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Metabolites of arachidonic acid (AA) released into bronchoalveolar lavage fluid of animals exposed to hyperoxia have previously been implicated as mediators of pulmonary oxygen toxicity. The alveolar macrophage (AM) represents an important potential source of these eicosanoids. We have therefore investigated the effects of in vitro hyperoxia (95% O2/5% CO2) versus normoxia (95% air/5% CO2) on the metabolism of AA in the AM of the rat. Exposure to 95% O2 for up to 72 h did not impair the viability or affect the protein content of cultured AMs. Hyperoxia for 24 to 72 h increased the accumulation of free AA liberated from endogenous stores in cultures of resting AMs. Despite this increase in free AA, no changes in synthesis of thromboxane B2, prostaglandin (PG) E2, PGF2 alpha, leukotriene (LT) B4, or LTC4 were observed in resting AMs exposed to hyperoxia for up to 72 h. This was not due to degradation of eicosanoids in hyperoxia. However, formation of cyclooxygenase metabolites from exogenously supplied AA was reduced in hyperoxia-incubated AMs, suggesting that hyperoxia inhibited the cyclooxygenase enzyme. In AMs stimulated with calcium ionophore A23187, both AA release and synthesis of cyclooxygenase and lipoxygenase eicosanoids were augmented after incubation in hyperoxia for 24 to 72 h. The increase in A23187-stimulated LTB4 synthesis caused by hyperoxia was inhibited by the antioxidants catalase, superoxide dismutase, and the intracellular cysteine loading agent L-2-oxothiazolidine-4-carboxylic acid, suggesting that the augmentation by hyperoxia of A23187-induced AA metabolism was mediated by reactive oxygen metabolites. Thus, hyperoxia has complex effects on AA metabolism in the AM, which include the ability to augment the release of AA and formation of bioactive eicosanoids. These findings support a possible role for eicosanoid synthesis by the AM in the pathogenesis of oxygen toxicity of the lung.
Am J Respir Cell Mol Biol 1990 Jan
PMID:Complex effects of in vitro hyperoxia on alveolar macrophage arachidonic acid metabolism. 215 14

Confluent monolayers of bovine pulmonary artery endothelial cells (BPAE) or human umbilical vein endothelial cells (HUVE) inhibited by 80 to 90% the production of O2- by added human neutrophils (PMNs) stimulated by plasma membrane receptor-mediated activators (formylmethionylleucylphenylalanine [fMLP], opsonized zymosan, heat-killed Staphylococci), but not by non-plasma membrane receptor-mediated activators (phorbol myristate acetate and delta-hexachlorocyclohexane). Degranulation induced by fMLP was also inhibited by BPAE. Inhibition was not affected by eicosatetraynoic acid (ETYA) or indomethacin. To assess the role of cell-cell contact, 0.45-microns-pore culture plate inserts were employed to prevent PMN-endothelial cell contact during incubation. A similar amount of inhibition of stimulated PMNs superoxide production was seen as compared to PMN-endothelial incubations where contact occurred. A soluble component released by BPAE monolayers, when added to PMNs, duplicated the inhibition seen by BPAE-PMN co-incubation. Incubation of BPAE with adenosine deaminase did not reduce inhibition of O2- production compared to controls without adenosine deaminase. There was no evidence of endothelial scavenging of O2- generated by hypoxanthine-xanthine oxidase, and inhibition of endothelial superoxide dismutase did not diminish the inhibitory effort. We conclude that cell contact is not required for BPAE inhibition of fMLP-stimulated O2- production by PMN, and that scavenging of superoxide anion is not the mechanism. The inhibitor appears to be a polypeptide with an apparent molecular weight between 1,000 and 10,000 D and does not appear to be adenosine, an arachidonate metabolite, or superoxide dismutase. The mechanism may involve down-regulation of plasma membrane receptor-mediated activation of PMNs.
Am J Respir Cell Mol Biol 1990 Mar
PMID:Endothelial cells inhibit receptor-mediated superoxide anion production by human polymorphonuclear leukocytes via a soluble inhibitor. 215 31

An electron spin resonance (ESR) spin trapping technique was applied to determine the generation of superoxide anions in submitochondrial particles prepared from the ischemic heart. Ischemia was produced in the dog heart by occlusion of the circumflex coronary artery for 60 min. Mitochondria were prepared from ischemic and non-ischemic regions of myocardial tissue. To avoid the influence of superoxide dismutase located in the mitochondrial matrix, submitochondrial particles were utilized instead of whole mitochondria. Using the spin trap 5,5'-dimethyl-1-pyrroline-N-oxide (DMPO), the kind of active oxygen species generated from the mitochondrial electron transport system was determined from ESR spectrum. The relative signal intensity of the DMPO-superoxide anion adduct was found to be high in submitochondrial particles prepared from subsarcolemmal mitochondria obtained from the ischemic region, as compared with those from the non-ischemic region.
J Mol Cell Cardiol 1990 Aug
PMID:O2-. spin trapping on cardiac submitochondrial particles isolated from ischemic and non-ischemic myocardium. 217 58

Isolated myocytes of rat heart, and sealed sarcolemmal vesicles of bovine heart, were used to examine the selectivity of the effects of partially reduced oxygen species (generated by a mixture of xanthine and xanthine oxidase) on cardiac sodium pump and several other ion transporters of the plasma membrane. When myocytes were exposed to xanthine plus xanthine oxidase, there were time-dependent inhibitions of ouabain-sensitive 86Rb+ uptake and (Na+ + K+)-ATPase activity that could be prevented by allopurinol, or by catalase and superoxide dismutase; suggesting the involvements of H2O2 or oxygen free radicals in the inhibition of the pump. This inhibition preceded any significant decrease in cellular ATP or in the number of viable cells. While ouabain increased 45Ca2+ uptake by myocytes as expected, exposure to xanthine plus xanthine oxidase decreased 45Ca2+ uptake; suggesting that the Na+, Ca2(+)-exchanger of the intact myocytes is also inhibited by oxygen metabolites. Simultaneous inhibitions of the pump, the Na+, Ca2(+)-exchange, the Na+, H(+)-exchange, and the Na+, Pi-cotransport activities also occurred in sarcolemmal vesicles that were treated with xanthine plus xanthine oxidase. These findings indicate that inactivations of the sodium pump and other sarcolemmal ion carriers are early events in the oxidant-induced damage to the cardiomyocyte. In the rat heart myocytes, a fraction of (Na+ + K+)-ATPase that seems to be more sensitive to ouabain, was inactivated more rapidly upon exposure of myocytes to xanthine plus xanthine oxidase; raising the possibility of the existence of different pump populations with different sensitivities to extracellularly generated oxygen metabolites.
J Mol Cell Cardiol 1990 Aug
PMID:Studies on the specificity of the effects of oxygen metabolites on cardiac sodium pump. 217 59

Ozone (O3) is a powerful oxidizing component of air pollution that may react with other air pollutants before or after inhalation. Because ozonized compounds can be mutagenic to bacteria, we examined whether ambient O3 levels can transform tobacco smoke arylamines into products that are genotoxic to human lung cells. To test this possibility, aqueous solutions of 1-naphthylamine (1-NA) were first exposed to air or O3 in the absence of cells and then used to treat cultured human lung cells, i.e., the diploid fibroblasts CCD-18Lu and the transformed type II epithelial cells A549. DNA single-strand breaks were assayed by DNA alkaline elution. Neither air-exposed 1-NA nor O3-exposed buffer or water were DNA-damaging. However, exposure of 1-NA (15 microM) to O3 (0.1 ppm; 1 h) produced 400 rad equivalents of DNA breaks in either cell type. Although maximal induction of DNA breaks depended upon arylamine concentration, the rates at which DNA-damaging products were formed (activated) and subsequently deactivated depended upon O3 concentration. O3-activated 1-NA was stable for at least 4 h and could damage cellular DNA at 4 degrees C. During ozonization, hydroperoxides were formed at levels equivalent to between 2 and 20 microM of hydrogen peroxide and were eliminated by treatment with catalase. However, failure of catalase and superoxide dismutase to block formation of DNA breaks indicated that neither hydrogen peroxide nor superoxide anions were involved in breaking DNA.(ABSTRACT TRUNCATED AT 250 WORDS)
Am J Respir Cell Mol Biol 1990 Dec
PMID:Induction of DNA damage in cultured human lung cells by tobacco smoke arylamines exposed to ambient levels of ozone. 217 79

We have previously demonstrated that induction of the heat-shock response in rats results in improved recovery of isolated Langendorff-perfused rat hearts subjected to low-flow ischemia followed by reperfusion (Currie et al., 1988). The mechanisms underlying this protective effect of heat-shock are uncertain although the protection was associated with enhanced content of the antioxidant enzyme catalase but not superoxide dismutase or glutathione peroxidase (Currie et al., 1988). Various investigators have suggested the importance of improved energy metabolism in determining recovery following ischemia (Pasque and Wechsler, 1984; Haas et al., 1984; Devous and Lewandowski, 1987). We therefore examined, using a working rat heart model subjected to 10 or 15 min zero flow ischemia whether changes in energy metabolites could account for the protective effect of the heat-shock response. Hearts perfused 24 h after induction of heat-shock failed to demonstrate significant improvement of recovery following 10 min ischemia, however recovery was significantly enhanced in hearts reperfused after 15 min ischemia. Ischemia produced a depression in both ATP and creatine phosphate (CP) content whereas a moderate elevation in ADP and AMP and a marked increase in tissue lactate were evident. These changes were unaffected by prior heat-shock treatment. For both durations of ischemia tissue metabolites were determined during early (5 min) and late (30 min) reperfusion. Although partial recovery in high energy phosphates and a return of ADP, AMP and lactate to near-normal levels were evident, no differences in energy products were observed between hearts from normal or heat-shocked animals, in spite of significantly enhanced recovery.(ABSTRACT TRUNCATED AT 250 WORDS)
J Mol Cell Cardiol 1990 Jun
PMID:Improved post-ischemic ventricular recovery in the absence of changes in energy metabolism in working rat hearts following heat-shock. 223 33

A new method for calculating the total electrostatic free energy of a macromolecule in solution is presented. It is applicable to molecules of arbitrary shape and size, including membranes or macromolecular assemblies with substrate molecules and ions. The method is derived from integrating the energy density of the electrostatic field and is termed the field energy method. It is based on the dielectric model, in which the solute and the surrounding water are regarded as different continuous dielectrics. The field energy method yields both the interaction energy between all charge pairs and the self energy of single charges, effectively accounting for the interaction with water. First, the dielectric boundary and mirror charges are determined for all charges of the solute. The energy is then given as a simple function of the interatomic distances, and the standard atomic partial charges and volumes. The interaction and self energy are shown to result from three-body and pairwise interactions. Both energy terms explicitly involve apolar atoms, revealing that apolar groups are also subject to electrostatic forces. We applied the field energy method to a spherical model protein. Comparison with the Kirkwood solution shows that errors are within a small percentage. As a further test, the field energy method was used to calculate the electrostatic potential of the protein superoxide dismutase. We obtained good agreement with the result from a program that implements the numerical finite difference algorithm. The field energy method provides a basis for energy minimization and dynamics programs that account for the solvent and screening effect of water at little computational expense.
J Mol Biol 1990 Dec 20
PMID:A precise analytical method for calculating the electrostatic energy of macromolecules in aqueous solution. 226 55

The effects of infusing superoxide dismutase (SOD) and catalase (CAT) into the coronary circulation were investigated in isolated, working rat hearts prior to and during a 15 minute episode of regional ischemia followed by 30 minutes reperfusion. Aortic output, left ventricular pressure and dP/dT were recorded. Compared to untreated hearts, SOD and CAT significantly improved function during reperfusion, but had no effect during the pre-ischemic or the ischemic period. To investigate possible transport of SOD and CAT into rat myocytes, cryotome sections of isolated, Langendorff perfused rat hearts were exposed to rabbit antibody prepared against the exogenous SOD and CAT. Bound antibody was detected by the indirect-fluorescent antibody test. The interior of myocytes from rat hearts exposed to SOD and CAT bound antibodies prepared against these enzymes, whereas myocytes from rat hearts not exposed to exogenous SOD and CAT only bound the CAT antibodies. This indicates the anti-SOD we prepared is specific for exogenous SOD, and also suggests exogenous SOD can gain access to the cytoplasm of myocytes from the coronary circulation.
Mol Cell Biochem 1990 Aug 10
PMID:Exogenous superoxide dismutase and catalase promote recovery of function in isolated rat heart after regional ischemia and may be transported from capillaries into myocytes. 227 50

To study the effect of protein flexibility on electrostatic recognition, we have devised two novel computer graphic representations of the changes in the electrostatic field of a protein resulting from its internal motions. The atomic structure of Cu, Zn superoxide dismutase was minimized, and the 200 lowest frequency normal modes of the enzyme were determined. Individual and combined normal-mode vibrations were visualized interactively with the program Flex. Normal-mode motions are fast enough (approximately 10(-11) s cycle-1) to evade solvent damping, thus allowing long-range electrostatic interactions to dominate. The changing electrostatic environment of the protein was examined by animating precalculated frames of electrostatic field vectors with GRAMPS. With Vu, changes in electrostatic potential were displayed as variations in the color-coding of dots lying on a consensus surface that maintains the protein's shape. The consensus surface was calculated with the program Sphinx, and was derived from spherical harmonic approximations of expanded molecular surfaces. The ability to view the effects of molecular motions interactively should be useful in understanding the relationships of protein structure to function.
J Mol Graph 1990 Sep
PMID:Visualization of molecular flexibility and its effects on electrostatic recognition. 227 8

To better understand the protective effect of water-soluble antioxidants against free radical injury to the reperfused ischemic myocardium, we studied the antioxidant effectiveness of superoxide dismutase (SOD), catalase, ascorbic acid, and Trolox, a water-soluble analogue of alpha-tocopherol, in protecting cultured adult human ventricular myocytes and fibroblasts and saphenous vein endothelial cells from hypoxanthine-xanthine oxidase generated free radicals. The cells were cultured at oxygen tension to 150 and 40 mmHg. Passage P2 to P4 cells were injured by a hypoxanthine-xanthine oxidase free radical generation system. The time when all the cells became shriveled divided by the cell count expressed in terms of 100,000 cells was used to compare cellular susceptibilities to free radical injury and the relative effectiveness of the antioxidants. Fibroblasts were more resistant to free radical injury than myocytes which were more resistant than endothelial cells, when all three cell types were cultured at the same oxygen tension. Trolox and ascorbic acid were effective antioxidants for myocytes while SOD and catalase were ineffective. SOD and catalase were more effective than ascorbic acid as antioxidants for endothelial cells and fibroblasts, while Trolox was ineffective. In summary, we have shown that each cultured cell type has a different susceptibility to free radical damage and that antioxidants are not effective for all cell types.
J Mol Cell Cardiol 1990 Nov
PMID:Water-soluble antioxidant specificity against free radical injury using cultured human ventricular myocytes and fibroblasts and saphenous vein endothelial cells. 228 86


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