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Biomedical subjects

E R Block

Publications and source records attributed to E R Block.

At least 91 records · Page 5Linked to original sources
PubMed1985

Cyclophosphamide-induced depression of the antioxidant defense mechanisms of the lung.

Cyclophosphamide causes lung toxicity in a wide variety of animals, including humans. Recent evidence suggests that oxygen (O2) potentiates cyclophosphamide-induced pulmonary injury. We hypothesized that cyclophosphamide or one of its toxic metabolites, acrolein, may potentiate O2 toxicity by depressing lung antioxidant defense mechanisms. To test this, we gave rats cyclophosphamide (100 mg/kg), acrolein (5 mg/kg), or a vehicle (control) in a single intraperitoneal injection and then killed them during a 5-day study period. Excised lungs were analyzed for reduced glutathione (GSH) content, glucose-6-phosphate dehydrogenase (G6PD), glutathione reductase (GSH-R), glutathione peroxidase (GSH-P), and superoxide dismutase (SOD) activities. In the lungs of cyclophosphamide-treated rats, GSH content was increased 48% (P less than 0.001) on day 2 but progressively decreased to 50% of control values (P less than 0.001) on day 5. Significant reductions (P less than 0.005) in G6PD, GSH-R, and GSH-P activities occurred on days 1-5, and SOD activity was significantly decreased (P less than 0.005) on days 4 and 5 by cyclophosphamide. In acrolein-treated rats, GSH content and GSH-R, GSH-P, and SOD activities were indistinguishable from those in controls. However, G6PD was increased (35-38%) on days 2 and 3 but returned to control values thereafter. To assess whether the cyclophosphamide-induced reduction in lung antioxidant defenses increased susceptibility to acute O2 toxicity, we gave a separate group of rats cyclophosphamide, acrolein, or vehicle, and 4 days later exposed them to 100% O2 or air at 1 atmosphere absolute. All cyclophosphamide-, acrolein-, and vehicle-treated rats survived 60 h air exposure, and all vehicle-treated rats exposed to 100% O2 survived. In contrast, all of the cyclophosphamide-treated rats exposed to 100% O2 died (P less than 0.05) within 40 h. Acrolein had no effect on survival in 100% O2. These results indicate that cyclophosphamide, but not acrolein, depresses lung antioxidant defense mechanisms, which may be responsible for increased mortality from O2 toxicity in cyclophosphamide-treated animals.

Acrolein↗
PubMed1984

Biochemical indices of cyclophosphamide-induced lung toxicity.

Cyclophosphamide (CP) requires metabolic activation for its therapeutic action, and this metabolism results in the formation of two toxic metabolites, acrolein (ACR) and phosphoramide mustard (PM). To determine which metabolite is responsible for CP-induced lung injury, biochemical indices of toxicity and histopathologic changes in the lungs of CP-, ACR-, or PM-treated rats were evaluated. Experimental rats were given 200 mg kg-1 day-1 CP, 5 mg kg-1 day-1 ACR, or 50 mg kg-1 day-1 PM for 1 to 3 days, or were given 100 mg/kg CP for 1 day; control rats received vehicle alone for 1 to 3 days. Twenty-four hr after the last treatment the lungs were analyzed for (a) microsomal NADPH cytochrome c reductase and aniline hydroxylase activities; (b) microsomal lipid peroxide formation; and (c) glutathione content. In rats given 200 mg/kg CP, NADPH cytochrome c reductase and aniline hydroxylase activities decreased 66% (p less than 0.001) and 40% (p less than 0.001), respectively. Lipid peroxidation was increased 100 to 200% (p less than 0.001), and glutathione content was increased 60 to 70% (p less than 0.001). Similar but smaller changes were observed in the lungs of rats given 100 mg/kg CP. In rats given ACR, NADPH cytochrome c reductase and aniline hydroxylase activities decreased 66% (p less than 0.001) and 45% (p less than 0.001), and glutathione content increased 38% (p less than 0.05). In rats given PM, none of the biochemical variables examined were significantly altered. Phenobarbital and SKF 525-A prevented CP-induced biochemical alterations. Despite CP-induced biochemical alterations, no significant light microscopic changes were observed in the lungs. Alterations in lung mixed-function oxidase activity, GSH content, and microsomal lipid peroxide formation are early biochemical indices of CP-induced lung toxicity, and are due at least in part to the reactive metabolite ACR.

Aniline Hydroxylase↗
PubMed1984

Early metabolic changes in response to lung injury: extrapolation from animals to humans.

The pulmonary capillary endothelium provides a nonthrombogenic, semipermeable barrier between pulmonary blood and tissues. In recent years, particular attention has been focused on the ability of these cells to metabolize a variety of circulating biologically active substances either by interiorizing the substance through specific membrane transport processes or by directly altering the substance by way of enzymatic activity at the plasma membrane. Serotonin, norepinephrine, and several prostaglandins are examples of biologically active substances that are removed from the circulation by the pulmonary endothelium by way of specific transmembrane transport processes. Concomitant with the increased interest in metabolic functions of the pulmonary endothelium, there has been a growing awareness of the central role of endothelial cell abnormalities in the pathogenesis of various lung injuries and disease states. During the past several years, considerable evidence has accumulated in support of the hypothesis that alterations in the metabolic functions of the lung provide a method of detecting lung injury in vivo, and tests of the metabolic functions of the lung have progressed from in vitro systems to animal models to humans. This paper reviews some of the evidence responsible for this progression and discusses some of the limitations inherent in the extrapolation of lung metabolism studies from animal models to humans. In this discussion, particular emphasis is placed on the pulmonary uptake and metabolism of serotonin, norepinephrine, and prostaglandins E and F by mammalian lungs.

Animals↗
PubMed1983

Endotoxin protects against hyperoxic alterations in lung endothelial cell metabolism.

By evaluating the ability of endotoxin to prevent hyperoxic depressions in lung amine uptake, this study assessed whether bacterial endotoxin protects against hyperoxic injury to the pulmonary endothelium. Rats were given 500 or 1,500 micrograms/kg body wt of endotoxin or saline (controls) 30 min before a 24-h or 7-day exposure to air or 100% O2 at 1 ATA. Immediately after exposure, lungs were isolated, ventilated, and perfused via the pulmonary artery and the uptake of two amines, [14C] serotonin and [3H]norepinephrine, was measured. Amine uptake by the lungs of control rats exposed to 100% O2 for 24 h was significantly depressed, whereas amine uptake by the lungs of endotoxin-treated rats exposed to 100% O2 for 24 h was comparable to that in air-exposed controls. Endotoxin also prevented hyperoxic depression of lung amine uptake and prolonged survival in rats exposed to 100% O2 for 7 days. Pretreatment of rats with endotoxin protects against hyperoxic injury to the pulmonary endothelium, which may account for the reduced mortality in endotoxin-treated animals.

Animals↗
PubMed1982

Alpha-naphthylthiourea (ANTU) protects against hyperoxic depression of pulmonary serotonin uptake.

To evaluate whether alpha-naphthylthioura (ANTU) protects against hyperoxic injury to the pulmonary endothelium, we monitored survival and serotonin uptake by the lungs of ANTU-treated rats (5 mg/kg) and Tween 80-treated control rats exposed to 100% O2 or air at 1 atmosphere absolute. Exposure to 100% O2 for 24 h or 48 h significantly depressed serotonin uptake in control rats. Serotonin uptake in ANTU-treated rats compared with that in control rats exposed to air for 24 or 48 h was also significantly depressed. However, serotonin uptake by the lungs of ANTU-treated rats exposed to 100% O2 for 48 h was significantly greater than uptake by control lungs similarly exposed to O2. Nine of 14 ANTU-treated rats were alive after 7 days of exposure to 100% O2, and serotonin uptake by the lungs of survivors had returned to control values (3.29 +/- 0.25). In contrast, only 1 of 14 control rats survived and serotonin uptake was 1.17 in this lone survivor. These results indicate that ANTU injuries pulmonary endothelial cells but protects against subsequently hyperoxic injury. This protection may account for the reduced mortality in ANTU-treated rats exposed to hyperoxia.

Animals↗
PubMed1982

Potentiation of bleomycin toxicity by oxygen.

The clinical usefulness of bleomycin is limited by pulmonary toxicity. Recent clinical observations indicate that the pulmonary toxicity is potentiated in patients who are exposed to elevated but nontoxic concentrations of O2. We studied the interactions of O2 and bleomycin using a murine model. Mice were divided into two groups. One group was continuously exposed to 40% O2 at 1 atmosphere while the other group breathed compressed room air. The elevated O2 concentration alone was not toxic to animals. Mice in each group received either 40 mg/kg of bleomycin or normal saline twice a week sc. Median survival of mice receiving bleomycin was shortened from 8.24 to 4.35 weeks when the animals were maintained on 40% O2 (P = 0.0001). We conclude that exposure to a nontoxic but elevated O2 concentration can potentiate the toxic effects of bleomycin.

Animals↗
PubMed1982

Depression of serotonin uptake by rat lungs exposed to paraquat.

Paraquat is a widely used herbicide which causes lung injury in animals and humans. To determine whether pulmonary endothelial cell function is altered during the course of paraquat lung toxicity, we measured uptake of serotonin in isolated perfused lungs from rats injected i.p. with 25 mg/kg of paraquat dichloride. In 38 control lungs, serotonin uptake was 0.71 +/- 0.02 (S.E.) and was not significantly different in rats studied 4 and 18 hr after paraquat administration. In contrast, uptakes were 0.60 +/- 0.04 (P less than .05) 24 hr after injection of paraquat. At that time, lung histology and endothelial ultrastructure were unremarkable and dry-to-wet-weight ratios of lungs were normal. Forty-eight hours after paraquat administration, when light and electron microscope evidence of edema and inflammation were extensive, serotonin uptake was further decreased (P less than .01). Two weeks after injection of paraquat, when fibrosis was present, based on lung histology and hydroxyproline content, serotonin uptakes had returned to control levels. Administration of superoxide dismutase prolonged survival but did not protect against paraquat-induced depression of serotonin uptake. These results indicate that paraquat causes an early and reversible depression of pulmonary endothelial cell uptake of serotonin which antedates morphological alterations in lung and the endothelial cell and which is not prevented by treatment with exogenous superoxide dismutase. Uptake of serotonin may provide a sensitive and specific index of injury to the pulmonary endothelium.

Animals↗
PubMed1981

Effects of hyperoxia on transtracheal chloramphenicol influx.

Effects of exposure to high partial pressures of oxygen on transtracheal influx of chloramphenicol (Chlor) were examined using in vitro perfusion of the rat trachea. Net Chlor influx decreased with increasing duration of exposure to 100% O2 from control levels of 37.0 +/- 2.4 ng.min-1.trachea-1 to 30.0 +/- 1.0 ng.min-1.trachea-1 after 36 h of exposure to 100% O2 and was further depressed after 48 h of exposure to 100% O2 60 23.0 +/- 0.9 ng.min-1.trachea-1. Examination of the O2-exposed tracheas by light microscopy showed normal morphology. In contrast, net Chlor influx was not affected by exposure to 50% O2 for 48 h. In a separate group of rats recovery from the effects of hyperoxia was studied. Within 24 h after removal from the hyperoxic environment, net Chlor influx had returned to control levels. We conclude that high partial pressures of oxygen inhibit net Chlor influx in the rat trachea at a time when tracheal histology is normal. This inhibition is a function of the partial pressure of oxygen and the duration of exposure and it is reversible after removal from the hyperoxic environment.

Animals↗
PubMed1981

Depression of serotonin uptake by cultured endothelial cells exposed to high O2 tension.

Serotonin (5-hydroxytryptamine, 5-HT), a vasoactive amine, is removed from the pulmonary circulation by active transcellular transport into endothelial cells, followed by intracellular metabolism. Pulmonary uptake of 5-HT is depressed by high partial pressures of O2 (Po2). To characterized the cellular basis and mechanism for hyperoxic depression of lung 5-HT uptake, we evaluated the effect of high Po2 on 5-HT uptake by calf aortic endothelial cells in primary confluent monolayer. Cells were exposed to either 95% O2, or 14% O2 (controls) in 5% Co2 at 1 ATA for 20 or 42 h. Following exposure 5-[14C]HT (1 X 10-7 M) was added to the culture medium, and 5-HT uptake in pmol/10(6) cells was measured. Exposure to 95% O2 for 20 h or 42 H resulted in significant depression of 5-HT uptake by cultured endothelial cells, and uptakes remained significantly depressed 48 h after exposure to 95% O2 had ended. Inhibition of intracellular metabolism of 5-HT by iproniazid did not affect 5-HT uptake by control or O2-exposed endothelial cells. These results indicate that 1) high Po2 levels depress 5-HT uptake in endothelial cells by direct inhibition of the transcellular transport of 5-HT and 2) hyperoxic depression of 5-HT uptake in cultured endothelial cells is not readily reversible.

Animals↗
PubMed1981

Effect of alpha naphthylthiourea on uptake of 5-hydroxytryptamine from the pulmonary circulation.

Pulmonary injury caused by alpha naphthylthiourea (ANTU) is characterized by alterations of the capillary endothelial barrier followed by lung edema. Because pulmonary uptake of 5-hydroxytryptamine (5-HT) is dependent upon active transcellular transport by lung endothelium, it may be an index of early impairment of endothelial function caused by ANTU. We studied the effect of a single intraperitoneal dose of 5 or of 10 mg/kg of ANTU on pulmonary uptake of 5-HT by isolated rat lungs. Four h after the administration of ANTU, when lung tissue structure and dry-to-wet-weight ratios were comparable to those of control animals, 5-HT uptakes were significantly reduced (p < 0.05). Twenty-four h after the administration of ANTU, when lung edema was present on histologic examination and by lung weights, 5-HT uptakes were further reduced. They returned to control values 14 days after the administration of ANTU. Depression of 5-HT uptake is an early and reversible alteration of lung endothelial cell function caused by ANTU. Uptake of 5-HT may provide a sensitive probe with which to detect and evaluate pulmonary endothelial cell injury caused by toxicants.

Animals↗
PubMed1981

5-Hydroxytryptamine uptake by lungs of hamsters with pulmonary emphysema.

Elastase-induced emphysema in hamsters was used as a model to determine whether this type of chronic lung injury affected the metabolic function of pulmonary endothelium. 5-Hydroxytryptamine (5-HT) uptake was studied in isolated perfused lungs of hamsters from a control group and from those with emphysema of various severity. After measuring 5-HT uptake, we determined the mean linear intercept and internal surface area for each lung. The concentration of 5-HT used in the perfusate ranged from the level in the resting hamster to supraphysiologic levels. The results reveal that elastase-induced emphysema does not affect 5-HT uptake by the isolated perfused hamster lung despite significant loss of alveolar surface area.

Animals↗
PubMed1980

Environmental influences on uptake of serotonin and other amines.

Lungs accumulate 5-hydroxytryptamine (serotonin, 5-HT) from the perfusate by a sodium-dependent, energy-requiring, saturable process. The rate-limiting step for uptake is the transport of 5-HT and not its subsequent metabolism to 5-hydroxyindoleacetic acid. Autoradiographic studies indicate that the pulmonary endothelium is the cellular site of uptake. The effect of hyperoxia on lung clearance of 5-HT was studied with isolated perfused and ventilated lungs from rats that were previously exposed to hyperoxia. Lungs were perfused with recirculating electrolyte solution and initial [5-HT] of 0.24 microM. The calculated fractional 5-HT clearance (fracion of 5-HT removed in a single pass) ws 0.77 +/- 0.02 (mean +/- SE: n = 44) for control rats. Mean fractional clearance decreased by 20% in rats exposed to 1 atm O2 for 18 hr and 30% after 4 atmospheres absolute (ata) O2 for 1 hr (p < 0.05). The effects of O2 at 4 ata were in part reversed by exposure to air for 3.5 hr and in part prevented by injection of superoxide dismutase (60 nmole/kg body weight). This degree of O2 exposure at either 1 or 4 ata had no effect on lung content of adenine nucleotides or the distribution of 3H-5HT on autoradiography. Rats maintained for 6 weeks on a vitamin E-deficient diet showed an increased effect of hyperoxia on 5-HT clearance and did not show reversal of changes after 24 hr of air breathing. The results indicate that exposure to elevatd po2 results in reversible depression of pulmonary 5-HT clearance that is potentiated by vitamin E deficiency. This suggests alteration of pulmonary endothelial membrane transport properties due to O2 toxicity.

Amines↗