Surfactant in pulmonary oxygen toxicity.
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Biomedical subjects
Publications and source records attributed to B Lachmann.
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Xanthine oxidase was given intratracheally in a single dose to guinea pigs. Lung compliance was measured after 4 h and 14 days respectively. Lung-thorax compliance was significantly lower compared with saline-treated controls both 4 h and 14 days after application of fluid. At 14 days there was a dose-related response between lung-thorax compliance and xanthine oxidase administered in the range 0-1.0 U. Superoxide dismutase (SOD) had a protective effect on xanthine oxidase action at 4 h, but not after 14 days. We suggest that the decreased lung-thorax compliance was caused by superoxide radicals, produced by the hypoxanthine-xanthine oxidase system, damaging lung tissue. We speculate that free oxygen radicals produced by the hypoxanthine-xanthine oxidase system could be an important contributory pathogenetic factor in producing both acute and chronic lung damage in, for instance, premature babies or adults, with respiratory distress syndrome.
The influence of surfactant depletion on clearance from the lungs of inhaled technetium-99m-labeled diethylenetriamine pentaacetate (99mTc-DTPA) was studied in rabbits. Surfactant was removed by repeated lung lavage with isotone saline. To minimize structural damage to the lungs, pressure generated insufflation with short expiration was utilized. Aerosolized 99mTc-DTPA was administered via a bag-in-bottle system. Radioactivity was measured with a gamma camera and time-activity curves were obtained over the base of the right lung. Six nonlavaged rabbits served as controls. In six lavaged rabbits clearance of 99mTc-DTPA was significantly faster than in controls. In three rabbits given natural surfactant into the trachea after lung lavage, 99mTc-DTPA was eliminated faster than in controls but slower than in surfactant-depleted animals. The results indicate a role of surfactant on clearance rate of 99mTc-DTPA from rabbit lungs. Measurements of 99mTc-DTPA clearance may be useful in studying the function of the surfactant system in different lung disorders.
Within 2 minutes intravenous anti-lung serum (ALS) into guinea pig induces a respiratory failure that is fatal within 30 min. The relationship between surfactant, alveolar-capillary permeability and respiratory failure was studied. Within two minutes ALS induced a leak in the alveolar-capillary barrier. Within 30 minutes 28.3% (controls, given normal rabbit serum: 0.7%) of iv 131I-albumin, and 0.5% (controls 0.02%) of iv surfactant phospholipid tracer were recovered in bronchoalveolar lavage. Furthermore, 57% (controls 32%) of the endotracheally administered surfactant phospholipid became associated with lung tissue and only less than 0.5% left the lung. The distribution of proteins and phospholipids between the in vivo small volume bronchoalveolar lavages and the ex vivo bronchoalveolar lavages were dissimilar: 84% (controls 20%) of intravenously injected, lavageable 131I-albumin and 23% (controls 18%) of total lavageable phospholipid were recovered in the in vivo small volume bronchoalveolar lavages. ALS also decreased lavageable surfactant phospholipid by 41%. After ALS the minimum surface tension increased. The supernatant of the lavage increased the minimum surface tension of normal surfactant. In addition, the sediment fraction of the lavage had slow surface adsorption, and a marked reduction in 35,000 and 10,000 MW peptides. Exogenous surfactant ameliorated the ALS-induced respiratory failure. We propose that inhibition, altered intrapulmonary distribution, and dissociation of protein and phospholipid components of surfactant are important in early pathogenesis of acute respiratory failure.
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Pregnant rabbit does were treated intravenously with aminophylline (6 mg/kg/day) from the twenty-fifth day after the day of mating, and the fetuses were delivered by hysterotomy on the twenty-eighth day. One group of neonates was breathing air, and another group 100% oxygen. Lung mechanics were evaluated in the newborn animals during spontaneous or artificial ventilation, and the lungs were studied histologically with particular reference to the alveolar volume density. In one series of experiments, the lungs were washed and the lavage fluid was analyzed for phosphatidylcholine and phosphatidylglycerol. Aminophylline-treated litters had greater body weights, an improved survival rate, and an increased amount of phosphatidylglycerol in lung lavage fluid. Respiratory frequency was increased in aminophylline-treated animals breathing air, but data on lung compliance showed no significant difference between treated and control animals. In the present model, the beneficial effect of aminophylline can be attributed largely to a combination of accelerated fetal growth and improved postnatal regulation of breathing and less to a specific influence on the biochemical and functional maturation of the lung.
Severe respiratory insufficiency was induced in adult guinea pigs by repeated lung lavage. The animals were then ventilated for 75 min with 100% O2, insufflation pressure 28/6-8 cmH2O (2.7/0.6-0.8 kPa), frequency 30/min, and 33% inspiration time. One group of animals (I) was treated with protein-depleted porcine surfactant, prepared by a combination of sucrose-gradient centrifugation, heating to 90 degrees C, and chloroform/methanol extraction. Another group (II) received the phospholipid fraction of porcine surfactant, isolated from minced lungs by chloroform/methanol extraction and liquid-gel chromatography. Surfactant was administered in two 1-ml doses (lipid concentration 90 mg/ml) instilled via the tracheal cannula about 15 and 45 min after the lavage procedure. Non-treated, lavaged animals served as controls. After 75 min of ventilation, control values for PaO2 and PaCO2 were 13.3 +/- 6.8 and 6.8 +/- 2.3 kPa (mean +/- s.d.), respectively. The corresponding values in Group I of surfactant-treated animals were 52.9 +/- 7.7 and 4.4 +/- 1.1 kPa, in Group II 53.5 +/- 7.3 and 4.8 +/- 1.3 kPa (P less than 0.02-0.002). The two groups of surfactant-treated animals also had significantly improved alveolar air expansion in histological sections, as reflected by increased alveolar volume density (0.67 +/- 0.05 and 0.62 +/- 0.11 vs 0.45 +/- 0.08 in controls; P less than 0.002). The benefits of surfactant replacement in this experimental model were thus similar to those previously observed in animal models of neonatal surfactant deficiency as well as in babies with respiratory distress syndrome (RDS). Our data suggest that surfactant replacement might have a therapeutic effect also in clinical adult RDS.
We examined the effect of surfactant depletion on the rate of pulmonary clearance of inhaled 99mTc-diethyl-triamino-penta-acetate (DTPA). 99mTc-DTPA was administered as a fine aerosol to four control animals and to four animals after wash-out of pulmonary surfactant. Care was taken to minimize structural damage to the lavaged lungs. Clearance of 99mTc-DTPA was measured over the right lung by external counting. The clearance rate was substantially increased in the lavaged animals compared to the control animals. We conclude that the pulmonary surfactant system is a rate-limiting factor for the absorption of inhaled 99mTc-DTPA. Measurement of the pulmonary clearance of 99mTc-DTPA may provide a new means for studying the pathogenetic role of the surfactant system in a variety of lung diseases.
Sixty-eight rabbit fetuses of 27 days gestation were tracheotomised, artificially ventilated, and their lung mechanics studied in a body-enclosing plethysmograph. The animals were treated by tracheal instillation of natural surfactant concentrate or large unilamellar vesicles containing dipalmitoylphosphatidylcholine:egg phosphatidylglycerol, 9:1. Both preparations were highly surface active in terms of film adsorption and surface tension-lowering potential. Before treatment, the lung mechanics were analysed to indicate the presence of respiratory distress syndrome (RDS). Controls received 0.15 M saline. Differences were found between the in vitro and in vivo activities of both preparations in some animals. In 30 preterm animals with partial lung maturity and without respiratory distress syndrome, no significant effect could be achieved with either the natural or the artificial surfactant. In 38 animals with severe RDS, the tidal volume and compliance increased markedly within 15 min of substitution of both preparations. Compliance increased to 178% of the initial value in ventilated, control animals, to 391% in animals treated with natural, and to 344% in animals treated with artificial surfactant.
In the present study we investigated the phospholipid composition of small-volume (up to 20 ml) in vivo bronchoalveolar lavage and that of quantitative ex vivo bronchoalveolar lavage. Furthermore, the accuracy of the small-volume lavage in predicting lung disease was evaluated. There was a positive linear correlation (r approximately equal to 0.87-0.91) between the amount of saturated phosphatidylcholine and the saturated phosphatidylcholine/sphingomyelin ratio in quantitative bronchoalveolar lavage. The phospholipid distributions in the small-volume lavage and the quantitative lavage were similar (r approximately equal to 0.78-0.94, n = 14). The overall accuracy of phosphatidylcholine/sphingomyelin ratio and phosphatidylglycerol/total phospholipid ratio in predicting the presence or absence of respiratory failure was 85-87% in newborns, children, and adults. In respiratory diseases without respiratory failure, the abnormalities in the phospholipids were frequent, although less distinct. According to animal experiments the surfactant system is inhibited at the onset of high permeability lung edema. Soon thereafter, the lavageable surfactant pool is decreased. Present findings support the view that surfactant defects are of importance in the pathogenesis of respiratory disease, and that surfactant-oriented therapy may be effective in the treatment and prevention of respiratory failure.
In addition to stabilizing peripheral airways bronchial surfactant is essential for bronchoalveolar transport mechanisms including non-ciliary and ciliary mucus transport. Furthermore, it could play a role in the masking of smooth muscle receptors with respect to contractile stimuli. A model has recently been devised in which predominant impairment of the bronchial surfactant is induced by a combination of positive or negative pressure ventilation with tracheal saline instillation (approximately 3 ml/kg). It is shown that tracheal instillation or inhalation of surfactant could be a promising approach for the treatment of damage to the bronchial surfactant system. In vitro investigations of the transport properties of various phospholipid mixtures and of detergents revealed that the transport function of surface active materials is independent of both the hysteresis characteristics and the surface tension changes during compression and expansion in the Langmuir trough.
High-frequency pulse ventilation (HFPV) was compared to conventional ventilation (CV) in a model of severe respiratory failure induced by serial lung lavages with warm saline in 8 mongrel dogs. Before the lavage, during HFPV at 4 Hz with a pulse volume (PV) of 125 ml, mean PaO2 was 107 torr and mean PaCO2 was 34 torr. After the last lavage, during CV at an inspired oxygen fraction FIO2 of 1.0 and a tidal volume (VT) of 535 ml, the PaO2 averaged 60 torr and PaCO2 was 45 torr. At an FIO2 of 0.21, 20 cm H2O of positive end-expiratory pressure (PEEP) was applied to prevent hypoxemia. The resulting PaO2 was 87 torr; PaCO2 was 40 torr. Peak airway pressure (Ppa) rose from 21 to 51 cm H2O. When ventilation was switched to HFPV on room air, a PV similar to the control levels was associated with severe hypoxemia (PaO2 less than 45 torr, PaCO2 greater than 50 torr). As PV was increased PaO2 improved, reaching 113 torr at a PV of about 470 ml. The corresponding mean airway pressure (Paw) was about 20 cm H2O. Thus, application of PEEP during HFPV at low PV did not improve PaO2 even when measured Paw approximated 20 cm H2O. This suggests that HFPV with high PV is more effective than either CV with PEEP, or HFPV with low PV and PEEP.
A method is described which allows the investigation of lung mechanics during artificial ventilation in live mice. Inhalation of nebulized influenza virus (A/PR/8/34, H1N1) decreased in NMRI mice compliance (means = 0.012 ml/cm H2O, n = 18) due to severe virus pneumonia and edema on days 5-7 after infection. In comparison to noninfected controls (means = 0.029 ml/cm H2O, n = 17) compliance was unchanged in infected, but orally immunized mice (means = 0.030 ml/cm H2O, n = 21). The results demonstrate that decreased compliance due to influenza virus pneumonia can be prevented by oral immunization with influenza viruses.
Premature rabbit neonates, delivered on day 28 of gestation, were treated with a single dose of dibuturyladenosine-3':5'-cyclic monophosphate (cyclic AMP), 300 mg/kg, immediately after delivery, saline-injected litter-mates serving as controls. All animals were kept in body plethysmographs and ventilated artificially with 100% oxygen for 1 h, with a maximal tidal volume of 10 ml/kg body weight. Lung-thorax compliance was significantly improved in animals treated with cyclic AMP, both 30 and 60 min after onset of ventilation (0.92 +/- 0.09 vs. 0.59 +/- 0.08 ml/cm H2O.kg and 0.96 +/- 0.09 vs. 0.53 +/- 0.08, p less than 0.005), but there was no improvement in alveolar air expansion, evaluated histologically. Phosphatidylglycerol was absent in alveolar wash from all control animals, but present in 3 of the 8 pooled samples from the animals treated with cyclic AMP; this difference was not statistically significant, however.
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