Minimize Lung Injury Research Articles

Inhalation exposure systems for the development of rodent models of sulfur mustard-induced pulmonary injury

Sulfur mustard (SM) is a chemical threat agent for which its effects have no current treatment. Due to the ease of synthesis and dispersal of this material, the need to develop therapeutics is evident. The present manuscript details the techniques used to develop SM laboratory exposure systems for the development of animal models of pulmonary injury. These models are critical for evaluating SM injury and developing therapeutics against that injury. Iterative trials were conducted to optimize a lung injury model. The resulting pathology was used as a guide, with a goal of effecting homogeneous and diffuse lung injury comparable to that of human injury. Inhalation exposures were conducted by either nose-only inhalation or intubated inhalation. The exposures were conducted to either directly vaporized SM or SM that was nebulized from an ethanol solution. Inhalation of SM by nose-only inhalation resulted in severe nasal epithelial degeneration and minimal lung injury. The reactivity of SM did not permit it to transit past the upper airways to promote lower airway injury. Intratracheal inhalation of SM vapors at a concentration of 5400 mg · min/m3 resulted in homogeneous lung injury with no nasal degeneration.

Preservation solution for lung transplantation

Despite the increasing success of lung transplantation as the mainstay therapeutic modality for end-stage lung disease, the 1-year survival rate after lung transplantation remains 80% and primary graft dysfunction (PGD) accounts for 30% of mortality. Ischemia-reperfusion injury has been identified as one of the main causes of PGD, and thus significant efforts have been made to optimize the methods for lung preservation in an attempt to minimize lung injury during the period of ischemia. The composition of the lung preservation solution used in the pulmonary artery flush has been considered to be the key to successful lung preservation, and many lung transplant programs have been shifting the use of the preservation solution from the intracellular fluid type to the extracellular fluid type because of preferable posttransplant lung function with the latter. This review summarizes the experimental and clinical studies on lung preservation, particularly focusing attention on the preservation solution being employed for clinical lung transplantation.

Gabexate Mesilate Inhibits the Expression of HMGB1 in Lipopolysaccharide-Induced Acute Lung Injury

High mobility group box 1 (HMGB1) is an important late mediator of acute lung injury. Gabexate mesilate (GM) is a synthetic protease inhibitor with some anti-inflammatory action. We aimed to evaluate the effect of GM on HMGB1 in lipopolysaccharide (LPS)-induced lung injury in rats. Prior to the injection of LPS to induce lung injury, rats were administered saline or GM. Injury to the lung and expression of HMGB1, plasminogen activator inhibitor-1 (PAI-1), and protease-activated receptor-2 (PAR-2) were examined. In an accompanying in vitro study, we performed LPS stimulation under GM administration in a mouse macrophage cell line and measured the quantity of HMGB1 and cytokines in the supernatant, and cell signal in the cells. Histologic examination revealed that interstitial edema, leukocytic infiltration, and HMGB1 protein expression were markedly reduced in the GM+LPS group compared wih the LPS group. Furthermore, LPS-induced increases in PAI-1 and PAR-2 activity and in plasma HMGB1 concentrations were lower in the rats given both GM and LPS than in the rats given LPS alone. Release of HMGB1 and cytokines from the cell after the administration of LPS were decreased by GM. Phosphorylation of IκB was inhibited by GM. GM may have inhibited PAI-1 and PAR-2, thereby indirectly inhibiting HMGB1 and reducing tissue damage in the lung. This indicates that GM can inhibit lung injury induced by LPS in rats. GM is a candidate for use in novel strategies to prevent or minimize lung injury in sepsis.

Reducing Lung Injury during Neonatal Resuscitation of Preterm Infants

Neonatologists are familiar with the concept of ventilator-induced lung injury (VILI) 1,2 and are increasingly careful in the neonatal intensive care unit (NICU) to apply positive-pressure ventilation (PPV) strategies that are gentle to the lungs. 3 Although PPV also is commonly used in the delivery room (DR), clinicians appear less aware that the same gentle approach should be applied to reduce lung injury during the first few minutes of life. To achieve adequate gas exchange after delivery, lung fluid is cleared and replaced with air, and functional residual capacity (FRC) is established. Mechanical ventilation requires an appropriate minute volume to achieve adequate gas exchange. Clinical signs are used to evaluate the response to ventilation during neonatal resuscitation. The tidal volume (V T ) delivered is rarely measured; thus, airway pressure is not adjusted to optimize V T and reduce volutrauma or underventilation. 4,6 The use of end-expiratory pressure, considered essential to avoid lung injury in the NICU, is still not uniformly applied in the DR. PPV may cause lung injury through various mechanisms, including high airway pressure (barotrauma), high V T and overdistention (volutrauma), repeated alveolar collapse and reexpansion (atelectrauma), and infection and inflammation (bio-trauma).1 These injuries cause leakage of proteinaceous fluid and blood into the airways, alveoli, and lung interstitium, inhibiting surfactant function, interfering with lung mechanics, and contributing to lung injury.1 In this review, we describe what is known about the causes of neonatal lung injury, based on animal and human research. Although human data are scanty, and randomized control trials are needed, we suggest ways in which current practice might be changed to help minimize lung injury during neonatal resuscitation.

Nasal Ventilation Alters Mesenchymal Cell Turnover and Improves Alveolarization in Preterm Lambs

Bronchopulmonary dysplasia (BPD) is a frequent cause of morbidity in preterm infants that is characterized by prolonged need for ventilatory support in an intensive care environment. BPD is characterized histopathologically by persistently thick, cellular distal airspace walls. In normally developing lungs, by comparison, remodeling of the immature parenchymal architecture is characterized by thinning of the future alveolar walls, a process predicated on cell loss through apoptosis. We hypothesized that minimizing lung injury, using high-frequency nasal ventilation to provide positive distending pressure with minimal assisted tidal volume displacement, would increase apoptosis and decrease proliferation among mesenchymal cells in the distal airspace walls compared with a conventional mode of support (intermittent mandatory ventilation). Accordingly, we compared two groups of preterm lambs: one group managed by high-frequency nasal ventilation and a second group managed by intermittent mandatory ventilation. Each group was maintained for 3 days. Oxygenation and ventilation targets were sustained with lower airway pressures and less supplemental oxygen in the high-frequency nasal ventilation group, in which alveolarization progressed. Thinning of the distal airspace walls was accompanied by more apoptosis, and less proliferation, among mesenchymal cells of the high-frequency nasal ventilation group, based on morphometric, protein abundance, and mRNA expression indices of apoptosis and proliferation. Our study shows that high-frequency nasal ventilation preserves the balance between mesenchymal cell apoptosis and proliferation in the distal airspace walls, such that alveolarization progresses.

Fire-eater's lung

Hydrocarbon aspiration from fire-eating can result in severe necrotising pneumonia with complex cyst formation and large pleural effusions. Despite this, there is usually minimal persistent lung injury. We report the progress of two clinical cases, one of whom is the first reported case of citronella oil aspiration.

Lung protective ventilatory strategies in very low birth weight infants

Respiratory distress syndrome (RDS) is the most common respiratory diagnosis in preterm infants. Surfactant therapy and mechanical ventilation using conventional or high-frequency ventilation have been the standard of care in the management of RDS. Bronchopulmonary dysplasia (BPD) continues to remain as a major morbidity in very low birth weight infants despite these treatments. There is no significant difference in pulmonary outcome when an optimal lung volume strategy is used with conventional or high-frequency ventilation. Lung injury is directly related to the duration of invasive ventilation via the endotracheal tube. Studies using noninvasive ventilation, such as nasal continuous positive airway pressure and noninvasive positive pressure ventilation, have shown to decrease postextubation failures as well as a trend toward reduced risk of BPD. Lung protective ventilatory strategy may involve noninvasive ventilation as a primary therapy or following surfactant administration in very preterm infants with RDS. Initial steps in the management of preterm infants may also include sustained inflation to establish functional residual capacity, followed by noninvasive ventilation to minimize lung injury and subsequent development of BPD.

Airway function in infants treated with inhaled nitric oxide for persistent pulmonary hypertension

Inhaled nitric oxide (iNO), used for treatment of persistent pulmonary hypertension of newborn (PPHN), is an oxygen free radical with potential for lung injury. Deferring ECMO with iNO in these neonates could potentially have long-term detrimental effects on lung function. We studied respiratory morbidity (defined as occurrence of respiratory infections requiring treatment, episodes of wheezing, and/or need for ongoing medications following discharge) and airway function at 1 year postnatal age in term neonates treated with iNO but not ECMO for PPHN, and compared data from similar infants recruited to the UK ECMO Trial randomized to receive ECMO or conventional management (CM). Maximal expiratory flow at FRC (V(') (maxFRC)) was measured in infants treated with iNO for PPHN (oxygenation index >or=25) at birth. V(') (maxFRC) was measured in 23 infants and expressed as z-scores, to adjust for sex and body size and compared to data from 71 (46 ECMO, 25 CM) infants studied at a similar age in the ECMO Trial. Respiratory morbidity was low in iNO group. V(') (maxFRC) z-score was lower than predicted in all groups (P < 0.001), with no significant difference between those treated with iNO [mean (SD) z-score: -1.65 (1.2)] and those treated with ECMO [-1.59 (1.2)] or CM [-2.1(1.0)]. Within iNO, ECMO and CM groups; 26%, 37% and 56%, respectively, had V(') (maxFRC) z-scores below normal. Respiratory outcome at 1 year in iNO treated neonates with moderately severe PPHN is encouraging, with no apparent increase in respiratory morbidity when compared to the general population. Sub-clinical reductions in airway function are evident at 1 year, suggesting that continuing efforts to minimize lung injury in the neonatal period are warranted to maximize lung health in later life.

Congenital diaphragmatic hernia: a systematic review and summary of best-evidence practice strategies

Recent reports suggest that specific care strategies improve survival of infants with congenital diaphragmatic hernia (CDH). This review presents details of care from centers reporting high rates of survival among CDH infants. We conducted a MEDLINE search (1995 to 2006) and searched all citations in the Cochrane Central Register of Controlled Trials. Studies were included if they contained reports of >20 infants with symptomatic CDH, and >75% survival of isolated CDH. Thirteen reports from 11 centers met inclusion criteria. Overall survival, including infants with multiple anomalies, was 603/763 (79%; range: 69 to 93%). Survival for isolated CDH was 560/661 (85%; range: 78 to 96%). The frequency of extracorporeal membrane oxygenation (ECMO) use for isolated CDH varied widely among reporting centers 251/622 (40%; range: 11 to 61%), as did survival for infants with isolated CDH placed on ECMO: 149/206 (73%; range: 33 to 86%). There was no suggestion of benefit from use of antenatal glucocorticoids given after 34 weeks gestation or use of postnatal surfactant. Low mortality was frequently attributed to minimizing lung injury and adhering to center-specific criteria for ECMO. Use of strategies aimed at minimizing lung injury, tolerance of postductal acidosis and hypoxemia, and adhering to center-specific criteria for ECMO were strategies most consistently reported by successful centers. The literature lacks randomized clinical trials of these or other care strategies in this complex patient population; prospective studies of safety and long-term outcome are needed.

RETRACTED ARTICLE: Nafamostat mesilate inhibits the expression of HMGB1 in lipopolysaccharide-induced acute lung injury

High mobility group box 1 (HMGB1) protein has recently been shown to be an important late mediator of acute lung injury and a promising therapeutic target. Nafamostat mesilate (NM) is a broad-range synthetic protease inhibitor with some anti-inflammatory action. The purpose of this study was to evaluate the effect of NM on HMGB1 in lipopolysaccharide (LPS)-induced lung injury in rats. Male Wistar rats were given either saline (LPS group) or NM (NM+LPS group) 30 min before the intravenous injection of a bolus of LPS (5 mg.kg(-1)). After the administration of LPS, injury to the lung and the expression of HMGB1, tumor necrosis factor-alpha (TNF-alpha), and plasminogen activator inhibitor-1 (PAI-1) were examined. Histological examination revealed that interstitial edema, leukocytic infiltration, and HMGB1 protein expression were markedly reduced in the NM+LPS group compared to the LPS group. Furthermore, the LPS-induced increases in PAI-1 activity and in plasma TNF-alpha concentrations were also lower in the rats given both NM and LPS than in the rats given LPS alone. The anticoagulatory activity of NM may have inhibited PAI-1, while its anti-inflammatory activity blockaded TNF-alpha, thereby indirectly inhibiting HMGB1 and reducing tissue damage in the lung. These findings indicate that NM can inhibit the lung injury induced by LPS in rats. NM is an excellent candidate for use in new therapeutic strategies to prevent or minimize lung injury.

High‐frequency oscillation (HFO) prevents activation of NF‐κB found with conventional mechanical ventilation (CMV) in surfactant‐depleted rabbit lung

High-frequency oscillation (HFO) has been recognized as an effective ventilatory strategy to minimize lung injury during respiratory support. Conventional mechanical ventilation (CMV) compared with HFO was shown to result in an increased number of PMNs and inflammatory cytokines in the lung lavage fluid. However how mechanical forces can be sensed by cells and converted into biochemical signals for intracellular signal transduction is still unknown. In this current study, we sought to determine whether the activation of Nuclear factor-kappa B (NF-kappaB) might be involved in the lung injury caused by CMV. Surfactant-depleted Japanese white rabbits received 1- or 4-hr CMV or 1- or 4-hr HFO. Then, activation of NF-kappaB in the lungs was assessed by conducting electrophoretic mobility shift assays (EMSA). In the experiment with whole lungs, NF-kappaB activity was much higher in the 4-hr CMV lungs than in the 4-hr HFO lungs. To clarify the origin of the cells in which NF-kappaB was activated, we did a second lung lavage at the end of ventilation and washed out the cells that had infiltrated the alveoli. The levels of NF-kappaB activity were the similar in the lungs of 4-hr HFO rabbits and in those of 4-hr CMV ones. On the other hand, NF-kappaB activity was much higher in the 4-hr CMV lungs than in the 4-hr HFO lungs in the experiment with the lung lavage fluid cells. These results show that the increase in NF-kappaB activity in the lungs of 4-hr CMV rabbits was due mainly to the cells that had infiltrated the alveoli.

Pneumocyte Apoptosis Induction during Cardiopulmonary Bypass: Effective Prevention by Radical Scavenging Using N-Acetylcysteine

Cardiopulmonary bypass (CPB) and cardioplegic arrest are associated with pulmonary dysfunction. We sought to investigate whether pulmonary ischemia/reperfusion during standard CPB and cardioplegic arrest is associated with reactive oxygen species (ROS)-mediated pulmonary tissue injury and pneumocyte apoptosis induction, and whether ROS scavenging using N-acetylcysteine (NAC) attenuates these alterations. Twelve pigs (41 ± 8 kg) were randomized to receive either NAC (100 mg/kg prior to CPB; n = 7) or placebo (n = 5) and subjected to CPB and 60 min of cold (4°C) crystalloid cardioplegic arrest. We collected lung biopsies prior to CPB, at 60 min CPB, as well as at 30, 60, and 120 min post CPB. Lung specimens were immunocytochemically stained against nitrotyrosine, 8-isoprostaglandin-F2α, and 8-hydroxy-2′-deoxyguanosine (8-OH-dG) as indicators for ROS-mediated tissue injury and active caspase-3, an apoptosis signal pathway key enzyme. Oxidative stress markers were judged using a scale from 1 to 4 (low to intensive staining), and caspase-3-positive pneumocytes were counted per view field. In placebo, the number of caspase-3-positive pneumocytes significantly increased over time to reach a maximum at 120 min post CPB (p =. 03 vs baseline). NAC significantly prevented caspase-3 activation in pneumocytes (p =. 001 vs Placebo). Pneumocyte nitrotyrosine and 8-OH-dG staining significantly increased over time (p =. 003) in the placebo group, but decreased in the NAC group (p =. 004). In both groups staining for 8-isoprostaglandin-F2α showed no significant changes. This yields the conclusion that standard CPB and cardioplegic arrest initiate ROS-mediated tissue injury and apoptosis in pneumocytes that can be reduced by NAC. Thus, ROS scavenging using NAC may represent a novel approach to minimize lung injury associated with CPB.

Mechanical ventilation interacts with endotoxemia to induce extrapulmonary organ dysfunction

IntroductionMultiple organ dysfunction syndrome (MODS) is a common complication of sepsis in mechanically ventilated patients with acute respiratory distress syndrome, but the links between mechanical ventilation and MODS are unclear. Our goal was to determine whether a minimally injurious mechanical ventilation strategy synergizes with low-dose endotoxemia to induce the activation of pro-inflammatory pathways in the lungs and in the systemic circulation, resulting in distal organ dysfunction and/or injury.MethodsWe administered intraperitoneal Escherichia coli lipopolysaccharide (LPS; 1 μg/g) to C57BL/6 mice, and 14 hours later subjected the mice to 6 hours of mechanical ventilation with tidal volumes of 10 ml/kg (LPS + MV). Comparison groups received ventilation but no LPS (MV), LPS but no ventilation (LPS), or neither LPS nor ventilation (phosphate-buffered saline; PBS).ResultsMyeloperoxidase activity and the concentrations of the chemokines macrophage inflammatory protein-2 (MIP-2) and KC were significantly increased in the lungs of mice in the LPS + MV group, in comparison with mice in the PBS group. Interestingly, permeability changes across the alveolar epithelium and histological changes suggestive of lung injury were minimal in mice in the LPS + MV group. However, despite the minimal lung injury, the combination of mechanical ventilation and LPS resulted in chemical and histological evidence of liver and kidney injury, and this was associated with increases in the plasma concentrations of KC, MIP-2, IL-6, and TNF-α.ConclusionNon-injurious mechanical ventilation strategies interact with endotoxemia in mice to enhance pro-inflammatory mechanisms in the lungs and promote extra-pulmonary end-organ injury, even in the absence of demonstrable acute lung injury.

Strategies to minimize lung injury in extremely low birth weight infants

Strategies to minimize lung injury in extremely low birth weight infants

Strategies to minimize lung injury in extremely low birth weight infants

To review the main causes of new bronchopulmonary dysplasia and the strategies utilized to decrease its incidence in extremely low birth weight infants. For this review a MEDLINE search from 1966 to October 2004, the Cochrane Database, abstracts from the Society for Pediatric Research and recent meetings on the topic were used. The survival of extremely low birth weight infants has increased significantly due to improvement in both scientific knowledge and technology. This improvement in survival has therefore resulted in an increased incidence of bronchopulmonary dysplasia. The characteristics of bronchopulmonary dysplasia in extremely low birth weight infants, the so called "new" bronchopulmonary dysplasia are quite different from the classic bronchopulmonary dysplasia described by Northway. This new bronchopulmonary dysplasia has a multifactorial etiology, which includes volutrauma, atelectrauma, oxygen toxicity and lung inflammation. Therapy such as prenatal corticosteroids, exogenous surfactant, nasal continuous positive airway pressure, new mechanical ventilation modalities and gentle ventilation have been used in attempts to decrease lung injury severity. In order to prevent lung injury in extremely low birth weight infants, it is necessary to minimize several factors that induce bronchopulmonary dysplasia and to utilize less aggressive therapeutic strategies. In addition to the current therapy used to decrease lung injury, knowledge of these causative factors may create new therapies that may be fundamental in improving the clinical outcomes of premature infants.

Bronchopulmonary dysplasia: A new look at an old problem

William Northway Jr. first described bronchopulmonary dysplasia (BPD) in 1967. Even with the many advances in the care of neonatal respiratory diseases BPD has remained a problem, but the gestational age of most affected infants has gradually lowered. Some therapies have been tried and abandoned or remain unproven. BPD in the extremely immature population follows a different pathology than originally described. There appears to be a disruption in lung development. The mechanisms of injury are similar (oxygen toxicity, ventilator-induced injury), with new evidence of perinatal inflammation playing a role. Preventing or minimizing lung injury beyond surfactant may be possible with high frequency oscillatory ventilation or the newer modes of tidal volume ventilation but remains unproven. Avoidance of mechanical ventilation and treatment with only continuous positive airway pressure holds promise. This article is an overview of current knowledge.

Treatment of immature baboons for 28 days with early nasal continuous positive airway pressure.

Using the 125-day baboon model of long-term bronchopulmonary dysplasia, we hypothesized that early use of nasal continuous positive airway pressure (nCPAP), a noninvasive ventilatory method, combined with prophylactic surfactant therapy would permit continuation of alveolar and vascular development in the lung. Retrospective human studies have shown that infants treated with nCPAP spend less time on mechanical ventilation and thereby sustain less volutrauma. After delivery by cesarean section at 125 days (term, 185 days), the infants received two doses of surfactant (Curosurf) and daily caffeine citrate. Weaning from low-volume positive pressure ventilation to nCPAP was attempted at 24 hours of age. Serial physiological parameters were recorded. Lung histopathology and morphometric measurements of nCPAP animals were done after necropsy at 28 days and data were compared with 125- and 156-day gestational controls. Documented episodes of clinical sepsis and pneumonia at postmortem examination were absent. nCPAP lungs showed enlarged thin-walled air spaces with minimal fibroproliferation and scattered secondary crests. Internal surface area and surface-to-volume ratio dimensions were similar to those of 156-day gestational control lungs, the intrauterine developmental control. nCPAP is an effective noninvasive ventilatory technique that minimizes lung injury in baboons at risk of developing bronchopulmonary dysplasia.

Effect of retinoic acid on oxygen-induced lung injury in the newborn rat

Oxygen-induced lung injury is believed to lead to the development of bronchopulmonary dysplasia (BPD). To determine whether retinoic acid (RA) treatment prevents the development of BPD by minimizing lung injury, we investigated the effect of RA on the histopathologic characteristics of oxygen-induced lung injury in a newborn rat model. Eighteen rat pups were divided into three groups: room air-exposed control group (n=5), oxygen-exposed placebo group (n=7), and RA-treated oxygen-exposed group (n=6). Measurement of alveolar area, quantitation of secondary crest formation, microvessel count, evaluation of alveolar septal fibrosis, and smooth muscle actin (SMA) immunostaining were performed to assess oxygen-induced changes in lung morphology. Treatment of oxygen-exposed animals with RA resulted in a significant increase in mean alveolar area; however, it had no effect on the number of secondary crests and microvessel count. The degree of fibrosis and SMA expression showed a significant decrease in RA-treated animals. We conclude that RA treatment improves alveolar structure and decreases fibrosis in the newborn rat with oxygen-induced lung injury. Extrapolating these findings to humans, we speculate that similar treatment with RA may reduce lung injury in preterm infants at risk for BPD.

Safety and efficacy of intratracheal recombinant human Clara cell protein in a newborn piglet model of acute lung injury.

Despite the widespread use of exogenous surfactant, acute and chronic lung injury continues to be a major cause of morbidity in preterm infants. CC10 is a protein produced by Clara cells that inhibits phospholipase A2 and has anti-inflammatory and antifibrotic properties. We studied whether intratracheal (IT) recombinant human Clara cell protein (rhCC10) could safely minimize lung injury in a newborn piglet model of acute lung injury. Twenty-nine newborn piglets were given Survanta and then ventilated for 48 h receiving the following: room air (group 1); 100% O2 (group 2); or 100% O2 and 25, 5, or 1 mg/kg (groups 3, 4, and 5, respectively) of IT rhCC10 (diluted to 2 mL/kg with saline) at time 0. Laboratory studies, oxygen ratios, static pressure-volume curves, bronchoalveolar lavage (for inflammatory markers), and histologic analyses were performed over the 48-h study period. Pulmonary compliance and oxygenation were significantly improved in animals receiving 5 mg/kg IT rhCC10 compared with room air and 100% O2 controls (p < 0.004 and p < 0.05, respectively, ANOVA). Reductions in inflammatory markers were seen in animals receiving rhCC10, although changes did not reach statistical significance. No significant toxicity was noted. rhCC10 appeared safe and improved pulmonary function in this newborn piglet model of hyperoxic lung injury. We speculate that rhCC10 may represent a promising therapy for the prevention of lung injury in preterm infants.

One-lung ventilation with high tidal volumes and zero positive end-expiratory pressure is injurious in the isolated rabbit lung model.

We tested the hypothesis that one-lung ventilation (OLV) with high tidal volumes (VT) and zero positive end-expiratory pressure (PEEP) may lead to ventilator-induced lung injury. In an isolated, perfused rabbit lung model, VT and PEEP were set to avoid lung collapse and overdistension in both lungs, resulting in a straight pressure-time (P-vs-t) curve during constant flow. Animals were randomized to (a) nonprotective OLV (left lung) (n = 6), with VT values as high as before randomization and zero PEEP; (b) protective OLV (left lung) (n = 6), with 50% reduction of VT and maintenance of PEEP as before randomization; and (c) control group (n = 6), with ventilation of two lungs as before randomization. The nonprotective OLV was associated with significantly smaller degrees of collapse and overdistension in the ventilated lung (P < 0.001). Peak inspiratory pressure values were higher in the nonprotective OLV group (P < 0.001) and increased progressively throughout the observation period (P < 0.01). The mean pulmonary artery pressure and lung weight gain values, as well as the concentration of thromboxane B(2), were comparatively higher in the nonprotective OLV group (P < 0.05). A ventilatory strategy with VT values as high as those used in the clinical setting and zero PEEP leads to ventilator-induced lung injury in this model of OLV, but this can be minimized with VT and PEEP values set to avoid lung overdistension and collapse. One-lung ventilation with high tidal volumes and zero positive end-expiratory pressure (PEEP) is injurious in the isolated rabbit lung model. A ventilatory strategy with tidal volumes and PEEP set to avoid lung overdistension and collapse minimizes lung injury during one-lung ventilation in this model.