ISSN:0190-2148    

DOI:10.3109/01902148809064179

出版商:Taylor&Francis    

年代:1988

数据来源: Taylor

摘要:

Exposure to high concentrations of oxygen causes injury throughout the respiratory tract. Good markers for the earliest stages of injury are not available although the course of tissue and cell responses to injury has been well characterized in a variety of animal models including rats and subhuman primates. Exposure to subacute levels of hyperoxia (40%-60% O2) causes lung injury that is difficult to detect even after exposures of up to 7 days in duration unless animals are subsequently stressed with a second form of lung injury. Rats preexposed to 40% and 60% O2die sooner when exposed to 100% O2than do control animals, suggesting an increased susceptibility to a second injury. Rats exposed to 60% O2are more susceptible to development of pulmonary edema during high tidal volume mechanical ventilation, suggesting an increased susceptibility to mechanical stress. Exposures to 60% O2may set up chronic progressive inflammatory reactions in the lung interstitium manifested by an increase in interstitial cells and matrix occurring weeks after the hyperoxic exposure. Both rats and baboons show similar responses to acute lethal exposures to hyperoxia, although the time course is more prolonged in the baboon. Both species demonstrate increased numbers of neutrophils in the lung microvasculature as one of the earliest structural evidences of lung injury. Both species demonstrate an increase in interstitial cells, quantitative evidence of injury to alveolar epithelial cells, and a significant fall in the number of capillary endothelial cells during the late phases of hyperoxic lung injury. These changes are associated with significant decreases in the total lung capacity and residual volume, increases in pulmonary artery pressure and pulmonary vascular resistance, and tachycardia. Baboons develop a 30% reduction in cardiac output after 80 h of 100% oxygen exposure because of a diminished ejection fraction. The primary difference in the progression of lung injury between species is in the time course rather than in the basic pattern of morphologic and physiologic responses.

ISSN:0190-2148    

DOI:10.3109/01902148809064180

出版商:Taylor&Francis    

年代:1988

数据来源: Taylor

摘要:

Hypoxia (10%-12% O2) preadaptation for 4-7 days effectively protects rats from oxygen toxicity. The present study was designed to investigate the hypothesis that the lung's microvascular endothelium shares in development of oxygen tolerance and therefore that endothelial metabolic function would he protected from oxygen toxicity by prior adaptation to hypoxia. Since pulmonary oxygen toxicity decreases lung capillary angiotensin converting enzyme (ACE) activity, we assayed converting enzyme active sites in an isolated perfused rat lung preparation as a marker for the development of oxygen toxicity and tolerance. Rats were exposed to air, hypoxia (10% O2for 4 days), hyperoxia (95% O2for 2 days) alone, or hypoxia followed immediately by hyperoxia. Lung vascular ACE content was quantitated by measuring the single pass binding of an iodinated-converting enzyme inhibitor,125I-MK351A, a derivative of lisinopril. Hypoxia adaptation per se had no effect on ACE content reflected in normal125I-MK351A binding, whereas hyperoxia exposure caused a significant decrease in lung vascular ACE. Hyperoxia-induced decreases in ACE content were prevented partially by hypoxia adaptation, indicating that A CE content on luminal endothelial surfaces was protected from oxygen toxicity. In isolated perfused lungs125I-MK351A binding reflects development of oxygen tolerance after hypoxia preadaptation and suggests that lung endothelial metabolic function is protected from oxygen toxicity.

ISSN:0190-2148    

DOI:10.3109/01902148809064181

出版商:Taylor&Francis    

年代:1988

数据来源: Taylor

摘要:

As part of a comprehensive study of specific organ oxygen tolerance [1-4], oxygen effects on pulmonary function were measured in normal, resting men who breathed oxygen continuously at 3.0, 2.5, 2.0, and 1.5 atmospheres absolute (ATA) for average durations of 3.4, 5.7, 9.0, and 17.7 h, respectively. Rates of development of effects of pulmonary oxygen toxicity were monitored during oxygen exposure at 2.5, 2.0, and 1.5 ATA with repeated flow-volume loops, spirometry, and symptom assessment. Additional pulmonary measurements before and after exposure included lung compliance, airway resistance, density dependence of flow, nitrogen closing volumes, carbon monoxide diffusing capacity, and alveolar-arterial oxygen differences. Of these measurements only airway resistance and closing volumes were not significantly affected at any pressure, but patterns and magnitudes of effects varied at different pressures. Overall, the data indicate that continuous oxygen exposure at 3.0 to 1.5 ATA affects pulmonary mechanical function earlier and more prominently than CO diffusing capacity. Recovery of lung mechanical function usually occurred within 12-24 h after exposure, but required more than 24 h in some individuals. No individual measure of pulmonary function was found to be uniquely satisfactory for monitoring rates of development or reversal of pulmonary oxygen poisoning. The existence of multiple pulmonary effects of oxygen toxicity and the complexity of their interactions require selective applications of individual toxicity indices to specific conditions of exposure and recovery.

ISSN:0190-2148    

DOI:10.3109/01902148809064182

出版商:Taylor&Francis    

年代:1988

数据来源: Taylor

摘要:

Male rats (Charles River COBS-CD derived) fed protein-deficient diets showed enhanced toxicity with failure of elevation of lung glutathione levels with exposure to greater than 98% O2. Replenishment of S-containing amino acids in the protein-deficient diets allowed elevation of lung glutathione and prevention of enhanced toxicity. Studies with endothelial cell cultures exposed to hyperoxia showed elevation of cellular glutathione coupled with enhanced uptake of amino acid precursors of glutathione. We postulate that hyperoxia causes an enhancement of uptake of S-containing amino acids necessary for glutathione synthesis, overriding glutathione feedback of its own synthesis. Limitation of available S-containing amino acids prevents elevation of glutathione synthesis and is detrimental to the cell exposed to hyperoxia.

ISSN:0190-2148    

DOI:10.3109/01902148809064183

出版商:Taylor&Francis    

年代:1988

数据来源: Taylor

摘要:

Glutathione peroxidase is a crucial component of cellular antioxidant defenses. Using tertiary butyl hydroperoxide (tBOOH) as a model for oxidant stress in alveolar macrophages, we determined the effectiveness of glutathione peroxidase in preventing both cell“death”(lactate dehydrogenase release) and more subtle alterations in cell function. The KMof glutathione peroxidase for tBOOH was 54μM, and the Vmaxwas 26 nmol/min/106cells in alveolar macrophages. Concentrations of tBOOH greater than 100μM caused lactate dehydrogenase release; however, a lag greater than 30 min was observed when with 10μM tBOOH. With 200μM tBOOH, the rate of decrease in membrane potential, measured by 3,3′-dipentyloxacarbocyanine iodide fluorescence, inversely correlated with glutathione peroxidase. Computer-enhanced microscopy showed that this fluorescence predominately was in mitochondria. NADPH fluorescence was altered in selenium-deficient alveolar macrophages; the tBOOH-dependent rate of NADPH oxidation was slowed, and higher concentrations of tBOOH were required to disturb the steady state NADPH/NADP+ratio. Although alteration in NADPH or glutathione oxidation can reflect oxidant stress and can adversely affect cell function, such a change does not dictate irreversible injury. Nevertheless, irreversible injury by oxidants appears to involve an overwhelming of the glutathione-NADPH antioxidant system.

ISSN:0190-2148    

DOI:10.3109/01902148809064184

出版商:Taylor&Francis    

年代:1988

数据来源: Taylor

摘要:

Because high partial pressures of oxygen (Of) can cause peroxidative cleavage of membrane lipids, it is plausible to hypothesize that hyperoxia alters the physical state and composition of lipids in the membranes of pulmonary endothelial cells and that manipulation of the lipid profile may modify endothelial cell tolerance to hyperoxic injury. To test this, porcine pulmonary artery endothelial cells were exposed to 95% O2at 1 atmosphere absolute (ATA) in the presence or absence of as vacennic acid (CVA), a monounsaturated fatty acid (C18:1#11). Plasma membrane fluidity was assessed by fluorescence spectroscopy, plasma membrane lipid composition was quantitated using thin layer and gas chromatography, and cytotoxicity was monitored by measuring release of lactate dehydrogenase (LDH). Hyperoxia caused peroxidation of membrane lipids and decreased fluidity in three distinct lipid domains within the plasma membrane. Incubation with CVA was associated with a reduction in the degree of unsaturation of the constituent fatty acids within all plasma membrane lipid subclasses except monoglycerides. CVA-treated cells were also more resistant to hyperoxic injury as judged by LDH release. These results support the hypothesis that cells with membranes in which the fatty acyl chains are more resistant to the disordering effects of high O2tensions may be more resistant to O2toxicity.

ISSN:0190-2148    

DOI:10.3109/01902148809064185

出版商:Taylor&Francis    

年代:1988

数据来源: Taylor

摘要:

Preexposure of rats to sublethal levels of hyperoxia or ozone reduces morbidity and mortality when the animals are subsequently exposed to lethal levels of either oxidant stress. Lung homogenates and isolated type II pneumocytes from rats exposed to these oxidant stresses demonstrate enhanced antioxidant enzyme activities. Antioxidant enzymes, superoxide dismutase, catalase, and glutathione peroxidase are responsible for the detoxification of partially reduced oxygen species, superoxide and hydrogen peroxide, to less reactive states. Potential pulmonary cellular loci of partially reduced oxygen include mitochondrial NADH dehydrogenase, endoplasmic reticulum-derived NADPH cytochrome c reductase, and cytosolic xanthine oxido reductase. Thus partially reduced oxygen species are hypothesized to mediate hyperoxia and ozone-induced pulmonary damage. This damage may be attenuated by enhanced intracellular antioxidant enzyme activities. Pharmacologic augmentation of pulmonary antioxidant enzymes may be accomplished via intratracheal or intravascular delivery of liposomes containing antioxidant enzymes. Rats pretreated with liposomes containing both superoxide dismutase and catalase, when subsequently exposed to lethal levels of hyperoxia, demonstrate enhanced survival compared with control animals or with animals treated with control liposomes or native antioxidant enzymes. Finally, knowledge obtained from in vitro investigations optimizing liposomal delivery to specific pulmonary cell types may further aid in reducing in vivo pulmonary damage to hyperoxia and ozone.

ISSN:0190-2148    

DOI:10.3109/01902148809064186

出版商:Taylor&Francis    

年代:1988

数据来源: Taylor

摘要:

Results of attempts to ameliorate hyperoxic pulmonary injury using novel systems for delivery of antioxidant enzymes are reviewed. Intratracheal insufflation of either liposome encapsulated superoxide dismutase or encapsulated catalase increased levels of enzyme activities in rat lung homogenates and prevented lethal effects of an atmosphere of oxygen. Intact erythrocytes placed in the tracheobronchial tree of rats also dramatically improved survival in hyperoxia. Recyclable glutathione appeared to be the constituent of erythrocytes, which was responsible for the protection. In rabbits, erythrocytes also protected from oxidant-mediated ischemic-reoxygenation lung injury. These studies suggest a possible role for erythrocytes as biologic packets of antioxidant enzymes.

ISSN:0190-2148    

DOI:10.3109/01902148809064187

出版商:Taylor&Francis    

年代:1988

数据来源: Taylor

摘要:

Treatment of adult rats with low doses of bacterial lipopolysaccharide (endotoxin) consistently results in a marked protective effect against 02-induced lung damage and lethality. We report here two means to improve the therapeutic ratio of endotoxin (ratio of dose producing desired beneficial effect/dose producing undesired toxic effects), which could make it a more acceptable pharmacologic agent for possible use in patients who require prolonged hyperoxic therapy, (a) Rats made“tolerant”to the lethal/toxic effects of high doses of endotoxin (25 mg/kg) by pretreatment with very low doses of endotoxin (10 ng 10μg/kg) were found to still respond to a standard protective dose of endotoxin (500μ.g/kg) with marked resistance to 02toxicity. (Survival in 95%O272 h = 19/20 (95%), vs. 4/17 (24%) for controls.) (b) Two chemically modified native endotoxin preparations (“endotoxoids”), with−100 decreased toxic potential, were found to have retained their ability to protect adult rats from prolonged hyperoxic exposure (90%-100% survival rates). These two experimental manipulations (use of the“endotoxin tolerance”phenomenon and treatment with partially detoxified“endotoxoids”) were associated with increased lung antioxidant enzyme activities during 02exposure in the treated animals. Continued research may eventuate in the possible clinical application of a safe form of endotoxin treatment for the prevention of O2toxicity in humans.

ISSN:0190-2148    

DOI:10.3109/01902148809064188

出版商:Taylor&Francis    

年代:1988

数据来源: Taylor