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M J Reasor

Publications and source records attributed to M J Reasor.

At least 55 records · Page 3Linked to original sources
PubMed1989

Macrophage regulation of myelopoiesis is altered by exposure to the benzene metabolite hydroquinone.

Hydroquinone, a myelotoxic metabolite of benzene, decreases the ability of murine bone marrow stromal cells to support myelopoiesis in vitro. Bone marrow stroma consists of macrophages and fibroblastoid stromal cells that participate coordinately in regulating myelopoiesis. The goal of this study was to determine if macrophage or fibroblastoid cell function is more sensitive to the myelotoxic actions of hydroquinone. To address this question, we developed purified populations of macrophages and fibroblastoid stromal cells and treated each population with hydroquinone. These cells were reconstituted together with nontreated cells of the opposite type and assayed for their ability to support the formation of granulocyte and macrophage colonies in an agar overlay. Reconstituted cultures containing hydroquinone-treated macrophages supported fewer colonies than did corresponding cultures containing untreated macrophages. Reconstituted cultures containing hydroquinone-treated fibroblastoid stromal cells were not affected. Moreover, hydroquinone reduced detectable interleukin-1 activity in purified macrophage cultures stimulated with lipopolysaccharide. These results indicate that hydroquinone selectively interferes with macrophage function possibly, in part, via alteration of macrophage interleukin-1 secretion.

Animals↗
PubMed1989

A review of the biology and toxicologic implications of the induction of lysosomal lamellar bodies by drugs.

Over 30 drugs of differing pharmacologic action are capable of inducing lamellar bodies of lysosomal origin in cells of animals and humans. The structures develop because of a drug-induced impairment in lysosomal phospholipid catabolism. Toxicity frequently accompanies the induction of these bodies. However, little information exists as to whether their development or presence is causally linked to the cellular or tissue dysfunction. This review examines the biological aspects of the induction of lysosomal lamellar bodies by drugs and considers the toxicologic implications of their presence in cells.

Animals↗
PubMed1989

Amiodarone-induced pulmonary toxicity in rats: biochemical and pharmacological characteristics.

Treatment of humans with the antiarrhythmic drug, amiodarone (AD), may result in the development of pulmonary toxicity. To characterize this response, male Fischer 344 rats were treated with AD for 1, 3, 9, and 16 weeks. AD induces a twofold increase in the level of pulmonary phospholipid after 3 weeks of treatment. Continued administration results in only a small increase above this level. All classes of phospholipids are elevated; phosphatidylcholine displays the largest increase, both quantitatively and as a relative increase over the control level. Both AD and its principal metabolite, desethylAD, are sequestered in the lungs following AD treatment. The relative levels are similar at all time points except 16 weeks, where the relative amount of AD is decreased. After 3 weeks of AD, female 344 rats show the same increase in pulmonary phospholipid as males. While similar levels of desethyAD are sequestered in the lungs of both sexes, AD levels are much lower in female lungs. Evidence is presented to suggest that desethylAD may play an important role in the induction of the phospholipidosis. The activity of Na+,K+-ATPase in the lungs is inhibited by 75% after 9 weeks of AD while the activity of the acid hydrolase, beta-N-acetylglucosaminidase is increased significantly at this time point. All biochemical changes are reversible with values returning to control levels 2 weeks after termination of a 3-week AD treatment protocol. Measurable levels of AD and desethylAD are present in lung tissue after 5 weeks of recovery.

Acetylglucosaminidase↗
PubMed1988

Association of chlorphentermine with phospholipids in rat alveolar lavage materials, alveolar macrophages and type II cells.

Administration of chlorphentermine to rats leads to an increase in the phospholipid content of pulmonary surfactant materials and alveolar macrophages. It is known that this drug binds to pure phospholipids and prevents their degradation by phospholipases. Therefore, experiments were carried out to determine if chlorphentermine binds to surfactant phospholipids in vitro and to measure the in vivo association of drug with phospholipids in alveolar lavage materials from rats injected with [14C]chlorphentermine. The presence of chlorphentermine in alveolar macrophages, type II cells and other small pneumocytes (a population of lung cells which does not include alveolar macrophages or type II cells) from treated animals was also assessed. Binding of the drug to surfactant phospholipids, as measured with the fluorescent probe, 1-anilino-8-naphthalene sulfonate, occurs in vitro and does not differ in various subfractions of alveolar lavage materials isolated by differential centrifugation. Following daily administration of chlorphentermine to rats for 3 days, the drug appears to be associated with surfactant phospholipids such that the molar ratio is 1:100 (chlorphentermine/phospholipid). Chlorphentermine is also associated with alveolar macrophages (molar ratio, 1:18) and type II cells (molar ratio, 1:33). Not much drug is associated with the population of other lung cells (molar ratio, 1:333). In alveolar macrophages, approx. 70% of the drug seems to be bound to phospholipid and/or sequestered in subcellular organelles. However, only 20% of the chlorphentermine is bound and/or sequestered in type II cells. The results of these experiments suggest that following chlorphentermine administration, the drug is associated with phospholipids in acellular pulmonary lavage materials, alveolar macrophages and type II cells. This drug-phospholipid interaction may impair phospholipid degradation and lead to a phospholipidosis in surfactant materials and alveolar macrophages.

Animals↗
PubMed1988

Iodine in rat alveolar macrophages following amiodarone treatment: quantitative X-ray microanalysis.

The techniques of cryomicrotomy and X-ray microanalysis were used to quantitatively measure the subcellular distribution of iodine in rat alveolar macrophages following a single administration of the iodine-containing antiarrhythmic drug, amiodarone. When frozen, dried sections were analyzed, small amounts of iodine were found throughout the alveolar macrophages, but the major accumulations were observed in amorphous bodies and dense granules. The highest to lowest accumulation is in the following order: amorphous bodies (90 mmole I/kg dry wt) greater than dense granules (50 mmole I/kg dry wt) greater than nucleus = cytosol (10 mmoles I/kg dry wt). The amorphous bodies can contain high and low levels of iodine and the granules are found to have high and low levels of iron. Granules with the high and low levels of iron and amorphous bodies with the high and low levels of iodine can be found in the same cells. X-ray microanalysis proved useful in describing the intracellular distribution of iodine-labeled species following amiodarone administration.

Amiodarone↗
PubMed1988

Amiodarone-induced phospholipidosis in rat alveolar macrophages.

Humans treated with the antiarrhythmic drug amiodarone may develop pulmonary toxicity accompanied by the presence of alveolar macrophages (AM) containing lamellar inclusions. This cellular response is indicative of the development of a drug-induced phospholipidosis. To characterize this response of the AM, Fischer-344 rats were treated with amiodarone, and the macrophages were recovered by pulmonary lavage. The development of phospholipidosis was dose- and time-dependent and was reversible. Daily treatment for 1 wk (5 days/wk) at 150 mg/kg resulted in a 5-fold increase in total phospholipid in the cells. Phospholipid levels were increased only slightly more through 9 wk of treatment. Cells were filled with lamellar inclusions and contained areas of amorphous granular and membranous material. Individual classes of phospholipids were all increased during the development of phospholipidosis. When expressed as mumol/10(7) cells, phosphatidylcholine demonstrated the largest increase. Levels of amiodarone and its major metabolite, desethylamiodarone, increased in AM in parallel with the increase in phospholipid. From 3 days through 9 wk of treatment, the level of desethylamiodarone was always higher than that of amiodarone. Treatment with desethylamiodarone also induced phospholipidosis in AM. Administration of phenobarbital along with amiodarone for 1 wk caused a reduction in the levels of amiodarone, desethylamiodarone, and phospholipid in the cells. The molar ratio of amiodarone to phospholipid was decreased, whereas the molar ratio of desethylamiodarone to phospholipid remained unchanged. Taken together, the results indicate that, along with amiodarone, desethylamiodarone and/or its metabolites may play an important role in the phospholipidosis induced in AM when rats are treated with amiodarone.

Amiodarone↗
PubMed1988

Chlorphentermine suppresses the phosphatidylinositol pathway in concanavalin A-activated mouse splenic lymphocytes.

We have previously demonstrated that the chlorphentermine (CP)1-induced impairment in lymphocyte blastogenesis involves drug-induced inhibition of an event which occurs very early during lymphocyte activation. An early event, which is associated with mitogen-induced lymphocyte activation, involves the hydrolysis of phosphatidylinositol by phospholipase C to yield inositol phosphates and diacylglycerol as products. Inositol phosphates and diacylglycerol then function as mediators of a trans-membrane signal for the continuation of the cellular response. It was the purpose of the present study to determine the effects of CP on this phosphatidylinositol pathway. We demonstrated that formation of inositol phosphates in lymphocytes increases progressively above control over a 2 hour period following concanavalin A (Con A)-stimulation. In contrast, lymphocytes pre-incubated with 10(-5)M CP for 60 min, then stimulated with Con A for 2 hours in the presence of 10(-5)M CP, exhibit a significantly depressed inositol phosphate formation. In addition, CP also inhibited the activity of phospholipase C (IC50 = 0.58 mM), the enzyme responsible for the formation of inositol phosphates during lymphocyte activation. Further, lymphocytes activated in a manner that bypasses the phosphatidylinositol pathway are not inhibited by 10(-7)M or 10(-9)M CP as are cells activated with Con A. These results suggest that the suppression of the phosphatidylinositol pathway may be involved in the inhibition by CP of lymphocyte blastogenesis induced by Con A.

Animals↗
PubMed1986

Alterations in rat alveolar surfactant phospholipids and proteins induced by administration of chlorphentermine.

Chlorphentermine is a cationic amphiphilic drug which produces a phospholipid storage disorder in rat lungs. Experiments were carried out to characterize changes in the composition of acellular alveolar lavage materials and to study possible mechanisms by which pulmonary surfactant phospholipidosis is produced by administration of the drug. Following ten daily injections of chlorphentermine (25 mg/kg body weight), there are 12.2- and 13.6-fold increases of pulmonary lavage total phospholipids and disaturated phosphatidylcholines (disaturated PC), respectively. In addition, there is a 2.8-fold increase in total protein and a 12.7-fold increase in the surfactant apoprotein group with molecular weights from 28,000 to 32,000. We measured incorporation of labeled palmitate, choline and glycerol into disaturated PC in type II cells and alveolar macrophages isolated from control and chlorphentermine-treated animals. The drug does not affect the incorporation of labeled substrates into disaturated PC in either cell type. However, in alveolar macrophages there is a decrease in the rate of intracellular degradation of recently synthesized disaturated PC in chlorphentermine-treated animals. The drug also inhibits the phospholipase-induced catabolism of rat surfactant disaturated PC which occurs during incubation of alveolar lavage fluid in vitro at 37 degrees C. When the lavage fluid is divided into subfractions by differential centrifugation, a larger percentage of the phospholipid is distributed in the less sedimentable subfractions in chlorphentermine-treated animals relative to controls, suggesting the accumulation of older surfactant materials. These results suggest that chlorphentermine-induced phospholipidosis of pulmonary surfactant materials is due to decreased rates of phospholipid degradation.

Animals↗
PubMed1986

Role of phospholipase A inhibition in amiodarone pulmonary toxicity in rats.

Amiodarone is effective in the treatment of ventricular and supraventricular arrhythmias. In man its clinical use is associated with the accumulation of phospholipid-rich multilamellar inclusions in various tissues including lung, liver and others. This report presents evidence showing that amiodarone is a potent inhibitor of lysosomal phospholipase A from rat alveolar macrophages, J-744 macrophages and rat liver. When compared with other cationic amphiphilic agents which are known to produce phospholipidosis, amiodarone is one of the most potent inhibitors yet discovered. The subcellular localization of amiodarone has been determined in lung and its distribution was consistent with a lysosomal localization. It is hypothesized that amiodarone causes cellular phospholipidosis by concentrating in lysosomes and inhibiting phospholipid catabolism.

Amiodarone↗
PubMed1986

Morphological and functional changes in mouse splenic lymphocytes following in vivo and in vitro exposure to chlorphentermine.

With repeated administration to animals, the cationic, amphiphilic drug, chlorphentermine (CP), has been shown by others to induce a phospholipidosis in lymphocytes. In the present study mouse splenic lymphocytes, exposed to CP, either in vivo or in vitro, developed morphological changes consistant with the induction of phospholipidosis. In addition, CP induced functional changes in lymphocytes. Mice, treated with CP in vivo, demonstrated a significantly depressed ability to generate a delayed hypersensitivity response or to produce antibody-secreting cells against de novo antigens. Mouse splenic lymphocytes, exposed to 10(-7) M CP for 3 days in vitro, demonstrated a significantly depressed blastogenic response to the mitogens phytohemagglutinin, concanavalin A and lipopolysaccharide. CP inhibited an event that occurred early during lymphocyte activation, but was subsequent to mitogen/receptor coupling. In addition, CP significantly depressed the increased uptake of choline that occurs in lymphocytes following cellular activation. Since the presence of phospholipidosis is indicative of an impairment in phospholipid metabolism, these results taken together provide evidence for a relationship between this phenomenon and altered immune function.

Animals↗
PubMed1986

Role of the alveolar macrophage in the induction of pulmonary phospholipidosis by chlorphentermine. I. Drug and phospholipid levels.

In this study we have shown that the alveolar macrophage (AM) plays a major role in the induction of phospholipidosis in rat lung by chlorphentermine (CP). Rats were administered CP (30 mg/kg i.p., 5 days/week) for 1, 4 and 8 weeks and the levels of CP and total phospholipid were measured in whole lungs and in the AM fraction recovered from the lungs by pulmonary lavage. Lungs accumulate CP to a much greater extent than liver or kidney and show a marked increase in phospholipid content by 8 weeks. Drug treatment is accompanied by the recovery of an elevated number of AMs at all time points. The CP and phospholipid levels in AMs reach a peak at 4 weeks with little change beyond that time. Initially the phospholipidosis is localized largely in the AMs with the disorder developing in other compartments of the lungs with increasing treatment time. The AMs contribute 3% of the total pulmonary phospholipid in control rats. After 1 week of CP, 34% of the pulmonary phospholipid is in the AM fraction with this value being 21% after 8 weeks. The CP to phospholipid molar ratio is higher in AMs than whole lung at all three time points.

Animals↗
PubMed1986

Role of the alveolar macrophage in the induction of pulmonary phospholipidosis by chlorphentermine. II. Drug uptake into cells in vitro.

This study was conducted to further assess the role of the alveolar macrophage in the induction of pulmonary phospholipidosis by the cationic amphiphilic drug, chlorphentermine (CP). Alveolar macrophages were collected from normal rats by pulmonary lavage, allowed to attach to glass cover slips and incubated with CP in vitro at 37 degrees C. The uptake of CP was measured using [14C]CP. Uptake is rapid, reaching equilibrium by 2 min resulting in the concentration of CP within the cells. The process is temperature-dependent being depressed markedly at 2 degrees C. Two components of uptake were identified. Below 0.2 mM CP, a carrier-mediated mechanism and diffusion are involved whereas, at concentrations above 0.2 mM, the carrier is saturated and diffusion predominates, with the intracellular binding of CP to membranes probably responsible for the striking sequestration. The carrier-mediated component obeys Michaelis-Menten kinetics, does not appear to require Na+ and is not affected by metabolic inhibitors. This is consistent with the concept that the process occurs by facilitated diffusion. Metabolism of CP does not play a role in the accumulation of the drug. The transport system is different from those involved in glucose, nucleoside or amino acid uptake. Total initial uptake was inhibited by the three cationic amphilic drugs tested, iprindole, chlorcyclizine and imipramine indicating that cationic amphiphilic drugs may share a common uptake system.

Animals↗
PubMed1985

The response of rat alveolar macrophages to chronic inhalation of coal dust and/or diesel exhaust.

The use of diesel-powered equipment in underground mines has raised questions regarding possible synergistic effects of coal dust and diesel emissions. Therefore, the effects of chronic exposure of rats to coal dust and/or diesel exhaust on various properties of alveolar macrophages were investigated. Inhalation exposure of rats was 7 hr/day, 5 days/week for 2 years. Exposure groups were: filtered air controls, 2 mg/m3 coal dust, 2 mg/m3 diesel particulate, and 1 mg/m3 coal dust plus 1 mg/m3 diesel exhaust. Exposure to coal dust and/or diesel exhaust had little effect on oxygen consumption, membrane integrity, lysosomal enzyme activity, or protein content of alveolar macrophages. However, exposure to coal dust increased macrophage yield, enhanced chemiluminescence, and increased the activity of the cell membrane (i.e., increased cellular spreading and surface ruffling). In contrast, diesel emissions depressed chemiluminescence and decreased the ruffling of the cell membrane. Therefore, the data suggest that exposure to coal dust and/or diesel exhaust does not affect the viability of alveolar macrophages. However, coal dust may activate alveolar macrophages while diesel emissions may depress the phagocytic activity of these cells. The combination of exposures to coal dust and diesel exhaust results in a phagocytic activity which is an average of the effects of separate exposures.

Animals↗
PubMed1985

Newborn response to cationic amphiphilic drugs.

Administration of various cationic amphiphilic drugs in utero results in induction of a phospholipid storage disorder in many tissues, particularly in lungs. In addition to the phospholipidosis in utero, drug exposure results in toxicity to the offspring; newborn rats die within 48 h of birth. Although drug-induced pulmonary pathological changes appear to be involved in the observed mortality, this relationship remains unclear. In contrast to mammals, administration of cationic amphiphilic drugs to the chick embryo seems not to induce phospholipid storage in the tissues examined. Treatment of newborn rats directly with these drugs also induces phospholipidosis in several tissues including lung and kidney; however, mortality does not occur. Concurrent administration of phenobarbital and chlorphentermine reduces or prevents amphiphilic drug-induced phospholipid storage in newborn rat lung and kidney. Modification of chlorphentermine actions by phenobarbital may be caused by alterations in amphiphilic drug excretion, metabolism, and catabolic phospholipase activity. Evidence thus indicates that regardless of age, animals appear susceptible to the effects of cationic amphiphilic drugs; however, species and tissues examined, as well as specific drug administration, play an important role in the observed qualitative and quantitative responses.

Animals↗
PubMed1984

Chloroquine treatment does not cause phospholipid storage by depleting rat liver lysosomes of acid phospholipase A.

Chronic treatment of rats with chloroquine causes phospholipid storage in the lysosomes of liver and other tissues. This could be due to chloroquine-induced depletion of liver lysosomal phospholipase A. Alternatively, it could be caused by chloroquine inhibition of intralysosomal phospholipid catabolism. We treated rats with chloroquine in a dosage schedule sufficient to cause a 35% increase in liver phospholipid content. Acid phospholipase A activity was increased in liver homogenates and in lysosomal preparations obtained from chloroquine-treated animals. Thus, while fibroblasts respond to chloroquine treatment by cellular depletion of certain acid hydrolases as shown by others, the levels of acid phospholipase A increase in liver. Our results provide additional new support for the hypothesis that inhibition of lysosomal phospholipase A activity is the major mechanism of chloroquine-induced phospholipidosis.

Animals↗
PubMed1984

Oxidant-mediated electronic excitation of imipramine.

The interaction of imipramine with both resting and zymosan-activated human polymorphonuclear leukocytes (PMNs) resulted in the generation of chemiluminescence (CL). This CL was not accompanied, however, by an enhanced release of superoxide anion. CL was also observed following the interaction of imipramine with either a xanthine oxidase or a horseradish peroxidase catalyzed system. Collectively, these observations support the concept that the CL elicited from these interactions is reflective of the electronic excitation of the imipramine molecule. In contrast to the response seen with PMNs, addition of imipramine to resting alveolar macrophages (AMs) failed to yield CL. However, CL from imipramine was observed with resting AMs upon supplementation with exogenous horseradish peroxidase. The lack of response with control AMs and the significant inhibition of the imipramine-PMN CL by the myeloperoxidase inhibitor azide suggests that a peroxidase-derived oxidant facilitated the oxidation of imipramine, yielding a product in an electronically excited state. In addition to PMNs, CL was elicited from imipramine by rat or rabbit liver microsomes, suggesting that PMNs may be a useful model system to predict a xenobiotic effect on the CL response elicited by other cellular oxidant-generating systems. Moreover, these observations underscore the possibility that the metabolic activation of drugs by PMNs may be of pharmacologic and toxicologic importance.

Animals↗
PubMed1984

Phospholipidosis in the alveolar macrophage induced by cationic amphiphilic drugs.

The administration of a number of cationic amphiphilic drugs to certain species of laboratory animals results in a phospholipid storage disorder in the lungs. The alveolar macrophage (AM) shows a pronounced response to drug treatment. The most thorough quantification of this response has occurred after chlorphentermine treatment of rats. There is a striking increase in the accumulation of AMs in the alveolar spaces. The accumulated cells are very heterogeneous in size with many being larger than AMs from untreated rats. Cells are present that have a volume 10 times larger than normal AMs. The hypertrophic AMs show striking ultrastructural changes. The cells become engorged with lamellar inclusions, which may give rise to larger quantities of granular or membranous material. The affected AMs show an increase in total phospholipid content, and there is a good correlation between the size of the AM and its level of phospholipid. The phospholipidosis is reversible after termination of drug treatment; however, the above-mentioned changes do not return to control levels at the same time.

Animals↗