Ventilator-induced Acute Lung Injury Research Articles

Transforming growth factor-β1 is associated with inflammatory resolution via regulating macrophage polarization in lung injury model mice

ObjectiveVentilation is the main respiratory support therapy for acute respiratory distress syndrome, which triggers acute lung injury (ALI). Macrophage polarization is vital for the resolution of inflammation and tissue injury. We hypothesized that transforming growth factor (TGF)-β1 may attenuate inflammation and ventilator-induced ALI by promoting M2 macrophage polarization. MethodsC57BL/6 mice received 4-hour ventilation and extubation to observe the resolution of lung injury and inflammation. Lung vascular permeability, inflammation, and histological changes in the lungs were evaluated by bronchoalveolar lavage analysis, enzyme linked immunosorbent assay, hematoxylin and eosin staining, as well as transmission electron microscope. TGF-β1 cellular production and macrophage subsets were analyzed by flow cytometry. The relative expressions of targeted proteins and genes were measured by immunofuorescence staining, Western blot, and quantitative polymerase chain reaction. ResultsHigh tidal volume-induced injury and inflammation were resolved at 3 days of post-ventilation (PV3d) to PV10d, with increased elastic fibers, proteoglycans, and collagen content, as well as higher TGF-β1 levels. M1 macrophages were increased in the acute phase, whereas M2a macrophages began to increase from PV1d to PV3d, as well as increased M2c macrophages from PV3d to PV7d. A single dose of rTGF-β1 attenuated lung injury and inflammation at end of ventilation with polymorphonuclear leukocyte apoptosis, while nTAb pretreatment induced the abnormal elevation of TGF-β1 that aggravated lung injury and inflammation due to the significant inhibition of M1 macrophages polarized to M2a, M2b, and M2c macrophages. ConclusionsPrecise secretion of TGF-β1-mediated macrophage polarization plays a crucial role in the resolution of ventilator-induced inflammatory lung injury.

Protective effect of apelin-13 on ventilator-induced acute lung injury.

Mechanical Ventilation (MV) is an essential mechanism of life support in the clinic. It may also lead to ventilator-induced acute lung injury (VILI) due to local alveolar overstretching and/or repeated alveolar collapse. However, the pathogenesis of VILI is not completely understood, and its occurrence and development may be related to physiological processes such as the inflammatory response, oxidative stress, and apoptosis. Some studies have found that the the apelin/APJ axis is an endogenous antagonistic mechanism activated during acute respiratory distress syndrome(ARDS), that can counteract the injury response and prevent uncontrolled lung injury. To indicate that apelin-13 plays a protective role in VILI, an animal model of VILI was established in this study to explore whether apelin-13 can alleviate VILI in rats by inhibiting inflammation, apoptosis and oxidative stress. SD rats were divided into four groups: control, high tidal volume, high tidal volume + normal saline and high tidal volume + apelin-13. After tracheotomy, the rats in control maintained spontaneous breathing, and the other rats were connected to the small animal ventilator for 4h to establish the rat VILI model. The mRNA expression of apelin was measured by real-time quantitative polymerase chain reaction(qRT-PCR), immunofluorescence and Western blotting(WB) were used to detect the expression level of APJ, and WB was used to detect the expression of the apoptotic proteins Bax and bcl-2. The degree of lung injury was evaluated by pathological staining of lung tissue,W/D ratio, and BALF total protein concentration. The expression of inflammatory factors(IL-1β, IL-6, TNF-α) in alveolar lavage fluid was measured using ELISA. The activities of MPO and cat and the content of MDA, an oxidative product, in lung tissue were measured to evaluate the degree of oxidative stress in the lung. After treatment with apelin-13, the apelin/APJ axis in the lung tissue of VILI model rats was activated, and the effect was further enhanced. The pathological damage of lung tissue was alleviated, the expression of the antiapoptotic protein Bcl-2 and the proapoptotic protein Bax was reversed, and the levels of the inflammatory cytokines IL-1β, IL-6, TNF-α levels were all decreased. MPO activity and MDA content decreased, while CAT activity increased. The apelin/apj axis is activated in VILI. Overexpression of apelin-13 further plays a protective role in VILI, mainly by including reducing pathological damage, the inflammatory response, apoptosis and antioxidant stress in lung tissue, thus delaying the occurrence and development of VILI.

C-Fos is a mechanosensor that regulates inflammatory responses and lung barrier dysfunction during ventilator-induced acute lung injury

BackgroundAs one of the basic treatments performed in the intensive care unit, mechanical ventilation can cause ventilator-induced acute lung injury (VILI). The typical features of VILI are an uncontrolled inflammatory response and impaired lung barrier function; however, its pathogenesis is not fully understood, and c-Fos protein is activated under mechanical stress. c-Fos/activating protein-1 (AP-1) plays a role by binding to AP-1 within the promoter region, which promotes inflammation and apoptosis. T-5224 is a specific inhibitor of c-Fos/AP-1, that controls the gene expression of many proinflammatory cytokines. This study investigated whether T-5224 attenuates VILI in rats by inhibiting inflammation and apoptosis.MethodsThe SD rats were divided into six groups: a control group, low tidal volume group, high tidal volume group, DMSO group, T-5224 group (low concentration), and T-5224 group (high concentration). After 3 h, the pathological damage, c-Fos protein expression, inflammatory reaction and apoptosis degree of lung tissue in each group were detected.Resultsc-Fos protein expression was increased within the lung tissue of VILI rats, and the pathological damage degree, inflammatory reaction and apoptosis in the lung tissue of VILI rats were significantly increased; T-5224 inhibited c-Fos protein expression in lung tissues, and T-5224 inhibit the inflammatory reaction and apoptosis of lung tissue by regulating the Fas/Fasl pathway.Conclusionsc-Fos is a regulatory factor during ventilator-induced acute lung injury, and the inhibition of its expression has a protective effect. Which is associated with the antiinflammatory and antiapoptotic effects of T-5224.

Protective function of DJ-1/PARK7 in lipopolysaccharide and ventilator-induced acute lung injury

Oxidative stress is considered one of the early underlying contributors of acute lung injury (ALI) and ventilator-induced lung injury (VILI). DJ-1, also known as PARK7, has a well-established role as an antioxidant. We have previously shown maintaining oxidative balance via the ATF3-Nrf2 axis was important in protection from ALI. Here, we exclusively characterize the role of DJ-1 in sterile LPS-induced ALI and VILI. DJ-1 protein expression was increased after LPS treatment in human epithelial and endothelial cell lines and lungs of wild-type mice. DJ-1 deficient mice exhibited greater susceptibility to LPS-induced acute lung injury as demonstrated by increased cellular infiltration, augmented levels of pulmonary cytokines, enhanced ROS levels and oxidized by-products, increased pulmonary edema and cell death. In a two-hit model of LPS and mechanical ventilation (MV), DJ-1 deficient mice displayed enhanced susceptibility to inflammation and lung injury. Collectively, these results identify DJ-1 as a negative regulator of ROS and inflammation, and suggest its expression protects from sterile lung injury driven by high oxidative stress.

Myeloid tissue factor does not modulate lung inflammation or permeability during experimental acute lung injury.

Tissue factor (TF) is a critical mediator of direct acute lung injury (ALI) with global TF deficiency resulting in increased airspace inflammation, alveolar-capillary permeability, and alveolar hemorrhage after intra-tracheal lipopolysaccharide (LPS). In the lung, TF is expressed diffusely on the lung epithelium and intensely on cells of the myeloid lineage. We recently reported that TF on the lung epithelium, but not on myeloid cells, was the major source of TF during intra-tracheal LPS-induced ALI. Because of a growing body of literature demonstrating important pathophysiologic differences between ALI caused by different etiologies, we hypothesized that TF on myeloid cells may have distinct contributions to airspace inflammation and permeability between direct and indirect causes of ALI. To test this, we compared mice lacking TF on myeloid cells (TF∆mye, LysM.Cre+/−TFflox/flox) to littermate controls during direct (bacterial pneumonia, ventilator-induced ALI, bleomycin-induced ALI) and indirect ALI (systemic LPS, cecal ligation and puncture). ALI was quantified by weight loss, bronchoalveolar lavage (BAL) inflammatory cell number, cytokine concentration, protein concentration, and BAL procoagulant activity. There was no significant contribution of TF on myeloid cells in multiple models of experimental ALI, leading to the conclusion that TF in myeloid cells is not a major contributor to experimental ALI.

Cell-free hemoglobin: a novel mediator of acute lung injury.

Patients with the acute respiratory distress syndrome (ARDS) have elevated levels of cell-free hemoglobin (CFH) in the air space, but the contribution of CFH to the pathogenesis of acute lung injury is unknown. In the present study, we demonstrate that levels of CFH in the air space correlate with measures of alveolar-capillary barrier dysfunction in humans with ARDS (r = 0.89, P < 0.001) and in mice with ventilator-induced acute lung injury (r = 0.89, P < 0.001). To investigate the specific contribution of CFH to ARDS, we studied the impact of purified CFH in the mouse lung and on cultured mouse lung epithelial (MLE-12) cells. Intratracheal delivery of CFH in mice causes acute lung injury with air space inflammation and alveolar-capillary barrier disruption. Similarly, in MLE-12 cells, CFH increases proinflammatory cytokine expression and increases paracellular permeability as measured by electrical cell-substrate impedance sensing. Next, to determine whether these effects are mediated by the iron-containing heme moiety of CFH, we treated mice with intratracheal hemin, the chloride salt of heme, and found that hemin was sufficient to increase alveolar permeability but failed to induce proinflammatory cytokine expression or epithelial cell injury. Together, these data identify CFH in the air space as a previously unrecognized driver of lung epithelial injury in human and experimental ARDS and suggest that CFH and hemin may contribute to ARDS through different mechanisms. Interventions targeting CFH and heme in the air space could provide a new therapeutic approach for ARDS.

Hesperetin attenuates ventilator-induced acute lung injury through inhibition of NF-κB-mediated inflammation

Hesperetin, a major bioflavonoid in sweet oranges and lemons, has been reported to have anti-inflammatory properties. However, the effect of hesperetin on ventilator-induced acute lung injury has not been studied. In present study, we investigated the protective effect of hesperetin on ventilator-induced acute lung injury in rats. Rats were orally administered hesperetin (10, 20, or 40mg/kg) two hour before acute lung injury was induced by mechanical ventilation. Rats were then randomly divided into six groups: the lung protective ventilation group (n=20, LV group), injurious ventilation group (n=20, HV group), vehicle-treated injurious ventilation group (n=20, LV+vehicle group), hesperetin (10mg/kg)-treated acute lung injury group (n=20, HV+Hsp (10mg)), hesperetin (20mg/kg)-treated acute lung injury group (n=20, HV+Hsp (20mg)), and hesperetin (40mg/kg)-treated acute lung injury group (n=20, HV+Hsp (40mg)). The lung tissues and bronchoalveolar lavage fluid were isolated for subsequent measurements. Treatment with hesperetin dramatically improved the histology of lung tissue, and reduced the wet/dry ratio, myeloperoxidase activity, protein concentration, and production of tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-1β, and MIP-2 in the bronchoalveolar lavage fluid of rats with ventilator-induced acute lung injury. Additionally, our study indicated that this protective effect of hesperetin results from its ability to increase the expression of peroxisome proliferator-activated receptor (PPAR)-γ and inhibit the activation of the nuclear factor (NF)-κB pathway. These results suggest that hesperetin may be a potential novel therapeutic candidate for protection against ventilator-induced acute lung injury.

Mechanotransduction via TRPV4 regulates inflammation and differentiation in fetal mouse distal lung epithelial cells.

BackgroundMechanical ventilation plays a central role in the injury of premature lungs. However, the mechanisms by which mechanical signals trigger an inflammatory cascade to promote lung injury are not well-characterized. Transient receptor potential vanilloid 4 (TRPV4), a calcium-permeable mechanoreceptor channel has been shown to be a major determinant of ventilator-induced acute lung injury in adult models. However, the role of these channels as modulators of inflammation in immature lungs is unknown. In this study, we tested the hypothesis that TRPV4 channels are important mechanotransducers in fetal lung injury.MethodsExpression of TRPV4 in the mouse fetal lung was investigated by immunohistochemistry, Western blot and qRT-PCR. Isolated fetal epithelial cells were exposed to mechanical stimulation using the Flexcell Strain Unit and inflammation and differentiation were analyzed by ELISA and SP-C mRNA, respectively.ResultsTRPV4 is developmentally regulated in the fetal mouse lung; it is expressed in the lung epithelium and increases with advanced gestation. In contrast, in isolated epithelial cells, TRPV4 expression is maximal at E17-E18 of gestation. Mechanical stretch increases TRPV4 in isolated fetal epithelial cells only during the canalicular stage of lung development. Using the TRPV4 agonist GSK1016790A, the antagonist HC-067047, and the cytokine IL-6 as a marker of inflammation, we observed that TRPV4 regulates release of IL-6 via p38 and ERK pathways. Interestingly, stretch-induced differentiation of fetal epithelial cells was also modulated by TRPV4.ConclusionThese studies demonstrate that TRPV4 may play an important role in the transduction of mechanical signals in the fetal lung epithelium by modulating not only inflammation but also the differentiation of fetal epithelial cells.

HIF1A Reduces Acute Lung Injury by Optimizing Carbohydrate Metabolism in the Alveolar Epithelium

Author SummaryAcute lung injury is a devastating lung disease caused by injuries or acute infections to the lung. In patients it manifests itself as acute respiratory distress syndrome. Severe pulmonary edema and uncontrolled lung inflammation are typical symptoms of acute lung injury, which make it hard for patients to breath efficiently. In the clinical course of the disease, patients require mechanical ventilation to support their lung function and to provide sufficient oxygen levels to vital organs such as the brain, the heart, or the kidneys. We hypothesized that stretch conditions—such as those that occur during mechanical ventilation—result in transcriptional adaptation of alveolar epithelial cells—the innermost lining of the lungs. In this study we identified an unexpected involvement of the transcription factor hypoxia-inducible factor HIF1A in lung protection. We observed that during acute lung injury, stabilization of HIF1A is mediated by increased levels of succinate, an intermediate product of the citrate cycle. Interestingly, we show that HIF1A in alveolar epithelia functions to induce a transcriptional program that improves the efficiency of carbohydrate metabolism by injured lungs, thereby helping to adapt to the injurious conditions of mechanical stretch and to reduce lung inflammation. These preclinical findings highlight the potential for pharmacological HIF1A stabilization in the treatment of acute lung injury.

Pulmonary Vascular Dysfunction Induced by High Tidal Volume Mechanical Ventilation*

Acute lung injury and acute respiratory distress syndrome are characterized by increased pulmonary artery pressure and ventilation-perfusion mismatch. We analyzed the changes in the pulmonary vascular function in a model of ventilator-induced acute lung injury. Controlled in vivo laboratory study. Animal research laboratory. Anesthetized male Sprague-Dawley rats. Rats were ventilated for 120 minutes using low tidal volume ventilation (control group, tidal volume 9 mL/kg, positive end-expiratory pressure 5 cm H2O, n = 15), high tidal volume ventilation (high tidal volume group, tidal volume 25 mL/kg, zero positive end-expiratory pressure, n = 14), or high tidal volume ventilation plus the poly-(adenosine diphosphate-ribose) polymerase inhibitor 3-aminobenzamide (10 mg/kg IP, high tidal volume group + 3-aminobenzamide group, n = 7). Vascular rings from small pulmonary arteries were mounted in a myograph for isometric tension recording. Lung messenger RNA and protein expression were analyzed by reverse transcriptase-polymerase chain reaction and Western blot, respectively. High tidal volume ventilation impaired phenylephrine- and acetylcholine-induced responses in pulmonary arteries in vitro, which were accompanied by induction of inducible nitric oxide synthase messenger RNA and protein. These effects, as well as hypoxemia and hypotension, were prevented by 3-aminobenzamide. Hypoxic pulmonary vasoconstriction and responses to exogenous sphingomyelinase were increased, whereas the responses to serotonin, Kv current density, and inhibition of Kv currents by hypoxia were unaffected by high tidal volume. High tidal volume ventilation-induced pulmonary vascular dysfunction was characterized by reduced alpha-adrenergic-induced vasoconstriction, reduced endothelium-dependent vasodilatation, and enhanced hypoxic pulmonary vasoconstriction.

The Role of Cyclooxygenase-2 in Mechanical Ventilation–Induced Lung Injury

Mechanical ventilation is necessary for patients with acute respiratory failure, but can cause or propagate lung injury. We previously identified cyclooxygenase-2 as a candidate gene in mechanical ventilation-induced lung injury. Our objective was to determine the role of cyclooxygenase-2 in mechanical ventilation-induced lung injury and the effects of cyclooxygenase-2 inhibition on lung inflammation and barrier disruption. Mice were mechanically ventilated at low and high tidal volumes, in the presence or absence of pharmacologic cyclooxygenase-2-specific inhibition with 3-(4-methylsulphonylphenyl)-4-phenyl-5-trifluoromethylisoxazole (CAY10404). Lung injury was assessed using markers of alveolar-capillary leakage and lung inflammation. Cyclooxygenase-2 expression and activity were measured by Western blotting, real-time PCR, and lung/plasma prostanoid analysis, and tissue sections were analyzed for cyclooxygenase-2 staining by immunohistochemistry. High tidal volume ventilation induced lung injury, significantly increasing both lung leakage and lung inflammation relative to control and low tidal volume ventilation. High tidal volume mechanical ventilation significantly induced cyclooxygenase-2 expression and activity, both in the lungs and systemically, compared with control mice and low tidal volume mice. The immunohistochemical analysis of lung sections localized cyclooxygenase-2 expression to monocytes and macrophages in the alveoli. The pharmacologic inhibition of cyclooxygenase-2 with CAY10404 significantly decreased cyclooxygenase activity and attenuated lung injury in mice ventilated at high tidal volume, attenuating barrier disruption, tissue inflammation, and inflammatory cell signaling. This study demonstrates the induction of cyclooxygenase-2 by mechanical ventilation, and suggests that the therapeutic inhibition of cyclooxygenase-2 may attenuate ventilator-induced acute lung injury.

Role and potentials of low-flow CO2 removal system in mechanical ventilation

An analysis of the technological implementation of extracorporeal CO(2) removal (ECCO(2)R) techniques and of its clinical application. A new classification of ECCO(2)R, based on technological aspects, clinical properties and physiological performance, is proposed. The use of a ventilation with lower tidal volumes has been proved successful in acute respiratory distress syndrome (ARDS) patients but can be extremely problematic, especially when dealing with respiratory acidosis. The implementation of ECCO(2)R devices can represent the missing link between the prevention of ventilator-induced lung injury and pH control. ECCO(2)R has attracted increasing interest because of new less-invasive approaches allowing an easier management of ARDS patients. Recent studies have also shown that ECCO(2)R can also be used in patients with exacerbation of chronic obstructive pulmonary disease (COPD) and as a bridge to lung transplantation. The future ventilatory management of patients with acute respiratory failure may include a minimally invasive extracorporeal carbon dioxide removal circuit associated with the least amount of ventilatory support (noninvasive in COPD and/or invasive in ARDS) to minimize sedation, prevent ventilator-induced acute lung injury and nosocomial infections. Randomized clinical trials in the pipeline will confirm this fascinating hypothesis.

Ventilator-induced Lung Injury

Ventilator-induced Lung Injury

Essential Role of Pre–B-Cell Colony Enhancing Factor in Ventilator-induced Lung Injury

We previously demonstrated pre-B-cell colony enhancing factor (PBEF) as a biomarker in sepsis and sepsis-induced acute lung injury (ALI) with genetic variants conferring ALI susceptibility. To explore mechanistic participation of PBEF in ALI and ventilator-induced lung injury (VILI). Two models of VILI were utilized to explore the role of PBEF using either recombinant PBEF or PBEF(+/-) mice. Initial in vitro studies demonstrated recombinant human PBEF (rhPBEF) as a direct rat neutrophil chemotactic factor with in vivo studies demonstrating marked increases in bronchoalveolar lavage (BAL) leukocytes (PMNs) after intratracheal injection in C57BL/6J mice. These changes were accompanied by increased BAL levels of PMN chemoattractants (KC and MIP-2) and modest increases in lung vascular and alveolar permeability. We next explored the potential synergism between rhPBEF challenge (intratracheal) and a model of limited VILI (4 h, 30 ml/kg tidal volume) and observed dramatic increases in BAL PMNs, BAL protein, and cytokine levels (IL-6, TNF-alpha, KC) compared with either challenge alone. Gene expression profiling identified induction of ALI- and VILI-associated gene modules (nuclear factor-kappaB, leukocyte extravasation, apoptosis, Toll receptor pathways). Heterozygous PBEF(+/-) mice were significantly protected (reduced BAL protein, BAL IL-6 levels, peak inspiratory pressures) when exposed to a model of severe VILI (4 h, 40 ml/kg tidal volume) and exhibited significantly reduced expression of VILI-associated gene expression modules. Finally, strategies to reduce PBEF availability (neutralizing antibody) resulted in significant protection from VILI. These studies implicate PBEF as a key inflammatory mediator intimately involved in both the development and severity of ventilator-induced ALI.

Protection from experimental ventilator-induced acute lung injury by IL-1 receptor blockade

Background: Clinical studies have shown that injurious mechanical ventilation is associated with increased airspace and plasma levels of interleukin-1β (IL-1β); however, the potential therapeutic value of IL-1 inhibition in acute...

Ventilator-induced lung injury upregulates and activates gelatinases and EMMPRIN: attenuation by the synthetic matrix metalloproteinase inhibitor, Prinomastat (AG3340).

Mechanical ventilation has become an indispensable therapeutic modality for patients with respiratory failure. However, a serious potential complication of MV is the newly recognized ventilator-induced acute lung injury. There is strong evidence suggesting that matrix metalloproteinases (MMPs) play an important role in the development of acute lung injury. Another factor to be considered is extracellular matrix metalloproteinase inducer (EMMPRIN). EMMPRIN is responsible for inducing fibroblasts to produce/secrete MMPs. In this report we sought to determine: (1) the role played by MMPs and EMMPRIN in the development of ventilator-induced lung injury (VILI) in an in vivo rat model of high volume ventilation; and (2) whether the synthetic MMP inhibitor Prinomastat (AG3340) could prevent this type of lung injury. We have demonstrated that high volume ventilation caused acute lung injury. This was accompanied by an upregulation of gelatinase A, gelatinase B, MT1-MMP, and EMMPRIN mRNA demonstrated by in situ hybridization. Pretreatment with the MMP inhibitor Prinomastat attenuated the lung injury caused by high volume ventilation. Our results suggest that MMPs play an important role in the development of VILI in rat lungs and that the MMP-inhibitor Prinomastat is effective in attenuating this type of lung injury.

Attenuation of ventilator-induced acute lung injury in an animal model by inhibition of neutrophil adhesion by leumedins (NPC 15669)

Beta2-integrin (CD11b/CD18) expression, an indicator of neutrophil activation, has been associated with the development of acute respiratory distress syndrome. Leumedins act directly on leukocytes to inhibit the up-regulated expression of beta2-integrins involved in leukocyte adhesion. We examined the effect of such a new anti-inflammatory agent, NPC 15669 (N-[9H-(2,7-dimethylfluorenyl-9-methoxy)-carbonyl]-L-leucine), on neutrophil-mediated acute lung injury in an animal model. Prospective, randomized, blinded, controlled animal study. An animal laboratory in a university setting. Adult New Zealand rabbits. After repeated lung lavages with normal saline to induce acute lung injury, anesthetized rabbits were randomly assigned to one of two groups (n = 6 per group): a) treatment group (pretreated with NPC 15669 [10 mg/kg i.v. bolus] 30 mins before lavage, followed by a continuous infusion [5 mg/kg/hr] for the duration [4 hrs] of the experiment); or b) control group (pretreatment and continuous infusion with placebo). All animals were mechanically ventilated with identical pressure settings over 4 hrs and were killed at the end of the experiment. PaO2, PaCO2, and tidal volumes were repeatedly measured and airway pressure settings were noted every 30 mins. At the end of the experiment, lungs were taken out for measurements of the myeloperoxidase content, for conventional histology (hematoxylin and eosin staining), and for intracellular adhesion molecule-1 immunohistostaining. Pretreatment with NPC 15669 profoundly improved oxygenation from a PaO2 of 52 +/- 5 torr (6.9 +/- 0.7 kPa) to 250 +/- 161 torr (33.3 +/- 21.5 kPa) within 60 mins after lung lavage (p < .05). Oxygenation continued to improve throughout the study, reaching a maximal PaO2 value of 395 +/- 98 torr (52.7 +/- 13.1 kPa) at 4 hrs. In the control group, oxygenation remained poor throughout the observation period. PaO2 values differed significantly (51 +/- 20 torr [6.8 +/- 2.7 kPa] vs. 306 +/- 126 torr [40.8 +/- 16.8 kPa], p < .005) at 90 mins and at all subsequent measurements from those values in the NPC 15669 group. Dynamic lung compliance improved significantly 60 to 90 mins after repeated lung lavage. Histology demonstrated markedly less lung damage (hyaline membrane formation and leukocyte infiltration) in treated animals (p < .05) than in controls. NPC 15669 seems to block inflammatory reactions by inhibiting the sequestration of neutrophils in acute, ventilator-associated lung injury. As a result, gas exchange and total lung compliance improve. Application of this and similar compounds affecting neutrophil adhesion warrants further investigation as a treatment modality for acute lung injury.