA, Ppa(tm) increased at 0 Torr PEEP but changing PEEP from 0 to 12 Torr did not significantly affect Ppa(tm), which increased from 19 +/- 1 to 20 +/- 1 mmHg. These data suggest that moderate levels of PEEP minimally aggravate the pulmonary hypertension secondary to OA lung injury.     

Bronchial artery ligation modifies pulmonary edema after exposure to smoke with acrolein

Pulmonary edema can follow smoke inhalation and is believed to be due to the multiple chemical toxins in smoke, not the heat. We have developed a synthetic smoke composed of aerosolized charcoal particles to which one toxin at a time can be added to determine whether it produces pulmonary edema. Acrolein, a common component of smoke, when added to the synthetic smoke, produced a delayed-onset pulmonary edema in dogs in which the extravascular lung water (EVLW) as detected by a double-indicator technique began to rise after 42 +/- 2 (SE) min from 148 +/- 16 to 376 +/- 60 ml at 165 min after smoke exposure. The resulting pulmonary edema was widespread macroscopically but appeared focal microscopically with fibrin deposits in alveoli adjacent to small bronchi and bronchioles. Bronchial vessels were markedly dilated and congested. Monastral blue B when injected intravenously leaked into the walls of the bronchial vessels down to the region of the small bronchioles (less than or equal to 0.5 mm ID) of acrolein-smoke-exposed dogs but not into the pulmonary vessels. Furthermore, ligation of the bronchial arteries delayed the onset of pulmonary edema (87 +/- 3 min, P less than 0.05) and lessened the magnitude (232 +/- 30 ml, P less than 0.05) at 166 +/- 3 min after acrolein-smoke exposure.(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

Pulmonary blood flow distribution after lobar oleic acid injury: a PET study

We evaluated the importance of hypoxic vasoconstriction as a mechanism for pulmonary blood flow reduction during unilobar oleic acid lung injury in dogs. Pulmonary blood flow (PBF) and lung water were measured with positron emission tomography. Data from the injured left (LCL) and right (RCL) caudal lobes were compared in 23 dogs. Six dogs were used to demonstrate that endotoxin (15 micrograms/kg) prevents changes in regional PBF during selective hypoxic ventilation of the LCL. In 17 dogs, oleic acid (OA, 0.015 ml/kg) was injected into the LCL through a balloon-wedged pulmonary arterial catheter. Five dogs received OA only (control group), eight received endotoxin (15 mcg/kg) before OA was administered (endotoxin group), and four were treated with prostaglandin E1 (PGE1) after OA (PGE1 group). The base-line left-to-right PBF ratio (LCL/RCL PBF) was 1.01 +/- 0.11 (SD) for the control group and 1.07 +/- 0.16 for the PGE1 group. One minute after OA, LCL/RCL PBF feel significantly (0.32 +/- 0.15 and 0.32 +/- 0.13 for the control and PGE1 groups, respectively) before any significant increase in lung water was detected. In all 17 dogs that received OA, the LCL/RCL PBF remained severely reduced 60 min after OA compared with base-line values (0.41 +/- 0.15, 0.49 +/- 0.06, and 0.26 +/- 0.13 for the control, PGF1, and endotoxin groups, respectively) despite treatment with endotoxin or PGE1. Lung water measurements obtained 60 min after OA increased significantly (P less than 0.05) in the injured lobe (LCL) but not in the normal lobe (RCL) in all dog groups, whereas PBF to the LCL remained significantly reduced.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of nonideal input functions on PET measurements of pulmonary blood flow.

Regional pulmonary blood flow (rPBF) can be measured with an intravenous infusion of 15O-labeled water and positron emission tomography (PET). The current method depends on two assumptions related to the input of activity to the lung during the scan: 1) the pulmonary arterial tracer input is constant (i.e., a "step function" in shape), and 2) the scan begins at the instant of arrival of the step function. To determine the effect that departures from these assumptions might have on the measurement of rPBF, we performed a series of mathematical simulations for three different input functions: 1) a step function that arrived either 1 or 2 s before or after scan start; 2) a dispersed input function, with activity rising during the scan period; and 3) a combination of these two errors. Calculated values, based on the standard assumptions, were compared against the "known" values used in generating the simulated data. The results show that timing errors associated with starting the scan late cause an overestimation of rPBF, whereas timing errors due to low regional flow or departures from the assumed step input function both cause an underestimation of true rPBF. Thus, in actual practice, the combined errors probably partially offset one another. Except for states of truly high rPBF and low lung density, the errors remain less than 15% of the true value. We conclude that PET measurements of rPBF are not highly sensitive to these presumably common departures from the assumed pulmonary arterial input function to lung regions of interest.     

Leukotriene inhibitors do not block hypoxic pulmonary vasoconstriction in dogs

We studied whether intravenously administered inhibitors of leukotriene synthesis (diethylcarbamazine, DEC) or end-organ effect (FPL-55712) would change the distribution of regional pulmonary blood flow (rPBF) caused by left lower lobe (LLL) alveolar hypoxia in dogs. Both drugs failed to alter rPBF. In addition, the pressor response to whole-lung hypoxia was not blocked by an FPL-55712 infusion. On the other hand, nitroprusside, as a nonspecific vasodilator also administered intravenously, was able to partially reverse the effects of LLL hypoxia on rPBF. Thus our data do not support a role for leukotriene mediation of hypoxic pulmonary vasoconstriction in dogs.     

Neutrophils in reexpansion pulmonary edema

This study investigated the possible contribution of neutrophils to development of reexpansion pulmonary edema (RPE) in rabbits. Rabbits' right lungs were collapsed for 7 days and then reexpanded with negative intrathoracic pressure for 2 h before study, a model that creates unilateral edema in the reexpanded lungs but not in contralateral left lungs. Two hours after lung reexpansion, significant increases in lavage albumin concentration (17-fold), percent neutrophils (14-fold), and total number of neutrophils (7-fold) recovered occurred in the reexpanded lung but not in the left. After 2 h of reexpansion increased leukotriene B4 was detected in lavage supernatant from right lungs (335 +/- 33 pg/ml) compared with the left (110 +/- 12 pg/mg, P less than 0.01), and right lung lavage acid phosphatase activity similarly increased (6.67 +/- 0.35 U/l) compared with left (4.73 +/- 0.60 U/l, P less than 0.05). Neutropenia induced by nitrogen mustard (17 +/- 14 greater than neutrophils/microliters) did not prevent RPE, because reexpanded lungs from six neutropenic rabbits were edematous (wet-to-dry lung weight ratio 6.34 +/- 0.43) compared with their contralateral lungs (4.97 +/- 0.04, P less than 0.01). An elevated albumin concentration in reexpanded lung lavage from neutropenic rabbits (8-fold) confirmed an increase in permeability. Neutrophil depletion before reexpansion did not prevent unilateral edema, although neutrophils were absent from lung sections and alveolar lavage fluid from neutropenic rabbits.     

Thromboxane A2 and prostacyclin do not modulate pulmonary hemodynamics during exercise in sheep

The purpose of this study was to determine the role of thromboxane and prostacyclin in modulating pulmonary hemodynamics during maximal cardiopulmonary stress in the healthy lung. We studied 11 yearling sheep in paired studies during progressive maximal treadmill exercise with and without meclofenamate (n = 5), ibuprofen (n = 6), or UK38485 (n = 2). We also studied five sheep during hypoxia and hypoxic exercise, and six sheep during prolonged steady-state treadmill exercise for 45-60 min with and without drug treatment. We measured the metabolites of thromboxane A2 (thromboxane B2, TxB2) and prostacyclin (6-ketoprostaglandin F1 alpha, 6-keto-PGF1 alpha) in blood plasma and lung lymph in each protocol. We found that progressive exercise significantly reduced pulmonary vascular resistance but that cyclooxygenase or thromboxane synthesis blockade did not alter the change. Plasma TxB2 rose minimally but significantly during maximal exercise, but 6-keto-PGF1 alpha did not change. During continuous hypoxia, exercise reduced pulmonary vascular resistance nearly to base-line levels, but the degree of reduction was also unchanged by drug treatment. There were also no significant changes in lymph or plasma TxB2 or 6-keto-PGF1 alpha during 45-60 min of continuous moderate exercise. We conclude that neither TxB2 nor prostacyclin modulate pulmonary hemodynamics in the normal lung during maximal exercise, prolonged moderate exercise, or exercise-induced reductions in vascular resistance during hypoxia.     

"Closing volume" changes in alloxan-induced pulmonary edema in anesthetized dogs.

"Closing volume" (CV) was measured by the single-breath oxygen (SBO2) test in six dogs (alloxan group) before and after alloxan 100-200 mg/kg iv) was injected. CV increased significantly (P less than 0.05) from 32 +/- 3.2% (base line) to 45 +/- 3.5 % in period 1 (0-30 min after alloxan), but vital capacity (VC), respiratory system pressure volume (PV) curves, and alveolar plateau slopes did not change. No radiologic evidence of pulmonary edema was demonstrated in two dogs studied in period 1. CV decreased to 20 +/- 3.9% during period 2 (30-80 min after alloxan) and was associated with tracheal frothing, decreased VC, changes in the PV curve, and alveolar plateau slope, as well as histologic evidence of severe pulmonary edema. CV was 29 +/- 3.0%, and there were no changes in VC, PV curves, or alveolar plateau slopes in 6 other dogs studied for 2 h (control group). CV increased during period 1 before pulmonary edema could be demonstrated by changes in VC, PV curves, or radiography, but in period 2 lung function was so altered that CV by the SBO2 technique gave no useful information.     

Endotoxin increases pulmonary vascular protein permeability in the dog

Endotoxin increases pulmonary vascular permeability consistently in some species but fails to reliably cause injury in the dog. We wondered whether this phenomenon depended on the method of injury assessment, as others have relied on edema measurement; we quantified injury by monitoring the rate of extravascular protein accumulation. 113mIn-labeled protein and 99mTc-labeled erythrocytes were injected into anesthetized dogs and monitored by an externally placed lung probe. A protein leak index, the rate of extravascular protein accumulation, was derived from the rate of increase in lung protein counts corrected for changes in intravascular protein activity. After administration of Salmonella enteriditis endotoxin (4 micrograms/kg), the protein leak index was elevated 2.5-fold (41.1 +/- 4.6 X 10(-4) min-1) compared with control (16.0 +/- 2.8 X 10(-4) min-1). In contrast, wet-to-dry weight ratios failed to increase after endotoxin (4.6 +/- 0.8 vs. control values of 4.2 +/- 0.5 g/g dry bloodless lung). However, we observed that endotoxin increased lung dry weight (per unit body weight), which may have attenuated the change in wet-to-dry weight ratios. To determine whether low microvascular pressures following endotoxin attenuated edema formation, we increased pulmonary arterial wedge pressures in five dogs by saline infusion, which caused an increase in wet-to-dry weight ratios following endotoxin but no change in the five controls. We conclude that low dose endotoxin causes pulmonary vascular protein leak in the dog while edema formation is minimal or absent.     

Regional extravascular density of the lung in patients with acute pulmonary edema

The regional distribution of extravascular lung density (lung tissue and interstitial or alveolar fluid per unit thoracic volume) and fractional pulmonary blood volume (volume of blood per unit thoracic volume) was measured in five patients with acute interstitial pulmonary edema and two patients with acute alveolar edema. We found a uniform increase in extravascular lung density in the patients with acute interstitial edema but a preferentially dependent distribution in the patients with alveolar edema. Fractional blood volume had an abnormally uniform distribution in patients with interstitial edema. In alveolar edema, there was marked redistribution of blood volume away from severely edematous regions. The results are in agreement with previous experimental work with animal models. The distribution of extravascular lung density and fractional blood volume in subjects with acute interstitial edema is, however, different from that found in subjects with chronic interstitial edema, suggesting that the pathophysiological characteristics of the two conditions may be different.     

Histamine-induced pulmonary edema distal to pulmonary arterial occlusion

Histological studies provide evidence that the bronchial veins are a site of leakage in histamine-induced pulmonary edema, but the physiological importance of this finding is not known. To determine if a lung perfused by only the bronchial arteries could develop pulmonary edema, we infused histamine for 2 h in anesthetized sheep with no pulmonary arterial blood flow to the right lung. In control sheep the postmortem extravascular lung water volume (EVLW) in both the right (occluded) and left (perfused) lung was 3.7 +/- 0.4 ml X g dry lung wt-1. Following histamine infusion, EVLW increased to 4.4 +/- 0.7 ml X g dry lung wt-1 in the right (occluded) lung (P less than 0.01) and to 5.3 +/- 1.0 ml X g dry wt-1 in the left (perfused) lung (P less than 0.01). Biopsies from the right (occluded) lungs scored for the presence of edema showed a significantly higher score in the lungs that received histamine (P less than 0.02). Some leakage from the pulmonary circulation of the right lung, perfused via anastomoses from the bronchial circulation, cannot be excluded but should be modest considering the low pressures in the pulmonary circulation following occlusion of the right pulmonary artery. These data show that perfusion via the pulmonary arteries is not a requirement for the production of histamine-induced pulmonary edema.     

OKY-046 prevents increases in LTB4 and pulmonary edema in phorbol ester-induced lung injury in dogs.

Thromboxanes (Txs) were implicated as possible participants in the altered microvascular permeability of acute lung injury when the Tx synthase inhibitor, OKY-046, was reported to prevent pulmonary edema induced by phorbol myristate acetate (PMA). Recently, however, we found that OKY-046, at a dose just sufficient to block Tx synthesis in intact dogs, did not prevent PMA-induced pulmonary edema but rather merely reduced it modestly. The present study was designed to explore other mechanisms whereby OKY-046 might prevent PMA-induced pulmonary edema. The finding that 5-lipoxygenase (5-LO) metabolites of arachidonic acid were increased within the lung after PMA administration, coupled with the report that OKY-046 inhibited slow-reacting substance of anaphylaxis formation, permitted formulation of the hypothesis that OKY-046, at a dose in excess of that required to inhibit Tx synthesis, inhibits the formation of a product(s) of 5-LO and, thereby, prevents edema formation. In vehicle-pretreated pentobarbital-anesthetized male mongrel dogs (n = 4), PMA (20 micrograms/kg i.v.) increased pulmonary vascular resistance (PVR) from 4.4 +/- 0.3 to 26.3 +/- 8.8 mmHg.l-1 x min (P < 0.01) and extravascular lung water from 6.7 +/- 0.5 to 19.1 +/- 6.2 ml/kg body wt (P < 0.05). Concomitantly, both TxB2 and leukotriene B4 (LTB4) were significantly increased in the lung. Pretreatment with OKY-046 (100 mg/kg i.v., n = 8) prevented PMA-induced increases in TxB2, LTB4, and pulmonary edema formation but did not prevent the increase in PVR.(ABSTRACT TRUNCATED AT 250 WORDS)