Pulmonary edema: ischemia reperfusion endothelial injury and its reversal by c-AMP.

A review of the factors that oppose pulmonary edema formation (alveolar flooding) when capillary pressure is elevated are presented for a normal capillary endothelial barrier and for damaged endothelium associated with ischemia/reperfusion in rabbit, rat, and dog lungs. Normally, tissue pressure, the plasma protein osmotic pressure gradient acting across the capillary wall and lymph flow (Edema Safety Factors) increase to prevent the build-up of fluid in the lung's interstitium when capillary pressure increases. No measureable alveolar edema fluid accumulates until capillary pressure exceeds 30 mmHg. When the capillary wall has been damaged, interstitial edema develops at lower capillary pressures because the plasma protein osmotic pressure will not change greatly to oppose capillary filtration, but lymph flow increases to very high levels to remove the increased filtrate and the result is that capillary pressures can increase to 20-25 mmHg before alveolar flooding results. In addition, the mechanisms responsible for producing pulmonary endothelial damage with ischemia/reperfusion are reviewed and the effects of O2 radical scavengers, neutrophil depletion or altering their adherence to the endothelium, and increasing cAMP on reversing the damage to the pulmonary endothelium is presented.     

Recommendations for using the standardized terminology of respiratory physiology in radiation research

A succinct review of the terminology and of correlations between basic quantities in respiration physiology is given with special regard to oxygen as the gas of topical interest in radiation research and tumor pathophysiology. The role of the oxygen partial pressure gradient as the driving force of O2 diffusion is emphasized. It is generally recommended that the O2 partial pressure be considered when investigating oxygen diffusion and distribution problems. During those studies the physical boundary conditions, in particular the temperature, the barometric pressure, and the water vapor saturation, have to be considered and should be indicated. During equilibration of suspensions containing oxygen-consuming sites the impact of geometry and fluid agitation on the efficiency of gas exchange has to be taken into account. Reviews on solutions of diffusion equations, on numerical data for relevant constants to be considered, and on terminology and units in respiration physiology are included.     

Effects of inspiratory resistance loading on lung fluid balance in awake sheep

Because pulmonary edema has been associated clinically with airway obstruction, we sought to determine whether decreased intrathoracic pressure, created by selective inspiratory obstruction, would affect lung fluid balance. We reasoned that if decreased intrathoracic pressure caused an increase in the transvascular hydrostatic pressure gradient, then lung lymph flow would increase and the lymph-to-plasma protein concentration ratio (L/P) would decrease. We performed experiments in six awake sheep with chronic lung lymph cannulas. After a base-line period, we added an inspiratory load (20 cmH2O) and allowed normal expiration at atmospheric pressure. Inspiratory loading was associated with a 12-cmH2O decrease in mean central airway pressure. Mean left atrial pressure fell 11 cmH2O, and mean pulmonary arterial pressure was unchanged; calculated microvascular pressure decreased 8 cmH2O. The changes that occurred in lung lymph were characteristic of those seen after other causes of increased transvascular hydrostatic gradient, such as increased intravascular pressure. Lung lymph flow increased twice base line, and L/P decreased. We conclude that inspiratory loading is associated with an increase in the pulmonary transvascular hydrostatic gradient, possibly by causing a greater fall in interstitial perimicrovascular pressure than in microvascular pressure.     

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)     

Evaluation of factors affecting relationship between transcutaneous PO2 and probe temperature

Several studies on transcutaneous O2 probes have shown that the transcutaneous PO2 increases to approximately 80% of the arterial PO2 when the probe is heated to 44 degrees C. It is not known whether this result reflects near-complete thermic arterialization or rather other factors such as the temperature-linked right shift of the hemoglobin O2-binding curve. In many clinical applications of transcutaneous probes the use of 44 degrees C is a major disadvantage because of the risk of skin burns. The development of new probes operating at lower temperatures is hampered by the lack of data on the temperature dependence of the factors influencing the relationship between the transcutaneous PO2 and the probe temperature. The present study attempts to estimate the temperature dependence of 1) the degree of arterialization of the blood in the skin capillaries, 2) the PO2 difference across the epidermis caused by the diffusion gradient and the epidermal O2 consumption, and 3) the arteriovenous saturation difference over the skin capillaries. The estimation is based on simultaneously measured transcutaneous PO2, PCO2, and argon partial pressure (PAr) values at seven different probe temperatures. The transcutaneous PCO2 is assumed equal to the mean capillary PCO2, which is used to calculate the mean capillary PO2 by the aid of a skin model. The O2 diffusion gradient is estimated from the transcutaneous PAr, and the PO2 difference caused by the epidermal O2 consumption is set equal to the difference between the mean capillary and transcutaneous PO2 less the partial pressure difference caused by the diffusion gradient. The degree of arterialization was found to be 53% at 38 degrees C and 65% at 44 degrees C. The partial pressure difference caused by the epidermal O2 consumption decreased from 33 Torr at 38 degrees C to 6 Torr at 44 degrees C. The PO2 difference across the epidermis caused by the diffusion gradient was 7 Torr at 38 degrees C and 5 Torr at 44 degrees C. The arteriovenous saturation difference fell from 31% at 38 degrees C to 12% at 44 degrees C.     

Measurement of bronchial arterial blood flow and bronchovascular resistance in sheep

We studied the bronchial arterial blood flow (Qbr) and bronchial vascular resistance (BVR) in sheep prepared with carotid-bronchial artery shunt. Nine adult sheep were anesthetized, and through a left thoracotomy a heparinized Teflon-tipped Silastic catheter was introduced into the bronchial artery. The other end of the catheter was brought out through the chest wall and through a neck incision was introduced into the carotid artery. A reservoir filled with warm heparinized blood was connected to this shunt. The height of blood column in the reservoir was kept constant at 150 cm by adding more blood. Qbr was measured, after interrupting the carotid-bronchial artery flow, by the changes in the reservoir volume. The bronchial arterial back pressure (Pbr) was measured through the shunt when both carotid-bronchial artery and reservoir Qbr had been temporarily interrupted. The mean Qbr was 34.1 +/- 2.9 (SE) ml/min, Pbr = 17.5 +/- 3.3 cmH2O, BVR = 3.9 +/- 0.5 cmH2O X ml-1 X min, mean pulmonary arterial pressure = 21.5 +/- 3.6 cmH2O, and pulmonary capillary wedge pressure (Ppcw) = 14.3 +/- 3.7 cmH2O. We further studied the effect of increased left atrial pressure on these parameters by inflating a balloon in the left atrium. The left atrial balloon inflation increased Ppcw to 25.3 +/- 3.1 cmH2O, Qbr decreased to 21.8 +/- 2.4 ml/min (P less than 0.05), and BVR increased to 5.5 +/- 1.0 cmH2O.ml-1.min (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

IL-2 induces pulmonary edema and vasoconstriction independent of circulating lymphocytes

We investigated the effect of IL-2 in the isolated guinea pig lung perfused with phosphate-buffered Ringer's solution (containing 0.5 g/100 ml albumin and 5.5 mM dextrose) to determine the mechanism of IL-2-induced pulmonary edema. IL-2 (0 to 10,000 U/ml) was added to the perfusate following a 10 min baseline steady-state period. Pulmonary arterial pressure (Ppa), pulmonary capillary pressure (Ppc), and change in lung weight (as a measure of developing pulmonary edema) were recorded at 0, 10, 30, 40, and 60 min. The capillary filtration coefficient (Kf.c), an index of vascular permeability to water, was measured at 30 and 60 min. Infusion of IL-2 increased Ppc (from 3.9 +/- 0.1 cm H2O at baseline to 8.8 +/- 1.1 cm H2O at 60 min for IL-2 at 2000 U/ml, p less than 0.01; and from 3.8 +/- 0.1 cm H2O at baseline to 8.9 +/- 0.6 cm H2O at 60 min for IL-2 at 10,000 U/ml, p less than 0.01. The lung weight also increased (32% at IL-2 concentration of 2000 U/ml, and 26% at IL-2 concentration of 10,000 U/ml) The capillary filtration coefficient did not change with IL-2 infusion. The IL-2 response was prevented using the pulmonary vasodilator, papaverine. The infusion of IL-2 was associated with the generation of thromboxane A2(TxA2) in the effluent perfusate. Inhibition of TxA2 synthetase using Dazoxiben prevented the pulmonary vasoconstriction and edema response to IL-2. In addition, IL-2 had no effect on the transendothelial clearance of 125I-albumin. The results indicate that IL-2 causes pulmonary edema secondary to an increase in Ppc. The response is mediated by IL-2 stimulation of TxA2 generation from the lung.     

Effects of altitude acclimatization on pulmonary gas exchange during exercise

Pulmonary gas exchange was studied in eight normal subjects both before and after 2 wk of altitude acclimatization at 3,800 m (12,470 ft, barometric pressure = 484 Torr). Respiratory and multiple inert gas tensions, ventilation, cardiac output (Q), and hemoglobin concentration were measured at rest and during three levels of constant-load cycle exercise during both normoxia [inspired PO2 (PIO2) = 148 Torr] and normobaric hypoxia (PIO2 = 91 Torr). After acclimatization, the measured alveolar-arterial PO2 difference (A-aPO2) for any given work rate decreased (P less than 0.02). The largest reductions were observed during the highest work rates and were 24.8 +/- 1.4 to 19.7 +/- 0.8 Torr (normoxia) and 22.0 +/- 1.1 to 19.4 +/- 0.7 Torr (hypoxia). This could not be explained by changes in ventilation-perfusion inequality or estimated O2 diffusing capacity, which were unaffected by acclimatization. However, Q for any given work rate was significantly decreased (P less than 0.001) after acclimatization. We suggest that the reduction in A-aPO2 after acclimatization is a result of more nearly complete alveolar/end-capillary diffusion equilibration on the basis of a longer pulmonary capillary transit time.     

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.     

A theoretical model for studying the rate of oxygenation of blood in pulmonary capillaries

A mathematical analysis of the process of gas exchange in the lung is presented taking into account the transport mechanisms of molecular diffusion, convection and facilitated diffusion of the species due to haemoglobin. Since the rate at which blood gets oxygenated in the pulmonary capillaries is very fast, it is difficult to set up an experimental study to determine the effects of various parameters on equilibration rate. The proposed study is aimed at determining the effects of various physiological parameters on equilibration rate in pathological conditions.Among the significant results are that 1. dissolved oxygen takes longer to achieve equilibration across the pulmonary membrane and carbon dioxide attains equilibration faster, 2. the equilibration length increases with increase in blood velocity, haemoglobin concentration, calibre of pulmonary capillaries and fall in alveolar PO₂, 3. the alveolar PCO₂ and forward and backward reaction rates of haemoglobin with CO₂ do not materially affect the equilibration rate or length. 4. At complete equilibration, by the end of the pulmonary capillary 92% of the total haemoglobin has combined with oxygen and 8% free pigment is left which is present as carbamino haemoglobin, met haemoglobin, carboxy haemoglobin etc.These results are of some importance for anaemic conditions, muscular exercise, meditation, altitude physiology, hypo-ventilation, hyperventilation, etc.Symbols H⁺ hydrogen ion - O₂ oxygen - CO₂ carbondioxide - HbO₂ oxyhaemoglobin - HbCO₂ carbaminohaemoglobin - PO₂ partial pressure of O₂ - PCO₂ partial pressure of CO₂ - PaO₂ O₂ tension in arterial blood - PaCO₂ CO₂ tension in arterial blood - k₁ forward rate constant for Eq. (1) - k₂ backward rate constant for Eq. (1) - m₁ forward rate constant for Eq. (2) - m₂ backward rate constant for Eq. (2) - k equilibration rate - a radius of the capillary - Q velocity of blood - L length of the capillary - D₀ diffusion coefficient of O₂ - D_c diffusion coefficient of CO₂ - D_H diffusion coefficient of Hb - H total haemoglobin concentration - A matrix - c₁ concentration of dissolved O₂ in blood - c₂ concentration of HbO₂ in blood - c₃ concentration of dissolved CO₂ in blood - c₄ concentration of HbCO₂ in blood - c₅ concentration of haemoglobin - c1alv concentration of O₂ in the alveolar region - c_3alv concentration of CO₂ in the alveolar region - c_iven concentration of the ith species in venous blood - c_iart concentrations of the ith species in arterial blood - F _is concentrations of the species in dimensionless form - J₀, I₀ Bessel's functions - P_alvO₂ tension of O₂ in alveolar region - P_alvCO₂ tension of CO₂ in alveolar region.     

Mechanism of peptidoleukotriene-induced increases in pulmonary transvascular fluid filtration

We examined the effects of leukotrienes C4 (LTC4) and D4 (LTD4) (1 microgram) on the pulmonary vascular filtration coefficient, a measure of vessel wall conductivity to water, and the alterations in pulmonary vascular resistance (PVR) in isolated-perfused guinea pig lungs. We also assessed whether LTC4 and LTD4 increased the permeability to albumin in cultured monolayers of pulmonary artery endothelial cells. In Ringer-perfused and blood-perfused lungs, LTC4 resulted in increases in pulmonary arterial pressure (Ppa) and the pulmonary capillary pressure (Pcap) measured as the equilibration pressure after simultaneous pulmonary arterial and venous occlusions. Pulmonary venous resistance (Rv) increased to a greater extent than arterial resistance (Ra) in both Ringer-perfused and blood-perused lungs challenged with LTC4. The greater increase in PVR in blood-perfused lungs corresponded with a greater elevation of lung effluent thromboxane B2 (TxB2) concentration. The LTC4-stimulated increase in PVR was prevented by pretreatment with meclofenamate (10(-4) M). LTD4 also induced rapid increases in Ppa and Pcap in both Ringer-perfused and blood-perfused lungs; however, Ppa decreased before stabilizing at a pressure higher than base line. The increases in Rv with LTD4 were greater than Ra. The LTD4-stimulated increases in Ra and Rv also paralleled the elevation in TxB2 concentration. As with LTC4, the increases in Ppa, Pcap, PVR, and TxB2 concentration were greater in blood-perfused than in Ringer-perfused lungs. Pretreatment with meclofenamate reduced the magnitude of the initial increase in Ppa, but did not prevent the response.(ABSTRACT TRUNCATED AT 250 WORDS)     

Physiological factors affecting O2 transport by hemoglobin in an in vitro capillary system

O2 transport was examined by measuring the fractional saturation of concentrated hemoglobin solutions flowing through an artificial capillary that was approximately 27 micron in diameter and embedded in a silicone rubber film approximately 170 micron thick. The effects of pH, hemoglobin concentration, O2 tension, temperature, and organic phosphate were measured and analyzed quantitatively by a rigorous mathematical model that included the geometry of the capillary in the silicone film, parabolic flow velocity distributions inside the lumen, and cooperative O2 binding by hemoglobin. The rates of both oxygenation and deoxygenation were limited by diffusion and governed by the magnitude of the O2 gradient between the intracapillary fluid phase and the external gas space. In uptake experiments, O2 flux is determined primarily by the external O2 tension (16-160 mmHg in our experiments) because the internal O2 pressure is kept small due to chemical combination with hemoglobin. In release experiments, the external O2 tension is maintained at zero, and the transport rate is determined by the intracapillary partial pressure of O2 that is proportional to the O2 half-saturation pressure of hemoglobin value of the hemoglobin sample. As a result, factors that change the affinity of hemoglobin for O2, such as pH, temperature, and organic phosphate concentration, influence strongly the rate of O2 release but have little effect on the rate of O2 uptake. These properties are physiologically advantageous, since a decrease in pH or an increase in temperature during exercise increases both the rate and extent of deoxygenation while not altering the kinetics of oxygenation.     

Carbon dioxide-oxygen relationships in gas exchange of animals. In memory of Hermann Rahn.

In external gas exchange of vertebrates, behavior of the respiratory gases CO2 and O2 can in many cases adequately be explained by the different physico-chemical properties of the gases, including solubility, chemical combination in blood and tissue, and diffusivity. In particular, the differences in behavior between CO2 and O2 are often of particular relevance. This is demonstrated on a number of examples of gas exchange mechanisms in vertebrates, including (1) exchange ratio after changes in ventilation, (2) local variations of pulmonary ventilation/perfusion ratio, (3) absorption of gas from gas pockets, (4) water vs. air breathing, (5) multimodal breathing, (6) skin breathing, (7) gas exchange of avian eggs, (8) anomalous gas/blood CO2 equilibration, (9) blood/gas CO2 equilibration in avian lungs, (10) pulmonary diffusing capacity, (11) blood/water CO2 equilibration in fish gills, (12) deposition of gas into fish swim bladder.     

A numerical model for studying the effect of plasma layer on the process of blood oxygenation in the pulmonary capillaries

A two layer model for the blood oxygenation in pulmonary capillaries is proposed. The model consists of a core of erythrocytes surrounded by a symmetrically placed plasma layer. The governing equations in the core describe the free molecular diffusion, convection, and facilitated diffusion due to the presence of haemoglobin. The corresponding equations in the plasma layer are based on the free molecular diffusion and the convective effect of the blood. According to the axial train model for the blood flow proposed by Whitmore (1967), the core will move with a uniform velocity whereas flow in the plasma layer will be fully developed. The resulting system of nonlinear partial differential equations is solved numerically. A fixed point iterative technique is used to deal with the nonlinearities. The distance traversed by the blood before getting fully oxygenated is computed. It is shown that the concentration of O2 increases continuously along the length of the capillary for a given ratio of core radius to capillary radius. It is found that the rate of oxygenation increases as the core to capillary ratio decreases. The equilibration length increases with a heterogeneous model in comparison to that in a homogeneous model. The effect of capillary diameters and core radii on the rate of oxygenation has also been examined.     

Ultrastructural appearances of pulmonary capillaries at high transmural pressures.

Electronmicroscopic appearances of pulmonary capillaries were studied in rabbit lungs perfused in situ when the capillary transmural pressure (Ptm) was systematically raised from 12.5 to 72.5 +/- 2.5 cmH2O. The animals were anesthetized and exsanguinated, and after the chest was opened, the pulmonary artery and left atrium were cannulated and attached to reservoirs. The lungs were perfused with autologous blood for 1 min, and this was followed by saline-dextran and then buffered glutaraldehyde to fix the lungs for electron microscopy. Normal appearances were seen at 12.5 cmH2O Ptm. At 52.5 and 72.5 cmH2O Ptm, striking discontinuities of the capillary endothelium and alveolar epithelium were seen. A few disruptions were seen at 32.5 cmH2O Ptm (mostly in one animal), but the number of breaks per millimeter cell lining increased markedly up to 72.5 cmH20 Ptm, where the mean frequency was 27.8 +/- 8.6 and 13.6 +/- 1.4 (SE) breaks/mm for endothelium and epithelium, respectively. In some instances, all layers of the blood-gas barrier were disrupted and erythrocytes could be seen moving into the alveolar spaces. In about half the endothelial and epithelial breaks, the basement membranes remained intact. The average break lengths for both endothelium and epithelium did not change significantly with pressure. The width of the blood-gas barrier increased at 52.5 and 72.5 cmH2O Ptm as a result of widening of the interstitium caused by edema. The cause of the disruptions is believed to be stress failure of the capillary wall. The results show that high capillary hydrostatic pressures cause major changes in the ultrastructure of the walls of the capillaries, leading to a high-permeability form of edema.     

Reference cardiopulmonary values in normal dogs

The purpose of this project was to collate canine cardiopulmonary measurements from published and unpublished studies in our laboratory in 97 instrumented, unsedated, normovolemic dogs. Body weight; arterial and mixed-venous pH and blood gases; mean arterial, pulmonary arterial, pulmonary artery occlusion, and central venous blood pressures; cardiac output; heart rate; hemoglobin; and core temperature were measured. Body surface area; bicarbonate concentration; base deficit; cardiac index; stroke volume index, systemic and pulmonary vascular resistance indices; left and right cardiac work indices; alveolar partial pressure of oxygen (pO2) ; alveolar-arterial pO2 gradient (A-apO2); arterial, mixed-venous, and pulmonary capillary oxygen content; oxygen delivery; oxygen consumption; oxygen extraction; venous admixture; arterial and mixed-venous blood CO2 contents; and CO2 production were calculated. In the 97 normal, resting dogs, mean arterial and mixed-venous pH were 7.38 and 7.36, respectively; partial pressure of carbon dioxide (pCO2), 40.2 and 44.1 mm Hg, respectively; base-deficit, -2.1 and -1.9 mEq/liter, respectively; pO2, 99.5 and 49.3 mm Hg, respectively; oxygen content, 17.8 and 14.2 ml/dl, respectively; A-a pO2 was 6.3 mm Hg; and venous admixture was 3.6%. The mean arterial blood pressure (ABPm), mean pulmonary arterial blood pressure (PAPm), pulmonary artery occlusion pressure (PAOP) were 103, 14, and 5.5 mm Hg, respectively; heart rate was 87 beats/min; cardiac index (CI) was 4.42 liters/min/m2; systemic and pulmonary vascular resistances were 1931 and 194 dynes.sec.cm-5, respectively; oxygen delivery, consumption and extraction were 790 and 164 ml/min/m2 and 20.5%, respectively. This study represents a collation of cardiopulmonary values obtained from a large number of dogs (97) from a single laboratory using the same measurement techniques.     

Microvascular pressure profile in intact in situ lung.

We measured the microvascular pressure profile in lungs physiologically expanded in the pleural space at functional residual capacity. In 29 anesthetized rabbits a caudal intercostal space was cleared of its external and internal muscles. A small area of endothoracic fascia was surgically thinned, exposing the parietal pleura through which pulmonary vessels were clearly detectable under stereomicroscopic view. Pulmonary microvascular pressure was measured with glass micropipettes connected to a servo-null system. During the pressure measurements the animal was kept apneic and 50% humidified oxygen was delivered in the trachea. Pulmonary arterial and left atrial pressures were 22.3 +/- 1.5 and 1.6 +/- 1.5 (SD) cmH2O, respectively. The segmental pulmonary vascular pressure drop expressed as a percentage of the pulmonary arterial to left atrial pressure was approximately 33% from pulmonary artery to approximately 130-microns-diam arterioles, 4.5% from approximately 130- to approximately 60-microns-diam arterioles, approximately 46% from approximately 60-microns-diam arterioles to approximately 30-microns-diam venules, approximately 9.5% from 30- to 150-microns-diam venules, and approximately 7% for the remaining venous segment. Pulmonary capillary pressure was estimated at approximately 9 cmH2O.     

Effect of hypoxia on permeability of pulmonary endothelium of canine visceral pleura

To determine if hypoxia increases the permeability of the pulmonary capillaries of the visceral pleura, water and protein movement across visceral pleura of isolated blood-perfused lungs ventilated with 20% O2-5% CO2 or 0% O2-5% CO2 was analyzed in terms of a two-compartment model of fluid exchange. Lungs from mongrel dogs were enclosed in a water-impermeable membrane, thereby creating an artificial visceral pleural space (VPS); fluid flux was determined as the filtration or reabsorption of water and protein in the VPS. Hypoxic vasoconstriction was prevented by adding verapamil to the perfusate. Hydrostatic pressures were continuously monitored and samples of perfusate and pleural fluid were obtained for protein determinations. Pulmonary capillary pressure was varied between 5 and 20 Torr by changing venous pressure while the protein concentration gradient was varied from 0.5 to 6.6 g/dl by introducing different solutions of plasma mixed with saline into the VPS. The hydraulic conductivity (Lp) increased from 4.25 +/- 0.74 to 9.18 +/- 0.67 X 10(-7) ml X s-1 X mmHg-1 X cm-2 and the diffusional permeability (Pd) of protein increased from 1.29 +/- 0.28 to 4.06 +/- 0.44 X 10(-6) cm/s under hypoxic conditions (P less than 0.05). Inhibition of xanthine oxidase by the addition of allopurinol (10 mg/kg body wt) to the perfusate prevented the increase in Lp and Pd observed under hypoxic conditions. We conclude that free radicals generated via xanthine oxidase may be responsible for the increased permeability observed during severe hypoxia.     

Mechanisms of extracellular reactive oxygen species injury to the pulmonary microvasculature.

We investigated the effect of xanthine (X) plus xanthine oxidase (XO) on pulmonary microvascular endothelial permeability in isolated rabbit lungs perfused with Krebs buffer containing bovine serum albumin (5 g/100 ml). Addition of five mU/ml XO and 500 microM X to the perfusate caused a twofold increase in the pulmonary capillary filtration coefficient (Kf,c) 30 min later without increasing the pulmonary capillary pressure. This increase was prevented by allopurinol or catalase but not by superoxide dismutase or dimethyl sulfoxide. Because these data implicated hydrogen peroxide (H2O2) as the injurious agent, we measured its concentration in the perfusate after the addition of X and XO for a 60-min interval. In the absence of lung tissue and albumin, H2O2 increased with time, reaching a concentration of approximately 250 microM by 60 min. If albumin (5 g/100 ml) was added to the perfusate, or in the presence of lung tissue, the corresponding values were 100 microM and less than 10 microM, respectively. To understand the mechanisms of H2O2 scavenging by lung tissue, we added a 250 microM bolus of H2O2 to the lung perfusate. We found that H2O2 was removed rapidly, with a half-life of 0.31 +/- 0.04 (SE) min. This variable was not increased significantly by inhibition of lung catalase activity with sodium azide or inhibition of the lung glutathione redox cycle with 1-chloro-2,4-dinitrobenzene. However, inhibition of both enzymatic systems increased the half-life of H2O2 removal to 0.71 +/- 0.09 (SE) min (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Pulmonary vascular changes following air embolism in the dog.

The effect of an intravenous injection of air in a dose of 1 ml/kg body weight was determined in 15 healthy mongrel dogs. In 4 control dogs the mean pulmonary artery pressure rose to 2-3 times the resting values at 30 seconds, and carbon monoxide diffusing capacity and pulmonary capillary blood volume decreased by half. In the animals pretreated either with heparin or with methysergide (antiserotonin group) the results were the same as in the control animals. In the vagotomized dogs, the rise in pulmonary artery pressure was not significant, and the decrease in pulmonary capillary blood volume was of lesser magnitude and shorter duration than in the control and the antiserotonin dogs. It is concluded that the intravenous injection of air in supine dogs causes a transient obstruction of small pulmonary arteries. Evidence is presented to implicate a vagal mechanism in both main aspects of the response, namely the pulmonary artery pressure rise, and the partial obstruction of the pulmonary capillary bed. These studies offer additional explanation of the symptoms of respiratory distress observed in rapid decompression.