Oleic Acid-induced Lung Injury Research Articles

Effect of positive end-expiratory pressure on inflammatory response in oleic acid-induced lung injury and whole-lung lavage-induced lung injury

The present study investigated the effects of positive end-expiratory pressure (PEEP) on the inflammatory response in two different lung injury models: edematous lung induced by oleic acid (OA); and atelectatic lung induced by whole-lung lavage (LAV). Japanese white rabbits (n = 28) were allocated to one of the two lung injury (OA or LAV) groups, and each group was treated with intermittent positive pressure ventilation, using zero end-expiratory pressure (ZEEP) or PEEP (1 cm H(2)O above the lower inflection point [LIP]). Thus, the animals were divided into LAV-ZEEP, LAV-PEEP, OA-ZEEP, and OA-PEEP groups. Blood and bronchoalveolar lavage fluid (BALF) were sampled 3 h after ventilatory treatment to analyze interleukin (IL)-8 levels. Pa(O) (2) was significantly decreased after the induction of lung injury, but was significantly higher in the PEEP groups compared to the ZEEP groups for each lung injury. Serum IL-8 levels were elevated in both experimental models. Serum IL-8 levels were significantly lower in LAV-PEEP than in LAV-ZEEP, whereas no difference was noted between OA-PEEP and OA-ZEEP. BALF IL-8 levels were lower in LAV-PEEP than in LAV-ZEEP. PEEP above LIP attenuated the elevation of IL-8 in BALF and serum in atelectatic lungs, but did not attenuate these increases in the edematous lungs. These results suggest that the protective effects of PEEP on injured lungs may depend on the underlying lung pathology.

Positive end-expiratory pressure at minimal respiratory elastance represents the best compromise between mechanical stress and lung aeration in oleic acid induced lung injury

IntroductionProtective ventilatory strategies have been applied to prevent ventilator-induced lung injury in patients with acute lung injury (ALI). However, adjustment of positive end-expiratory pressure (PEEP) to avoid alveolar de-recruitment and hyperinflation remains difficult. An alternative is to set the PEEP based on minimizing respiratory system elastance (Ers) by titrating PEEP. In the present study we evaluate the distribution of lung aeration (assessed using computed tomography scanning) and the behaviour of Ers in a porcine model of ALI, during a descending PEEP titration manoeuvre with a protective low tidal volume.MethodsPEEP titration (from 26 to 0 cmH2O, with a tidal volume of 6 to 7 ml/kg) was performed, following a recruitment manoeuvre. At each PEEP, helical computed tomography scans of juxta-diaphragmatic parts of the lower lobes were obtained during end-expiratory and end-inspiratory pauses in six piglets with ALI induced by oleic acid. The distribution of the lung compartments (hyperinflated, normally aerated, poorly aerated and non-aerated areas) was determined and the Ers was estimated on a breath-by-breath basis from the equation of motion of the respiratory system using the least-squares method.ResultsProgressive reduction in PEEP from 26 cmH2O to the PEEP at which the minimum Ers was observed improved poorly aerated areas, with a proportional reduction in hyperinflated areas. Also, the distribution of normally aerated areas remained steady over this interval, with no changes in non-aerated areas. The PEEP at which minimal Ers occurred corresponded to the greatest amount of normally aerated areas, with lesser hyperinflated, and poorly and non-aerated areas. Levels of PEEP below that at which minimal Ers was observed increased poorly and non-aerated areas, with concomitant reductions in normally inflated and hyperinflated areas.ConclusionThe PEEP at which minimal Ers occurred, obtained by descending PEEP titration with a protective low tidal volume, corresponded to the greatest amount of normally aerated areas, with lesser collapsed and hyperinflated areas. The institution of high levels of PEEP reduced poorly aerated areas but enlarged hyperinflated ones. Reduction in PEEP consistently enhanced poorly or non-aerated areas as well as tidal re-aeration. Hence, monitoring respiratory mechanics during a PEEP titration procedure may be a useful adjunct to optimize lung aeration.

Comparative Effects of Vaporized Perfluorohexane and Partial Liquid Ventilation in Oleic Acid-Induced Lung Injury

Comparative Effects of Vaporized Perfluorohexane and Partial Liquid Ventilation in Oleic Acid-Induced Lung Injury

VAPORIZED PERFLUOROHEXANE VS. PARTIAL LIQUID VENTILATION IN EXPERIMENTAL LUNG INJURY

It is currently not known whether vaporized perfluorohexane may be superior to partial liquid ventilation (PLV) for the therapy of acute lung injury. In this work, we aimed at comparing the effects of both therapies in oleic acid induced lung injury. Lung injury was induced in thirty anesthetized and mechanically ventilated pigs by means of central venous infusion of oleic acid. Animals were assigned to one of the following groups: 1) control or gas ventilation (GV); 2) 2.5 % perfluorohexane vapor; 3) 5 % perfluorohexane vapor; 4) 10 % perfluorohexane vapor and 5) PLV with perfluorooctane (30 ml/kg). Two hours after randomization, lungs were recruited and positive end-expiratory pressure was adjusted to obtain minimal elastance (open lung approach). Ventilation was continued during 4 additional hours, when animals were killed for lung histologic examination. Gas exchange and elastance were comparable among vaporized perfluorohexane, PLV and GV before the open lung approach was used and improved in a similar fashion in all groups after positive end-expiratory pressure was adjusted to optimal elastance (p < 0.05). A similar behavior was observed in the functional residual capacity in animals treated with vaporized perfluorohexane and GV. Lung resistance improved after recruitment (p < 0.05), but values were higher in the perfluorohexane 10 % and PLV groups, as compared to GV (p < 0.05). Interestingly, positive end-expiratory pressure values required to obtain minimal elastance were lower with 5 % perfluorohexane than PLV and GV (p <0.05). Diffuse alveolar damage was significantly lower in the 5 % and 10 % perfluorohexane vapor groups, as compared to PLV and GV (p < 0.05). Analysis of distribution of effects revealed that alveolar damage was lower with 5 % perfluorohexane than with GV or PLV in the non-dependent (p<0.001 and p<0.0001, respectively), as well as in central regions (p<0.0001 and p<0.001, respectively). In peripheral regions, 5 % perfluorohexane led to reduced alveolar damage (p<0.05), as compared to GV. In dependent regions, alveolar damage was lower with 5 % perfluorohexane and PLV as compared to GV (p<0.0001). Gas ventilated and animals treated with 5 % perfluorohexane showed less alveolar damage in the non-dependent as compared to dependent regions (p<0.001 and p<0.05, respectively), whereas PLV presented the opposite pattern (p<0.05). Oxidative stress was decreased with 5 % perfluorohexane as compared to GV (p<0.05). None of these perfluorcarbon therapies improved gas exchange or lung mechanics, as compared to GV. However, the use of 5 % vaporized perfluorohexane permitted to reduce pressures needed to stabilize the lungs and was associated with better histologic findings than PLV and GV. Whereas PLV led to more pronounced effects in dependent than in non-dependent regions, 5 % vaporized perfluorohexane showed the opposite pattern. Despite this gravity-related characteristic, 5 % vaporized perfluorohexane attenuated alveolar damage as efficiently as PLV in dependent regions and also reduced the oxidative stress in the lungs. Vaporized perfluorohexane may prove an alternative to PLV to reduce alveolar damage in acute lung injury.

Comparative Effects of Vaporized Perfluorohexane and Partial Liquid Ventilation in Oleic Acid– induced Lung Injury

It is currently not known whether vaporized perfluorohexane is superior to partial liquid ventilation (PLV) for therapy of acute lung injury. In this study, the authors compared the effects of both therapies in oleic acid-induced lung injury. Lung injury was induced in 30 anesthetized and mechanically ventilated pigs by means of central venous infusion of oleic acid. Animals were assigned to one of the following groups: (1) control or gas ventilation (GV), (2) 2.5% perfluorohexane vapor, (3) 5% perfluorohexane vapor, (4) 10% perfluorohexane vapor, or (5) PLV with perfluorooctane (30 ml/kg). Two hours after randomization, lungs were recruited and positive end-expiratory pressure was adjusted to obtain minimal elastance. Ventilation was continued during 4 additional hours, when animals were killed for lung histologic examination. Gas exchange and elastance were comparable among vaporized perfluorohexane, PLV, and GV before the open lung approach was used and improved in a similar fashion in all groups after positive end-expiratory pressure was adjusted to optimal elastance (P < 0.05). A similar behavior was observed in functional residual capacity (FRC) in animals treated with vaporized perfluorohexane and GV. Lung resistance improved after recruitment (P < 0.05), but values were higher in the 10% perfluorohexane and PLV groups as compared with GV (P < 0.05). Interestingly, positive end-expiratory pressure values required to obtain minimal elastance were lower with 5% perfluorohexane than with PLV and GV (P < 0.05). In addition, diffuse alveolar damage was significantly lower in the 5% and 10% perfluorohexane vapor groups as compared with PLV and GV (P < 0.05). Although the use of 5% vaporized perfluorohexane permitted the authors to reduce pressures needed to stabilize the lungs and was associated with better histologic findings than were PLV and GV, none of these perfluorocarbon therapies improved gas exchange or lung mechanics as compared with GV.

Effect of High Dose Steroids on Oleic Acid-induced Lung Injury in Rabbits: CT Findings

Effect of High Dose Steroids on Oleic Acid-induced Lung Injury in Rabbits: CT Findings

Methodologic Aspects of Attenuation Distributions From Static and Dynamic Thoracic CT Techniques in Experimental Acute Lung Injury

In acute lung injury, thoracic CT is used to gain information about lung aeration and consolidation. This can be done either during breath-holding by spiral CT scanning of the entire lung or dynamically by scanning lung slices without interrupting ventilation. We hypothesized that attenuation distribution is dependent on static or dynamic scanning techniques. We also studied whether a variation in the CT cut level, corresponding to the diaphragm movement over a breath, had any effect on the attenuation distribution. Twenty-two pigs with oleic acid-induced lung injury were randomly assigned to receive pressure-controlled mechanical ventilation with or without spontaneous breathing. Transversal dynamic CT scans of the chest were performed in apical and juxtadiaphragmatic regions, and end-expiratory and end-inspiratory slices were selected. In addition, after clamping the tube at end-expiration and end-inspiration, respectively, spiral CTs were performed. Guided by morphologic structures, spiral CT slices matching the dynamic scan slice and three additional neighbored slices above the diaphragm were selected. Distributions of CT attenuation were calculated and summarized in ranges for comparison. No significant difference in attenuation distributions between the two scanning methods or an interaction with the factors ventilation mode, ventilation phase, and attenuation range were found. In addition, attenuation distributions of four neighbored juxtadiaphragmatic slices, 8 mm thick, from the spiral CT did not differ statistically. In an animal model of oleic acid-induced lung injury, analyses of transverse thoracic slices based on dynamic or static CT scanning showed comparable distributions of attenuation. Variations on the CT cut level of 24 mm had no significant effect on the distribution of Hounsfield unit numbers. CT attenuation distributions of transversal juxtadiaphragmatic slices were not dependent on exact position.

SGC activation in pulmonary hypertension

Impairments of the NO-sGC-cGMP pathway provoke acute and chronic vascular injury, including endothelial dysfunction, vasoconstriction and vascular remodeling in the pulmonary circulation. We evaluated the effects of the novel sGC activator Bay 41-2272 in three different models of acute and chronic pulmonary hypertension: 1. Ischemia-reperfusion injury induced pulmonary vascular dysfunction in isolated rabbit lungs, 2. Oleic acid induced lung vascular injury in an intact animal model and 3. chronic hypoxia induced pulmonary hypertension in mice. I/R provoked dramatic production of reactive oxygen species, acute pulmonary hypertension upon reperfusion, and increased pulmonary vascular permeability. Bay 41-2272 dose dependently reduced all three events resulting in significant organ protection. In oleic acid induced lung injury, pulmonary vasoconstriction as well as gas exchange properties of the injured lungs were beneficially influenced by the sGC activator. Finally, in chronic hypoxic pulmonary hypertensive mice, sGC activation effectively treated pulmonary hypertension and right heart hypertrophy – in part in an eNOS dependent manner – as proven by the investigations in NOS3 KO mice. In conclusion BAY 41-2272, a novel sGC activator, offers great therapeutical potential by restoration of the sGC-cGMP pathway which is impaired in different forms of acute and chronic pulmonary vasculopathy. from 2nd International Conference of cGMP Generators, Effectors and Therapeutic Implications Potsdam, Germany, 10–12 June, 2005

Attenuation of acute lung injury in mice by oxymatrine is associated with inhibition of phosphorylated p38 mitogen-activated protein kinase

Oxymatrine is one of the alkaloids extracted from Chinese herb Sophora japonica ( Sophora flavescens Ait.) with activities of anti-inflammation, inhibiting immune reaction, antivirus, protecting hepatocytes and antihepatic fibrosis. However, the effect of oxymatrine on acute lung injury (ALI) has not been known yet. In this study, the effect of oxymatrine on ALI was investigated using an oleic acid-induced ALI mouse model. Morphological findings showed that the oleic acid group demonstrated a marked lung injury represented by prominent atelectasis, intraalveolar and interstitial patchy hemorrhage, edema, thickened alveolar septum, formation of hyaline membranes and the existence of inflammatory cells in alveolar spaces. While in the oxymatrine/dexamethasone group, these changes were less severe and in the vicinity of the control group. Furthermore, pretreatment with oxymatrine significantly alleviated oleic acid-induced lung injury accompanied by reduction of lung index and wet-to-dry weight ratio, decreases in serum TNF-α level and inhibition of phosphorylated p38 MAPK. These findings suggest that oxymatrine has a beneficial effect on acute lung injury induced by oleic acid in mice and may inhibit the production of proinflammatory cytokine, TNF-α, by means of the inhibition of p38 MAPK.

Rho-kinase (ROCK-1 and ROCK-2) upregulation in oleic acid-induced lung injury and its restoration by Y-27632

The possible contribution of Rho/Rho-kinase signalling in oleic acid (100 mg kg −1, i.v., for 4 h)-induced lung injury was investigated in rats. Furthermore, the possible protective effect of the administration of a Rho-kinase inhibitor, (+)-( R)- trans-4-(1-aminoethyl)- N-(4-pyridyl) cyclohexanecarboxamide dihydrochloride monohydrate (Y-27632, 0.5–5 mg kg −1, i.v., 15 min before the administration of oleic acid), was also examined. Western blot analysis as well as histopathological examination revealed that Rho-kinase (ROCK-1 and ROCK-2) was upregulated in lungs obtained from oleic acid-administrated rats. In addition, the markers of oxidative and nitrosative stress, i.e., malondialdehyde, myeloperoxidase, 3-nitro- l-tyrosine and nitrite/nitrate, in serum and lung tissue were also increased in the injury group. Treatment of rats with 5 mg kg −1 Y-27632 reversed the oleic acid-induced lung damage, which was demonstrated by histopathological assessment and confirmed in Western blot experiments: ROCK-blots were more intense in the oleic acid group than in control and Y-27632 treatment reversed ROCK upregulation. In addition, malondialdehyde, myeloperoxidase, 3-nitro- l-tyrosine and nitrite/nitrate were also normalized after the administration of Y-27632 (0.5 mg kg −1 and 5 mg kg −1). These findings suggest that ROCK-1 and ROCK-2 are involved in oleic acid-induced lung damage in rats, and that inhibition of this enzyme by Y-27632 may have a protective effect against such damage. Consequently, Rho kinase inhibitors may be potential therapeutic agents in the treatment of acute respiratory distress syndrome (ARDS).

Keratinocyte growth factor therapy in murine oleic acid-induced acute lung injury

Alveolar type II (ATII) cell proliferation and differentiation are important mechanisms in repair following injury to the alveolar epithelium. KGF is a potent ATII cell mitogen, which has been demonstrated to be protective in a number of animal models of lung injury. We have assessed the effect of recombinant human KGF (rhKGF) and liposome-mediated KGF gene delivery in vivo and evaluated the potential of KGF as a therapy for acute lung injury in mice. rhKGF was administered intratracheally in male BALB/c mice to assess dose response and time course of proliferation. SP-B immunohistochemistry demonstrated significant increases in ATII cell numbers at all rhKGF doses compared with control animals and peaked 2 days following administration of 10 mg/kg rhKGF. Protein therapy in general is very expensive, and gene therapy has been suggested as a cheaper alternative for many protein replacement therapies. We evaluated the effect of topical and systemic liposome-mediated KGF-gene delivery on ATII cell proliferation. SP-B immunohistochemistry showed only modest increases in ATII cell numbers following gene delivery, and these approaches were therefore not believed to be capable of reaching therapeutic levels. The effect of rhKGF was evaluated in a murine model of OA-induced lung injury. This model was found to be associated with significant alveolar damage leading to severe impairment of gas exchange and lung compliance. Pretreatment with rhKGF 2 days before intravenous OA challenge resulted in significant improvements in PO2, PCO2, and lung compliance. This study suggests the feasibility of KGF as a therapy for acute lung injury.

Low bias flow oscillation with heliox in oleic acid-induced lung injury

To evaluate Co(2) clearance in oleic acid-induced lung injury in rabbits receiving high-frequency oscillatory ventilation with helium-oxygen mixtures through a low bias flow oscillation system designed to conserve expensive gases. A prospective, controlled, interventional, in vivo animal laboratory study. Research laboratory of a health sciences university. Eight New Zealand White Rabbits. Lung injury (Pao(2)/Fio(2) of <250) was induced by intravenous infusion of oleic acid. Low bias flow oscillation was performed with a modified high-frequency oscillatory ventilation circuit that uses low bias flow (100 mL/kg/min) and a soda lime canister to clear CO(2). Low bias flow oscillation-heliox trials were performed with 40%, 50%, 60%, and 70% helium (balanced with oxygen) for 20 mins. Each heliox trial was preceded by a 20-min paired control trial with 40% oxygen/60% nitrogen. Helium concentrations of 40%, 50%, 60%, and 70% decreased Paco(2) by 13% (47 +/- 7 to 41 +/- 8 torr), 17% (50 +/- 7 to 41 +/- 6 torr), 22% (49 +/- 5 to 38 +/- 7 torr), and 26% (48 +/- 7 to 35 +/- 9 torr), respectively. The gradient between partial pressure of alveolar oxygen and Pao(2) was not affected by 60% helium; however, absolute Pao(2) increased by 15%. Fluid and inotropic requirements were similar in both control and heliox low bias flow oscillation trials. Helium concentrations greater than 40% increase Co(2) clearance from oleic acid-injured lungs of rabbits during low bias flow oscillation. The low bias flow oscillation system makes this possible using 1% of the gas volume required during high-frequency oscillatory ventilation.

Protection of Pirfenidone against an Early Phase of Oleic Acid-Induced Acute Lung Injury in Rats

The potential role of PFD [5-methyl-L-phenyl-2-(1H)-pyridone], an antifibrotic compound with anti-inflammatory effects, in several models of acute lung injury (ALI) has gained increasing attention; however, the protective effect of PFD in oleic acid (OA)-induced ALI remains unknown. We hypothesized that PFD protects from OA-induced ALI in rats, and we hoped to obtain the optimum preclinical conditions with PFD in ALI. Sprague-Dawley rats were randomized into five groups (five rats per group): normal control group, OA-treated group (0.15 ml/kg), and three PFD-treated groups (20, 40, and 80 mg/kg p.o., respectively). Arterial blood gases, lung wet/dry weight ratio, and postmortem histological changes were determined 0.5, 1, 2, 6, and 24 h after OA challenge. Electron spin resonance spectroscopy was used for free radical detection and measurement. Experiments were examined based on the orthogonal test L4 (4(2)) setting two factors (PFD dose and PFD valid time) with four different levels. The results of the orthogonal test showed that the sequence of effect of PFD was 0.5 h (oxygen radicals), 1 h (histological changes), 2 h (lung edema), and 6 h (partial pressure of oxygen) after OA challenge, and 40 mg/kg PFD was the most effective dose in this study. We conclude that PFD protects against OA-induced ALI in rats. The mechanism of these protective effects partly involves decrease of oxygen radicals. The data of this study proves that the orthogonal test will be a powerful method to help obtain the optimum experimental conditions with PFD in ALI in the future.

Effect of Ulinastatin, a human urinary trypsin inhibitor, on the oleic acid-induced acute lung injury in rats via the inhibition of activated leukocytes

The acute respiratory distress syndrome (ARDS) is often caused by fat tissue embolism. One of the most common animal models of ARDS is produced by direct administration of oleic acid (OA). Activated leukocytes are critically involved in the pathological mechanism in this model. Human urinary trypsin inhibitor (UTI) is known to inhibit production of tumor necrosis factor (TNF)-alpha, which potently stimulates leukocyte activation. The purpose of this study was to clarify whether UTI improves OA-induced lung injury in rats by inhibiting activated leukocytes via TNF-alpha production. Rats were subjected to a single intravenous administration of OA into the pedicle vein. Acute lung injury was evaluated by arterial blood gases and histological changes in lungs. Pulmonary vascular permeability, accumulation of neutrophils, and the levels of TNF-alpha in lung tissues were also examined. Rats were divided into four experimental groups: a sham operated, OA, OA + UTI, and OA + nitrogen mustard (NM)-induced leukocytopenia group. UTI was intravenously administered 30 min before OA administration. Leukocytopenia was induced by the administration of NM. UTI significantly improved the OA-induced histological changes for 4 h after OA administration. The OA-induced reduction of PaO2, the increase of pulmonary vascular permeability, and the levels of MPO activity and TNF-alpha in lung tissues were significantly improved in rats administrated UTI. The effects in the leukocytopenia group were similar to those in the UTI-administered group. Leukocytes play a critical role in the development of OA-induced lung injury. It was suggested that UTI contributed to the reduction in the OA-induced lung injury by inhibiting TNF-alpha and thereby suppressing leukocyte.

Oleic acid lung injury: a morphometric analysis using computed tomography.

The oleic acid-induced lung injury (OAI) model is considered to represent the early phase of acute respiratory distress syndrome (ARDS). Its inherent properties are important for the design and the interpretation of interventional studies. The aim of this study was to describe the evolution of morphometric lung changes during OAI using computed tomography (CT) analysis. Furthermore, the effect of a temporary change in positive end-expiratory pressure (PEEP) was evaluated. Fifteen anaesthetized pigs were ventilated in volume-controlled mode with a baseline PEEP of 5 cm H(2)O. Helical CT scans were taken at baseline and 1 h after oleic acid injection. The PEEP was then either increased to 10 cm H(2)O (n = 5), decreased to 0 cm H(2)O (n = 5) or kept constant (n = 5) for 30 min. For the next 30 min, the baseline PEEP level was applied in all animals before the final CT scans 2 h after the induction of OAI. Dimensional and volumetric changes were determined from radiographical attenuation values. There was a major decrease in gas volume and an increase in tissue volume within the first hour. A net increase in total lung volume, with a larger transverse area but no displacement of the diaphragm, was manifest after 2 h. A minor increase in volume of non-aerated lung, located to the caudal region, was observed during the second hour. The tidal volume was redistributed to the middle and apical regions. The temporary change in PEEP did not influence the morphological progress of OAI. Decreased gas volume and increased tissue volume are the dominating morphometric characteristics of oleic acid lung injury, occurring mainly within the first hour. With these changes manifest, the course of injury is not affected by a limited period of moderately changed PEEP during the second hour. The net increase of total lung volume suggests a predominance of oedema formation over airway and alveolar collapse.

N-acetylcysteine inhibits peroxynitrite-mediated damage in oleic acid-induced lung injury

Since oleic acid (OA) induces morphologic and cellular changes similar to those observed in human acute lung injury (ALI) and acute respiratory distress syndrome, it has become a widely used model to investigate the effects of several agents on pathogenesis of lung injury. The antioxidant and anti-inflammatory properties of N-acetylcysteine (NAC) has been documented in many lung injury models. In this study, we evaluated the role of NAC in an OA-induced lung injury model by measuring myeloperoxidase (MPO) activity, malondialdehyde (MDA) and 3-nitrotyrosine (3-NT) levels in lung tissue. Five groups labelled Sham, NAC, OA, Pre-OA–NAC and Post-OA–NAC were determined. ALI was induced by intravenous administration of OA. The pre-OA–NAC group received iv NAC 15 min before OA infusion and the post-OA–NAC group received iv NAC 2 h after OA infusion. In both of the NAC treatment groups' blood and tissue samples were collected 4 h after OA infusion, independent from the time of NAC infusion. The MPO activity, MDA and 3-NT levels in lung homogenates were found to be increased in OA group and the administration of NAC significantly reduced tissue MPO, MDA and 3-NT levels ( p=0.0001). Lung histopathology was also affected by NAC in this OA-induced experimental lung injury model.

Neutrophils and neutrophil products do not mediate pulmonary hemodynamic effects of endotoxin on oleic acid-induced lung injury.

Small-dose endotoxin (Etx) prevents pulmonary perfusion redistribution away from edematous dorsal lung regions after oleic acid (OA)-induced injury in dogs, causing a significant deterioration in oxygenation. We hypothesized that small-dose Etx might mediate this effect via polymorphonuclear neutrophil (PMN) priming with release of inflammatory mediators such as platelet activating factor (PAF) or secretory phospholipase A(2) (sPLA(2)). To test this hypothesis, we administered specific inhibitors directed against each mediator and used two strategies to generate neutropenia. PAF and sPLA(2) inhibitors were administered before OA injury, followed 2 h later by small-dose Etx (n = 4 each group). PMN depletion was achieved by hydroxyurea administration for 5 days before the study to achieve absolute neutrophil counts <1000/mm(3) (n = 4). Inhibition of PMN adherence to lung endothelium was achieved by the administration of an anti-CD18 monoclonal antibody immediately before lung injury (n = 5). Positron emission tomography was used to evaluate pulmonary perfusion distribution and lung water content. We observed no effect of these interventions on the perfusion pattern after Etx + OA. Thus, neither neutrophils nor PAF or sPLA(2) mediate the effects of Etx on the pattern of perfusion in this model of lung injury. Acute respiratory failure is characterized by severe decreases in blood oxygen. The pattern of blood flow within the lungs can contribute to this problem. This study investigated the potential role of white blood cells and their products in mediating abnormal pulmonary blood flow patterns in an experimental animal model of respiratory failure.

Reduction in the aggressiveness of ventilation by inhalation of perfluorohexane after therapy of oleic acid-induced respiratory failure

The application of perfluorohexane (PFH) vapor led to an improvement of oxygenation and mechanical lung function in a model of oleic acid-induced ARDS in sheep. The aim of this study was to investigate the effects of PFH on gas exchange over an extended time period and to reduce the invasiveness of ventilation. ARDS was induced in sheep ( n=12) by injecting 0.1 ml/kg body weight oleic acid intravenously. Six sheep were treated for 30 min with 18 vol.% PFH (PFH-Tx) and followed up over a time period of 240 min while untreated sheep ( n=6) served as controls. Subsequently the F(I)O(2) was reduced to generate a p(a)O(2) between 100-140 mmHg. Gas exchange, respiratory and hemodynamic data were collected at regular intervals. Data were analysed using covariance analysis. PFH treatment led to an improvement in oxygenation ( p<0.01) and in mechanical lung function ( p<0.01). Furthermore, mean pulmonary artery pressure ( p<0.01) and shunt ( p<0.01) were lower in PFH-Tx. F(I)O(2) could be reduced in all PFH-treated animals ( p<0.01). Treatment of oleic acid-induced lung injury with PFH vapor improved oxygenation and mechanical lung function over a extended time period allowing a reduction in the invasiveness of ventilation.

Preventive effect of tranilast on oleic acid-induced lung injury in guinea pigs.

Acute respiratory distress syndrome or acute lung injury (ARDS)/(ALI) involve the severe lung injury with pulmonary vascular hyper-permeability and hypoxemia induced by inflammatory reactions. Since ARDS/ALI carries high mortality, the development of new drugs against ARDS/ALI is required. We examined the effect of tranilast, an anti-allergic drug, on vascular hyper-permeability in the lungs and airways, and on hypoxemia, in oleic acid (OA)-induced acute lung injury, an animal model of ARDS/ALI. The increase in pulmonary and airway vascular permeability and the decrease in partial oxygen pressure of arterial blood induced by an intravenous injection of OA were drastically ameliorated by the oral administration of tranilast in a dose-dependent manner. This is the first report to prove that tranilast prevents pulmonary and airway vascular permeability and hypoxemia induced by OA. These results suggest that tranilast may be a candidate drug for the treatment of ARDS/ALI.

N-Acetylcysteine inhibits peroxynitrite-mediated damage in oleic acid-induced lung injury

Since oleic acid (OA) induces morphologic and cellular changes similar to those observed in human acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), it has become a widely used model to investigate the effects of several agents on pathogenesis of lung injury. The antioxidant, anti-inflammatory and antiapoptotic properties of N-acetylcysteine (NAC) have been documented in many lung injury models [1]. In this study, we evaluated the role of NAC in an OA-induced lung injury model by measuring myeloperoxidase (MPO) activity, malondialdehyde (MDA) and 3-nitrotyrosine (3-NT) levels in lung tissue. Five groups (sham, NAC, OA, pre-OA-NAC and post-OA-NAC) were determined. ALI/ARDS was induced by intravenous (IV) administration of OA. The pre-OA-NAC group received IV NAC 15 min before OA infusion and the post-OA-NAC group received IV NAC 2 hours after OA infusion. In both of the NAC treatment groups, blood and tissue samples were collected 4 hours after OA infusion, independent of the time of NAC infusion. The MPO activity, MDA and 3-NT levels in lung homogenates were found to be increased in the OA group, and the administration of NAC significantly reduced tissue MPO, MDA and 3-NT levels (P = 0.0001). Lung histopathology was also protected by NAC in this OA-induced experimental lung injury model. In conclusion, the present study demonstrates that oleic acid induces myeloperoxydase activation and consequently increases 3-NT and MDA levels in lung tissue. Our data suggest that elevated 3-NT levels in lung tissue represent the role of excessive formation of peroxynitrite and the efficacy of NAC treatment in the prevention of peroxynitrite-mediated OA-induced lung injury. Due to its antioxidant and anti-inflammatory properties, NAC seems to be a promising agent in treatment of critically ill patients with lung injury states.