Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0432222 (SEM)
 47,337 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Epithelial shedding is a characteristic feature of asthmatic airways and has been attributed to eosinophil products. We have examined the interaction of purified intraperitoneal guinea pig eosinophils with or without platelet-activating factor (PAF, 10(-7) M) or lyso-PAF (10(-7) M) with guinea pig tracheal epithelium in vitro. At 0, 4, 14, and 24 h, the percentage of ciliation of the tracheal circumference (CTC) was measured by light microscopy and the ciliary beat frequency (CBF) by photometry. PAF-activated eosinophils (50 x 10(6) cells/ml) disrupted the epithelium, mean CBF and CTC being reduced by 77.8 +/- 5.8% (mean +/- SEM; P less than 0.001 versus control) and 94.2 +/- 1.4% (P less than 0.001) over 24 h, respectively. PAF (10(-7) M) alone had no significant effect. Lyso-PAF with eosinophils (50 x 10(6) cells/ml) also reduced mean CBF and CTC but to a lesser extent. Eosinophils alone also led to a reduction of 36.2 +/- 11.4% in mean CBF and 53.0 +/- 15.5% in CTC, but these changes were not significant. The PAF antagonist, WEB 2086 (10(-6) M), significantly inhibited the mean CBF and CTC reduction due to PAF-activated eosinophils by 61.5 +/- 17.2% (P less than 0.01) and 20.8 +/- 6.5% (P less than 0.05), respectively. In addition, catalase (1,125 U/ml) partially inhibited the mean CBF and CTC reduction induced by PAF-activated eosinophils. Intraperitoneal neutrophils (PMN) (50 x 10(6) cells/ml) also disrupted epithelium but to a lesser extent (24-h reduction: 34.2 +/- 12.7% for mean CBF and 60.2 +/- 13.2% for CTC, respectively). Stimulation with PAF (10(-7) M) had no further effect. Marked exfoliation of the epithelial layer was observed after 14 h of incubation with activated eosinophils. We concluded the PAF-activated eosinophils are capable of grossly disrupting ciliated epithelium and may contribute to epithelial damage observed in asthma.
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PMID:The effects of activated eosinophils and neutrophils on guinea pig airway epithelium in vitro. 232 67

Amiodarone (ADR), a new antiarrhythmic drug for life-threatening cardiac arrhythmias, causes pneumonitis or lung fibrosis in a sizeable minority of patients. The cause of lung damage is not known. We have shown that infusion of 10 mg amiodarone into the inflow circuit of ventilated and perfused rabbit lungs causes immediate increase in pulmonary artery pressure (mean +/- SEM) (from 13.6 +/- 1.2 to 40.6 +/- 9.5 mm Hg, p less than 0.01) and pulmonary edema with marked increase in the pulmonary generation of thromboxane and leukotrienes C4 and/or D4. Albumin (2 g%) in the perfusate prevents any increase in lung perfusion pressure or edema formation. When lung perfusion pressure increase is blocked with the combined cyclooxygenase and lipoxygenase inhibitor enolicam sodium (CG5391B, 35 microM in perfusate), significant lung edema still occurs after amiodarone, indicating that amiodarone causes increased alveolar-capillary membrane permeability. Addition of catalase (100 U/ml) or superoxide dismutase and catalase (100 U/ml each) to perfusate fails to protect from amiodarone lung injury. Immediate infusion of amiodarone (10 mg) into lungs ventilated with room air (ADR + RA) causes an increase in lung weight gain from baseline (delta W) of 5.7 +/- 1.5 g/min. Compared with ADR + RA, ventilation of lungs with 4% O2 (delta W = 0.7 +/- 0.3 g/min, p less than 0.05), pretreatment of rabbits for 3 days with butylated hydroxyanisole (BHA, 100 mg/kg/day i.p., delta W = 0.05 +/- 0.02 g/min, p less than 0.01), pretreatment of rabbits for 3 days with vitamin E (Vit E, 300 U/day orally, delta W = 0.6 +/- 0.2 g/min, p less than 0.05), or addition of N-acetylcysteine to the lung perfusate (NAC, 5 mM, delta W = 0.1 +/- 0.08 g/min, p less than 0.01) all protect from lung edema formation after amiodarone. Amiodarone (100 mg) also caused a marked increase in luminol-enhanced lung chemiluminescence, lung production of superoxide anion (O2-), and tissue levels of lung glutathione disulfide. These results suggest that amiodarone causes lung injury by an oxidant mechanism.
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PMID:Amiodarone causes acute oxidant lung injury in ventilated and perfused rabbit lungs. 245 31

Besides their cytotoxic effects, Tumor necrosis factor (TNF) and Lymphotoxin (LT) were shown to modulate distinct PMN functions. Therefore, in the present study we evaluated the effect of recombinant human TNF and LT on the oxidative metabolism of isolated human PMN. In addition ultrastructural changes upon stimulation were evaluated. For detection of granulocyte activation different assay systems were used: 1) lucigenin-dependent chemiluminescence (CL), 2) superoxide-dismutase (SOD) inhibitable cytochrome C-reduction (superoxide), 3) horseradish peroxidase-mediated oxidation of phenol red (hydrogen peroxide), 4) release of myeloperoxidase, 5) ultrastructural detection of hydrogen peroxide-production, 6) scanning and transmission electron microscopy (SEM and TEM). TNF at concentrations as low as 10(-3) U/ml induced a distinct CL response, whereas LT appeared to be less active. PMN preincubated with TNF or LT for 150 min were completely deactivated to renewed stimulation with TNF, LT, and with GM-CSF, but responded to other triggers of the oxidative burst. Moreover, stimulation with f-met-leu-phe resulted in an enhanced response after preincubation with TNF or LT. The CL response was significantly inhibited by SOD, but not by catalase, D-mannitol, and DMTU, suggesting that mainly .O2- is responsible for the CL signal. The effect on PMN could be completely blocked by antibodies to TNF. Significant release of reactive oxygen species upon stimulation with TNF was also demonstrated by cytochrome C reduction and by detection of H2O2 using functional and ultrastructural assays. Only minimal amounts of peroxidase were released. Activation of PMN could be visualized by SEM and TEM. After addition of TNF at concentrations as low as 10(-1) U/ml PMN adhered to the substratum and were typically polarized within 15 min. Stimulation with LT resulted in comparable results, but based on its biologic activity in the cytotoxicity assay LT, in comparison to TNF, was significantly less active. Based on the data presented LT and, particularly, TNF appear to be potent activators of PMN oxidative metabolism.
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PMID:Human tumor necrosis factor is a potent activator of the oxidative metabolism in human polymorphonuclear neutrophilic granulocytes: comparison with human lymphotoxin. 253 65

Previous work in a neonatal lamb model has demonstrated abnormalities in cerebral blood flow (CBF) and oxygen consumption (CMRO2) after asphyxia. Immediately after resuscitation, there was a marked increase in CBF and a significant decrease in CMRO2 compared to control. During the late period after asphyxia (30 min to 4 h), both CBF and CMRO2 were significantly depressed. The same postasphyxia model (n = 16) was used to examine the hypothesis that generation of oxygen free radicals during cerebral reperfusion may be involved in the genesis of late postasphyxia hypoperfusion and depressed CMRO2. Before asphyxia, the animals were pretreated with either inactivated (n = 8) or active (n = 8) polyethylene glycol superoxide dismutase, 5000 U/kg, and polyethylene glycol catalase, 100 000 U/kg. CBF (radioactive microspheres) and arterial and venous (superior sagittal sinus) blood gases and O2 contents were measured during control, and at 5 min, 1 h, 2 h, and 4 h postasphyxia (PA). In the active enzyme group, 5 min postasphyxia CBF was significantly increased compared to control: 211.5 +/- 28.0 versus 78.6 +/- 11.4 ml.100 g-1.min-1, +/- SEM, p less than 0.005. At 1 h (82.9 +/- 17.6), 2 h (62.3 +/- 5.5), and 4 h (78.9 +/- 12.2) PA, CBF did not differ significantly from control. More importantly, CMRO2 did not differ from control at any time PA. In the inactive enzyme group, both CBF and CMRO2 were depressed at 1, 2 and 4 h PA. These findings are consistent with a conclusion that damage by oxygen free radicals during postasphyxia cerebral reperfusion is important to the genesis of late PA blood flow and O2 metabolism abnormalities. To the extent that depressions in CBF and CMRO2 result in ongoing brain injury, agents that ameliorate these abnormalities may improve neurologic outcome.
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PMID:The role of oxygen free radicals in postasphyxia cerebral hypoperfusion in newborn lambs. 258 23

In the present study we have investigated isolated rat hearts perfused with oxygen radicals generated by xanthine oxidase and hypoxanthine. The influence of verapamil (1 mg.1(-1] pretreatment on oxygen radical-induced contracture development and decrease in contractility was examined. In addition, we have measured mitochondrial calcium and magnesium levels in control hearts and hearts perfused with oxygen radicals with and without addition of superoxide dismutase (SOD) and catalase. The presence of oxygen radical-induced lipid peroxidation was confirmed by the increased level of conjugated diens in lipid extracts from oxygen radical-perfused hearts. Verapamil prevented contracture development in hearts perfused with oxygen radicals. Diastolic pressure measured with a left ventricle balloon was at the end of the experiments. 18 +/- 3 mm Hg (mean +/- SEM) with verapamil and 66 +/- 9 mm Hg without (p less than 0.001). Perfusion with oxygen radicals resulted in a reduction in mitochondrial calcium from 14.63 +/- 0.93 to 8.26 +/- 0.61 nmol.mg-1 (p less than 0.001) which was partly reversed by superoxide dismutase and catalase. Mitochondrial magnesium levels were unchanged in all groups.
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PMID:Mitochondrial calcium in hearts subjected to lipid peroxidation with contracture development. 261 1

Reactive oxygen intermediates such as free radicals have been proposed to mediate lung injury. The present work examined whether or not enzymatically generated oxygen metabolites altered serotonin clearance. Isolated, plasma-perfused rat lungs were exposed to xanthine oxidase (XO) and hypoxanthine (HX). Pulmonary arterial pressure (Ppa) and lung weight were recorded. Fulminant edema was defined as a spontaneous weight increase exceeding 500 mg. Inactivation of serotonin was determined by superfusion bioassay. XO and HX reduced serotonin inactivation from 74 +/- 3% (mean +/- SEM) to 62 +/- 2%. This reduction was inhibited by the scavenger enzymes superoxide dismutase (SOD) and catalase and by allopurinol, an inhibitor of XO. Hydrostatic edema and perfusion per se did not decrease the pulmonary clearance of serotonin. XO and HX did not significantly alter Ppa. Fulminant edema developed in four of six lungs after exposure to XO and HX compared with none in the other groups. It was concluded that reactive oxygen intermediates inhibited serotonin inactivation in isolated rat lungs.
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PMID:Reactive oxygen intermediates reduce inactivation of serotonin in isolated, perfused rat lungs. 273 28

Tissue- and organ-specific factors may be important in the regulation of cytotoxic lymphocytes. We therefore examined the ability of human alveolar macrophages (AMs) to alter the tumoricidal function of lymphokine-activated killer cells (LAK cells). AMs, obtained by bronchoalveolar lavage from healthy volunteers, or peripheral blood monocytes were added to a standard 4-h chromium release LAK assay at varying concentrations. AMs severely inhibited the killing of both NK-sensitive (K562) and NK-resistant (M14) tumor cells [42 +/- 2.6% (SEM) inhibition of M14 killing at the 0.125:1 AM:LAK ratio and 83 +/- 2.3% inhibition at the 1:1 ratio, n = 9]. Peripheral blood monocytes, in contrast, were only one-eighth as inhibitory as AMs. A positive smoking history was associated with a 3- to 7-fold increase in the number of AMs recovered by bronchoalveolar lavage but had no effect on the inhibition produced per AM cell. The mechanism of inhibition was investigated. Formalin fixation produced an 8-fold reduction in the inhibitory capacity of AMs, suggesting the need for active metabolism or an intact cell membrane. No soluble mediator could be detected with a two-chamber Transwell system, in 24-h AM culture supernatants, or following blocking experiments with indomethacin, catalase, or superoxide dismutase. Binding studies demonstrated selective binding between LAK cells and AMs, yet AMs were not susceptible to LAK-mediated lysis under the usual assay conditions. In summary, AMs are potent inhibitors of in vitro LAK function. Inhibition requires direct cell contact and is independent of soluble reactive oxygen species, prostaglandins, or activation by tobacco smoking. Inhibition is not due to lysis of the AM as a competitive cold target. These results suggest that AMs may actively limit antitumor cytotoxic responses in the lung.
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PMID:Inhibition of lymphokine-activated killer cell function by human alveolar macrophages. 278 29

Neutrophil-derived reactive oxygen metabolites have been implicated as one mechanism for the cellular injury in the adult respiratory distress syndrome. Previous studies have demonstrated that alveolar lung fluid of patients with adult respiratory distress syndrome has abnormal composition and surface active properties. To examine the effects of oxygen metabolites on the viability and metabolism of type II alveolar pneumocytes, the cellular source of surfactant, isolated rat type II pneumocytes were exposed to reactive oxygen metabolites generated by the enzymatic action of xanthine oxidase upon hypoxanthine. Utilizing a 51Cr release assay to detect cellular death, we found that oxygen metabolites were lethal to type II cells in a dose-dependent manner. To demonstrate that oxygen metabolites were responsible for the toxicity, we assessed the protective effects of catalase and superoxide dismutase, scavengers of hydrogen peroxide and the superoxide anion, respectively. At a xanthine oxidase concentration of 50 mU/ml, catalase reduced the percentage of 51Cr release from 58.9 +/- 3.1% (SEM) to 7.2 +/- 2.3% (p less than 0.0001), whereas superoxide dismutase was without protection (58.9 +/- 3.1% versus 54.2 +/- 1.8% (p greater than 0.05). To determine whether oxygen metabolites also impair surfactant metabolism, we measured the incorporation of [3H]palmitate into the surfactant component disaturated phosphatidylcholine by type II pneumocytes. We found that sublethal amounts of generated oxygen metabolites caused a progressive decrease in the amount of [3H]palmitate incorporated into disaturated phosphatidylcholine. For example, using a xanthine oxidase concentration of 5 mU/ml (which causes no increased 51Cr release), we found that [3H]palmitate incorporation into disaturated phosphatidylcholine fell from a control level of 3.53 +/- 0.22 X 10(5) to 0.66 +/- 0.10 X 10(5) dpm/10(6) cells/4 hours (p less than 0.0001). Both catalase and superoxide dismutase protected the [3H]palmitate incorporation of oxygen metabolite-exposed type II cells. We conclude that reactive oxygen metabolites are injurious to type II pneumocytes and may result in impaired surfactant synthesis even at sublethal doses. Thus, oxygen metabolites generated by stimulated phagocytic cells may be responsible in part for the decreased surfactant that has been observed in adult respiratory distress syndrome.
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PMID:Effects of oxygen metabolites on rat alveolar type II cell viability and surfactant metabolism. 283 58

We examined the role of reactive oxygen metabolites in the degradation of human glomerular basement membrane (GBM) by stimulated human neutrophils. Neutrophils stimulated with phorbol myristate acetate (PMA) caused a significant degradation of GBM over 3 h resulting in 11.4 +/- 0.9% (SEM), n = 11 release of hydroxyproline compared with 0.3 +/- 0.09%, n = 11 release by unstimulated neutrophils. Superoxide dismutase, a scavenger of superoxide, did not inhibit the GBM degradation, whereas catalase, a scavenger of hydrogen peroxide, caused a marked inhibition (-60 +/- 7%, n = 4, P less than 0.001) of hydroxyproline release. Neither alpha-1 proteinase inhibitor, an inhibitor of elastase, nor soya bean trypsin inhibitor, an inhibitor of cathepsin G, caused any significant inhibition of GBM degradation. GBM degradation by cell-free supernatants obtained from stimulated neutrophils was markedly impaired in the presence of metal chelators EDTA (-72 +/- 7, n = 6, P less than 0.001) and 1,10,phenanthroline (-85 +/- 5%, n = 3, P less than 0.001). Considering these results, we postulated that reactive oxygen metabolites generated by the stimulated neutrophils activate a latent GBM degrading metalloproteinase(s). GBM degradation by supernatants obtained from incubations with catalase, azide, an inhibitor of myeloperoxidase, and methionine and taurine, scavengers of hypochlorous acid, was markedly reduced. Our data thus indicate that degradation of the GBM by PMA-stimulated neutrophils is due to activation of a latent metalloproteinase by hypochlorous acid or a similar oxidant generated by the myeloperoxidase-hydrogen peroxide-halide system.
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PMID:Degradation of human glomerular basement membrane by stimulated neutrophils. Activation of a metalloproteinase(s) by reactive oxygen metabolites. 302 61

Streptozotocin induced diabetic rat hearts were perfused under constant flow conditions with or without 1 x 10(5) U.litre-1 each of superoxide dismutase and catalase (SOD + CAT). Total global ischaemia was produced for 20 min followed by 30 min of reperfusion at pre-ischaemic flow rates. After 5 min of reperfusion, isovolumic LV developed pressure was reduced in diabetic hearts, at 22 (SEM 11)% of baseline v 67(12)% in controls, with increased frequency of ventricular fibrillation (VF) (3/10 v 10/11 hearts). SOD + CAT improved isovolumic LV developed pressure to 67(8)% of baseline during early reperfusion of diabetic hearts but did not affect non-diabetic hearts. SOD + CAT also increased the adenylate energy charge potential in post-ischaemic diabetic hearts to 0.826(0.011) v 0.781(0.012) in diabetic controls, and reduced the incidence and duration of reperfusion induced VF in diabetic hearts. SOD + CAT augmented the production of prostacyclin in coronary effluents during early reperfusion of diabetic hearts, from (baseline) 11.5(1.7) to 18.1(3.0) ng.min-1.g-1 at 2 min, compared with 11.1(1.6) to 12.5(1.9) ng.min-1.g-1 at same interval in diabetic controls. Indomethacin prevented the protective effect of the free radical scavengers on function and VF. In contrast, perfusion with the prostacyclin analogue, iloprost (3 x 10(-8) M), alone completely prevented early post-ischaemic dysfunction and reduced VF from 559(172) to 16(8) s. Oxygen derived free radicals may mediate reperfusion induced contractile dysfunction and VF in acutely diabetic hearts following brief episodes of myocardial ischaemia. The beneficial effects of SOD + CAT appear to be mediated mainly by an increase in prostacyclin production during early reperfusion.
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PMID:Superoxide dismutase plus catalase improves post-ischaemic recovery in the diabetic heart. 325 31


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