Protective effect of lung inflation in reperfusion-induced lung microvascular injury

We used the isolated-perfused rat lung model to study the influence of pulmonary ventilation and surfactant instillation on the development of postreperfusion lung microvascular injury. We hypothesized that the state of lung inflation during ischemia contributes to the development of the injury during reperfusion. Pulmonary microvascular injury was assessed by continuously monitoring the wet lung weight and measuring the vessel wall (125)I-labeled albumin ((125)I-albumin) permeability-surface area product (PS). Sprague-Dawley rats (n = 24) were divided into one control group and five experimental groups (n = 4 rats per group). Control lungs were continuously ventilated with 20% O(2) and perfused for 120 min. All lung preparations were ventilated with 20% O(2) before the ischemia period and during the reperfusion period. The various groups differed only in the ventilatory gas mixtures used during the flow cessation: group I, ventilated with 20% O(2); group II, ventilated with 100% N(2); group III, lungs remained collapsed and unventilated; group IV, same as group III but pretreated with surfactant (4 ml/kg) instilled into the airway; and group V, same as group III but saline (4 ml/kg) was instilled into the airway. Control lungs remained isogravimetric with baseline (125)I-albumin PS value of 4.9 +/- 0.3 x 10(-3) ml x min(-1) x g wet lung wt(-1). Lung wet weight in group III increased by 1.45 +/- 0.35 g and albumin PS increased to 17.7 +/- 2.3 x 10(-3), indicating development of vascular injury during the reperfusion period. Lung wet weight and albumin PS did not increase in groups I and II, indicating that ventilation by either 20% O(2) or 100% N(2) prevented vascular injury. Pretreatment of collapsed lungs with surfactant before cessation of flow also prevented the vascular injury, whereas pretreatment with saline vehicle had no effect. These results indicate that the state of lung inflation during ischemia (irrespective of gas mixture used) and supplementation of surfactant prevent reperfusion-induced lung microvascular injury.     

Alterations of nitric oxide synthase expression and activity during rat lung transplantation

Decreased nitric oxide (NO) production has been reported during lung transplantation in patients. To study the effects of ischemia and reperfusion on endogenous NO synthase (NOS) expression, both an ex vivo and an in vivo lung injury model for transplantation were used. Donor rat lungs were flushed with cold low-potassium dextran solution and subjected to either cold (4 degrees C for 12 h) or warm (21 degrees C for 4 h) ischemic preservation followed by reperfusion with an ex vivo model. A significant increase in inducible NOS and a decrease in endothelial NOS mRNA was found after reperfusion. These results were confirmed in a rat single-lung transplant model after warm preservation. Interestingly, protein contents of both inducible NOS and endothelial NOS increased in the transplanted lung after 2 h of reperfusion. However, the total activity of NOS in the transplanted lungs remained at very low levels. We conclude that ischemic lung preservation and reperfusion result in altered NOS gene and protein expression with inhibited NOS activity, which may contribute to the injury of lung transplants.     

Increase in alveolar antioxidant levels in hyperoxic and anoxic ventilated rabbit lungs during ischemia

Increases in free radicals are believed to play a central role in the development of pulmonary ischemia/reperfusion (I-R) injury, leading to microvascular leakage and deterioration of pulmonary surfactant. Continued ventilation during ischemia offers significant protection against I-R injury, but the impact of alveolar oxygen supply both on lung injury and on radical generation is still unclear. We investigated the influence of hyperoxic (95% O2) and anoxic (0% O2) ventilation during ischemia on alveolar antioxidant status and surfactant properties in isolated rabbit lungs. Normoxic and hyperoxic ventilated, buffer-perfused lungs (n = 5 or 6) and native lungs (n = 6) served as controls. As compared with controls, biophysical and biochemical surfactant properties were not altered in anoxic as well as hyperoxic ventilated ischemic (2, 3, and 4 h) lungs. Assessment of several antioxidants (reduced glutathione (GSH), alpha-tocopherol (vitamin E), retinol (vitamin A), ascorbic acid (vitamin C), uric acid, and plasmalogens (1-O-alkenyl-2-acyl-phospholipids)) in bronchoalveolar lavage fluid (BALF) revealed a significant increase in antioxidant compounds under anoxic and hyperoxic ventilation, with maximum levels occuring after 3 h of ischemia. For example, GSH increased to 5.1 +/- 0.8 microM (mean +/- SE, p <.001) after 3 h of anoxic ventilated ischemia and to 2.7 +/- 0.2 microM (p <.01) after hyperoxic ventilated ischemia compared with native controls (1.3 +/- 0.2 microM), but did not significantly change under anoxic and hyperoxic ventilation alone. In parallel, under ischemic conditions, oxidized glutathione (GSSG) increased during hyperoxic (3 h: 0.81 +/- 0.04 microM, p <.001), but remained unchanged during anoxic (3 h: 0.31 +/- 0.04 microM) ventilation compared with native controls (0.22 +/- 0.02 microM), whereas F2-isoprostanes were elevated under both hyperoxic (3 h: 63 +/- 15 pM, p <.01) and anoxic (3 h: 50 +/- 9 pM, p <.01) ventilation compared with native controls (16 +/- 4 pM). We conclude that oxidative stress is increased in the lung alveolar lining layer during ischemia, during both anoxic and hyperoxic ventilation. This is paralleled by an increase rather than a decrease in alveolar antioxidant levels, suggested to reflect an adaptive response to oxidative stress during ischemia.     

Oxygen-dependent reperfusion injury in the isolated rat lung.

To further define the relationship between oxygen dependence of lung injury during ischemia and ischemia-reperfusion, we used the isolated, perfused, and ventilated rat lung model, so that oxygenation and perfusion could be separated. During ischemia, lungs were ventilated with various oxygen concentrations and then ventilated with 95% oxygen during the 60-min reperfusion period. Other lungs were ventilated with 0% oxygen (nitrogen) during ischemia, and the reperfusion phase oxygen concentration was varied. Tissue and perfusate lipid peroxidation products (thiobarbituric acid-reactive substances and conjugated dienes), dry-to-wet weight ratio, and lactate dehydrogenase were measured as indexes of lung damage. In addition, electron microscopy of some lungs was performed. Results demonstrate an oxygen dependence of lipid peroxidation in both the ischemic and reperfusion phases, but lipid peroxidation is severalfold greater in the reperfusion than in the ischemic phase. Products of lipid peroxidation closely correlate with indexes of lung injury (dry-to-wet weight ratio, lactate dehydrogenase, and electron microscopy).     

O2 radicals mediate reperfusion lung injury in ischemic O2-ventilated canine pulmonary lobe

This study was undertaken to determine whether lung injury after a period of ischemia reperfusion is caused by O2 ventilation during ischemia and whether this injury is mediated by reactive O2 metabolites. Isolated canine left lower pulmonary lobes were subjected to room temperature ischemia for 6 h while being ventilated with either 100% O2, room air, or 100% N2. After the ischemic period, all lobes were perfused with autologous blood and ventilated with 100% O2 for an additional 4 h. In lobes ventilated with 100% O2 during the ischemic period, massive weight gain (228%) occurred 4 h after reperfusion. A marked increase in pulmonary shunt was noted. Lobes ventilated with room air behaved similarly. In contrast, lobes ventilated with 100% N2 gained significantly less weight (54%) and did not manifest any increase in pulmonary shunt. When lobes ventilated with 100% O2 or room air were pretreated with superoxide dismutase (SOD), the injury was significantly reduced. Pressure-volume deflation study of lobes, after ischemia only, demonstrated that ventilation with 100% O2 and with 100% N2 both equally decreased pulmonary compliance. We conclude that lung ischemia-reperfusion injury is related to O2 ventilation during ischemia and that injury can be prevented by administration of SOD or ventilation with 100% N2. This suggests that the injury is related to O2 metabolites produced during O2 ventilation in the absence of the circulation.     

Inhibition of inducible nitric oxide synthase attenuates platelet adhesion in subpleural arterioles caused by lung ischemia-reperfusion in rabbits.

Oxidative stress, induced by lung ischemia-reperfusion, leads to platelet and leukocyte activation and may contribute to decreased alveolar perfusion by platelet adhesion to the arteriolar wall. We investigated the hypothesis that ischemia-reperfusion injury increases inducible nitric oxide synthase (iNOS) activity and subsequent generation of reactive nitrogen species with P-selectin-dependent platelet-endothelial interactions and vasoconstriction during lung reperfusion. Subpleural arterioles, labeled platelets, and leukocytes were examined in anesthetized, open-chest rabbits by intravital fluorescence microscopy. Ischemia was caused by reversible occlusion of the right pulmonary artery for 1 or 2 h (1IR and 2IR groups). During 2 h of reperfusion, postischemic platelet rolling and adhesion were independent from leukocyte-arteriolar wall interactions and correlated with pulmonary arteriolar constriction in proportion to the length of ischemia. In rabbits treated with an iNOS inhibitor (1400W) before occlusion (2IR + 1400W group), platelet-arteriolar wall interactions and vasoconstriction were prevented. iNOS expression and activity in ischemic lung tissue were markedly greater than control and also were proportional to ischemia duration. NOS activity, immunochemically detected P-selectin, and nitrotyrosine expression in ischemic lung tissue from animals subjected to ischemia-reperfusion, as well as the plasma level of soluble P-selectin, were significantly higher than in nonischemic lungs and were inhibited by pretreatment with 1400W. These results show that platelet adhesion and arteriolar constriction during early reperfusion in the ventilated lung can result from increased iNOS activity and is highly correlated with reactive nitrogen species and P-selectin expression.     

Separate effects of ischemia and reperfusion on vascular permeability in ventilated ferret lungs.

In systemic organs, ischemia-reperfusion injury is thought to occur during reperfusion, when oxygen is reintroduced to hypoxic ischemic tissue. In contrast, the ventilated lung may be more susceptible to injury during ischemia, before reperfusion, because oxygen tension will be high during ischemia and decrease with reperfusion. To evaluate this possibility, we compared the effects of hyperoxic ischemia alone and hyperoxic ischemia with normoxic reperfusion on vascular permeability in isolated ferret lungs. Permeability was estimated by measurement of filtration coefficient (Kf) and osmotic reflection coefficient for albumin (sigma alb), using methods that did not require reperfusion to make these measurements. Kf and sigma alb in control lungs (n = 5), which were ventilated with 14% O2-5% CO2 after minimal (15 +/- 1 min) ischemia, averaged 0.033 +/- 0.004 g.min-1.mmHg-1.100 g-1 and 0.69 +/- 0.07, respectively. These values did not differ from those reported in normal in vivo lungs of other species. The effects of short (54 +/- 9 min, n = 10) and long (180 min, n = 7) ischemia were evaluated in lungs ventilated with 95% O2-5% CO2. Kf and sigma alb did not change after short ischemia (Kf = 0.051 +/- 0.006 g.min-1.mmHg-1.100 g-1, sigma alb = 0.69 +/- 0.07) but increased significantly after long ischemia (Kf = 0.233 +/- 0.049 g.min-1 x mmHg-1 x 100 g-1, sigma alb = 0.36 +/- 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Fullerene derivative attenuates ischemia-reperfusion-induced lung injury

Reactive oxygen species are the major contributing factors to lung ischemia-reperfusion (IR) injury. In this study, we tested whether a water soluble antioxidant fullerene derivative [C(60)(ONO(2))(7 +/- 2)] attenuates IR lung injury. Young Wistar rats were divided into two groups: control and C(60)(ONO(2))(7 +/- 2). Under ventilation with 95% air-5% CO(2) gas mixture and a 2.5 cm H(2)O end-expiratory pressure, the isolated lungs were perfused with a physiological solution. The experimental protocol included three periods: baseline (10 min), ischemia (45 min) and reperfusion (60 min, ventilated with 95% O(2)-5% CO(2) gas mixture). Before and after ischemia, we measured pulmonary arterial pressure (Ppa), pulmonary venous pressure and lung weight (W). Then, pulmonary capillary pressure and filtration coefficient (K(fc)) were calculated. Ischemia caused increases in Ppa, W and K(fc) in the control group. For most cases, the above ischemia-induced increases were attenuated by the C(60)(ONO(2))(7 +/- 2) pretreatment. Our results suggest that the antioxidant C(60)(ONO(2))(7 +/- 2) attenuates IR-induced lung injury.     

Expression of SP-C and Ki67 in lungs of preterm infants dying from respiratory distress syndrome

This study aimed at exploring the expression of Surfactant protein-C (SP-C) and Ki67 in autopsy lung tissues of premature infants dying from respiratory distress syndrome (RDS) who were exposed to mechanical ventilation and elevated oxygen concentrations. The possible influence of pulmonary surfactant (PS) on the expression of SP-C and Ki67 was also investigated. Thirty preterm infants were selected who were histologically and clinically diagnosed as RDS. Preterm infants with RDS were divided into 4 groups, according to the time of death: infants ventilated for 1–3 days, 4–8 days, 9–16 days and >6 days. Five premature infants died within 1 day after delivery for non- pulmonary reasons served as controls. The expression of SP-C and Ki67 in lungs was detected by immunohistochemistry. Compared with the control group, the expression of SP-C and Ki67 in RDS infants decreased significantly after 1–3 days of ventilation, but increased after 4 days and reached peak value after 9–16 days. No significant difference in the expression of SP-C and Ki67 was found between infants treated with PS and those without. Thus our results suggest SP-C and Ki67 may have participated in the pulmonary pathological process in ventilated/oxygen treated preterm infants with RDS, and exogenous surfactant had no effect on the expression of SP-C and Ki67 in the lungs of ventilated/oxygen treated preterm infants with RDS.Key words: respiratory distress syndrome, surfactant protein-C, Ki67, preterm.     

High tidal volume ventilation induces NOS2 and impairs cAMP- dependent air space fluid clearance

Tidal volume reduction during mechanical ventilation reduces mortality in patients with acute lung injury and the acute respiratory distress syndrome. To determine the mechanisms underlying the protective effect of low tidal volume ventilation, we studied the time course and reversibility of ventilator-induced changes in permeability and distal air space edema fluid clearance in a rat model of ventilator-induced lung injury. Anesthetized rats were ventilated with a high tidal volume (30 ml/kg) or with a high tidal volume followed by ventilation with a low tidal volume of 6 ml/kg. Endothelial and epithelial protein permeability were significantly increased after high tidal volume ventilation but returned to baseline levels when tidal volume was reduced. The basal distal air space fluid clearance (AFC) rate decreased by 43% (P < 0.05) after 1 h of high tidal volume but returned to the preventilation rate 2 h after tidal volume was reduced. Not all of the effects of high tidal volume ventilation were reversible. The cAMP-dependent AFC rate after 1 h of 30 ml/kg ventilation was significantly reduced and was not restored when tidal volume was reduced. High tidal volume ventilation also increased lung inducible nitric oxide synthase (NOS2) expression and air space total nitrite at 3 h. Inhibition of NOS2 activity preserved cAMP-dependent AFC. Because air space edema fluid inactivates surfactant and reduces ventilated lung volume, the reduction of cAMP-dependent AFC by reactive nitrogen species may be an important mechanism of clinical ventilator-associated lung injury.     

Resistance of isolated pulmonary mitochondria during in vitro anoxia/reoxygenation

The aim of the study was to investigate the effect of in vitro anoxia/reoxygenation on the oxidative phosphorylation of isolated lung mitochondria. Mitochondria were isolated after harvesting from fresh pig lungs flushed with Euro-Collins solution. Mitochondrial respiratory parameters were determined in isolated mitochondria before anoxia (control), after 5-45 min anoxia followed by 5 min reoxygenation, and after 25 or 40 min of in vitro incubation in order to follow the in vitro aging of mitochondria during respiratory assays. Respiratory parameters measured after anoxia/reoxygenation did not show any oxidative phosphorylation dysfunction, indicating a high resistance of pulmonary mitochondria to in vitro anoxia/reoxygenation (up to 45 min anoxia). These results indicate that mitochondria are not directly responsible of their oxidative phosphorylation damage observed after in vivo ischemia (K. Willet et al., Transplantation 69 (2000) 582) but are a target of others cellular injuries leading to mitochondrial dysfunction in vivo.     

Neutrophils are not necessary for induction of ischemia-reperfusion lung injury

Ischemia-reperfusion lung injury limits lung transplantation. Neutrophil activation and/or xanthine oxidase-mediated purine degradation may cause toxic oxygen metabolite production and lung injury. We investigated whether circulating blood elements are involved in the pathogenesis of ischemia-reperfusion lung injury. Isolated rat lungs were perfused with physiological salt solution (PSS) stabilized with Ficoll until circulating blood elements were not detected in the lung effluent. Lungs were then rendered ischemic by stopping ventilation and perfusion for 45 min at room temperature. Lung injury occurred and was quantitated by the accumulation of 125I-bovine serum albumin into lung parenchyma and alveolar lavage fluid during reperfusion. Lung injury occurred, in the absence of circulating blood elements, when ischemic lungs were reperfused with PSS-Ficoll solution alone. Reperfusion with whole blood or PSS-Ficoll supplemented with human or rat neutrophils did not increase lung injury. Furthermore, during lung ischemia, the presence of neutrophils did not enhance injury. Experiments using PSS-albumin perfusate and quantitating lung injury by permeability-surface area product yielded similar results. Microvascular pressures were not different and could not account for the results. Toxic O2 metabolites were involved in the injury because addition of erythrocytes or catalase to the perfusate attenuated the injury. Thus reperfusion after lung ischemia causes injury that is dependent on a nonneutrophil source of toxic O2 metabolites.     

Modifying pulmonary ischemia-reperfusion injury by altering ventilatory strategies during ischemia.

We used an intact in vivo canine model of pulmonary ischemia-reperfusion (IR) injury to evaluate the differential effects of alveolar hypoxia and ventilation during 2 h of unilateral warm lung ischemia. Serial measurements of regional pulmonary blood flow, extravascular density (EVD), and transcapillary protein flux were made after reperfusion with the quantitative imaging technique of positron emission tomography. Twenty-seven animals were divided into five experimental groups: VENT O2 (n = 5) in which the left lung was ventilated with 40% O2 during ischemia, STATIC O2 (n = 4) in which the left lung was statically inflated with 40% O2 during ischemia, VENT N2 (n = 5) in which the left lung was ventilated with 100% N2 during ischemia, VENT N2/CO2 (n = 5) in which the left lung was ventilated with 95% N2-5% CO2 during ischemia, and STATIC N2 (n = 8) in which the left lung was statically inflated with 100% N2 during ischemia. These groups were compared with a control group (CONT, = 3) that was studied previously. Protein flux was significantly increased in the previous ischemic lung only for the STATIC N2 group [median 175 x 10(-4) min-1 (range 53-1,217) for the STATIC N2 group vs. 50 x 10(-4) min-1 (range 40-56) for the CONT group] 0.25 h after reperfusion and did not change over 3 h. EVD also increased but not significantly. Protein flux and EVD in the other groups were not different from CONT.(ABSTRACT TRUNCATED AT 250 WORDS)     

缺血再灌注对小鼠肠神经丛nNOS 和iNOS表达的影响

目的观察缺血再灌注后小鼠回肠神经型一氧化氮合酶(neuron alnitric oxide synthase,nNOS)和诱导型一氧化氮合酶(induciblenitric oxide synthase,iNOS)的表达,探讨肠缺血再灌注损伤(ischemia-reperfusion injury,IRI)的发生机制。方法采用小鼠肠系膜上动脉缺血再灌注模型,根据不同再灌注时间对小鼠随机分1d组、3d组、5d组、7d组、对照组和假手术组,用SP法检测小鼠回肠nNOS和iNOS的表达情况。结果与对照组和假手术组相比较,nNOS在再灌注1d后开始在肌间神经丛持续高表达(P<0.01);而iNOS在再灌注3d后开始在肌间神经丛持续高表达(P<0.05)。结论nNOS和iNOS在肠缺血再灌注后的表达增强,提示一氧化氮及一氧化氮合酶与肠神经节细胞在缺血再灌注中的损伤有着密切关系。     

Early surfactant administration protects against lung dysfunction in a mouse model of ARDS

Sepsis can predispose the lung to insults such as mechanical ventilation (MV). It was hypothesized that treating the lung with exogenous surfactant early in the development of sepsis will reduce the lung dysfunction associated with MV 18 h later. Mice underwent sham or cecal ligation and perforation (CLP) surgery. Immediately after surgery, mice were either untreated or given 100 mg/kg of bovine lipid extract surfactant intratracheally. Eighteen hours later, the lungs were removed and analyzed either immediately or following ventilation ex vivo for 2 h by an "injurious" mode of ventilation (20 ml/kg, 0 cm positive end-expiratory pressure). In nonventilated lungs, exogenous surfactant had no impact on compliance or IL-6 concentrations in the lungs. In the ventilated groups, the administered surfactant had a significant protective effect on the lung dysfunction induced by MV, but only in the CLP lungs. We conclude that administration of exogenous surfactant at the time of a systemic insult can protect the lung from the damaging effects of MV 18 h later.     

Mechanical ventilation of isolated rat lungs changes the structure and biophysical properties of surfactant.

Mechanical ventilation is an essential but potentially harmful therapeutic intervention for patients with acute lung injury. The objective of this study was to investigate the effects of mechanical ventilation on large-aggregate surfactant (LA) structure and function. Isolated rat lungs were randomized to either a nonventilated control group, a relatively noninjuriously ventilated group [1 h, 10 ml/kg tidal volume, 3 cmH(2)O positive end-expiratory pressure (PEEP)], or an injuriously ventilated group (1 h, 20 ml/kg tidal volume, 0 cmH(2)O PEEP). Injurious ventilation resulted in significantly decreased lung compliance compared with the other two groups. LA structure, as determined by electron microscopy, revealed that LA from the injurious group had significantly lower amounts of organized lipid-protein structures compared with LA obtained from the other groups. Analysis of the biophysical properties by using a captive bubble surfactometer demonstrated that adsorption and surface tension reduction were significantly impaired with LA from the injuriously ventilated lungs. We conclude that the injurious mechanical ventilation impairs LA function and that this impairment is associated with significant morphological alterations.     

TNF-alpha stimulates alveolar liquid clearance during intestinal ischemia-reperfusion in rats

Intestinal ischemia-reperfusion commonly occurs in critically ill patients and may lead to the development of remote organ injury, frequently involving the lungs. In the present study, alveolar liquid clearance was studied in ventilated, anesthetized rats subjected to 45 min of intestinal ischemia followed by 3 h of reperfusion. An isosmolar 5% albumin solution was instilled into the lungs, and alveolar liquid clearance was measured from the increase in alveolar protein concentration as water was reabsorbed over 45 min. Intestinal ischemia-reperfusion resulted in a 76% increase in alveolar liquid clearance compared with the control value (P < 0.05). The stimulated alveolar liquid clearance seen after intestinal ischemia-reperfusion was not inhibited by propranolol, indicating stimulation through a noncatecholamine-dependent pathway. Intestinal ischemia-reperfusion did not result in increased intracellular cAMP levels. Amiloride inhibited similar fractions in animals subjected to ischemia-reperfusion and control animals. Administration of a neutralizing polyclonal anti-tumor necrosis factor-alpha antibody before induction of intestinal ischemia completely inhibited the increased alveolar liquid clearance observed after intestinal ischemia-reperfusion. In conclusion, our results suggest that intestinal ischemia-reperfusion in rats leads to stimulation of alveolar liquid clearance and that this stimulation is mediated, at least in part, by a tumor necrosis factor-alpha-dependent mechanism.     

PEEP is necessary for exogenous surfactant to reduce pulmonary edema in canine aspiration pneumonitis.

Alveolar edema inactivates surfactant, and surfactant depletion causes edema by reducing lung interstitial pressure (Pis). We reasoned that surfactant repletion might reduce edema by raising Pis after acute lung injury and that positive end-expiratory pressure (PEEP) might facilitate this effect. One hour after tracheal administration of hydrochloric acid in 18 anesthetized dogs with transmural pulmonary capillary wedge pressure of 8 Torr, the animals were randomized into three groups: in the SURF + PEEP group, 50 mg/kg of calf lung surfactant extract (CLSE) was instilled into each main stem bronchus with 8 cmH2O of PEEP; in the SAL + PEEP group, PEEP was followed by an equal volume of saline (SAL); in the SURF group, CLSE was given without PEEP. After 5 h, edema in excised lungs (wet-to-dry weight ratios) was significantly less in the SURF + PEEP group (9.1 +/- 1.0) than in the other groups (11.3 +/- 1.8 and 11.3 +/- 1.8, respectively). In the SURF + PEEP group, pulmonary venous admixture fell by 6%; this change was different from the 7% increase in the SAL + PEEP group and 40% increase in the SURF group (P less than 0.05). Airway secretions obtained in the SURF + PEEP group had normal minimum surface tensions of 4 +/- 2 mN/m, a value much lower than in SAL + PEEP and SURF groups (32 +/- 4 and 22 +/- 7 mN/m, respectively). We conclude that surfactant normalizes surface tension and decreases transcapillary hydrostatic forces in this lung injury model, thereby reducing edema formation and improving gas exchange. These benefits occur only if surfactant is given with PEEP, allowing surfactant access to the alveoli and/or minimizing its inhibition by edema proteins.