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M J Reasor

Publications and source records attributed to M J Reasor.

At least 37 records · Page 2Linked to original sources
PubMed1994

Effect of short-term exogenous pulmonary surfactant treatment on acute lung damage associated with the intratracheal instillation of silica.

The objective of our study was to investigate whether coating the surface of silica with Survanta, a commercially available, bovine pulmonary surfactant, would reduce the in vitro cytotoxicity to alveolar macrophages (AMs), as well as attenuate lung damage in vivo following intratracheal instillation of silica. In the in vitro studies, alveolar macrophages from male Fischer 344 rats were incubated for 1 and 24 h with native or Survanta-treated silica (0.5 mg/ml). At both time points, the native, uncoated silica caused a dramatic loss of AM viability. The AMs were protected, however, when the silica was treated with the Survanta surfactant. This protective effect was significantly greater after 1 h when compared with 24 h. In the in vivo studies, a high dose of silica (10 mg/100 g body weight) was suspended in Survanta and intratracheally instilled into the lungs of male Fischer 344 rats. A number of biochemical and cellular parameters were measured within the bronchoalveolar lavage fluid (BALF) 1 and 14 d after the instillation exposures to assess lung damage. One day after the instillations, the suspension of silica in Survanta resulted in significant reductions in the silica-induced increases in total protein, beta-glucuronidase activity, and influx of neutrophils (PMNs) into the airspaces of the lungs. Fourteen days after the instillation exposures, this protective effect was lost. When Survanta was instilled into the lungs 15 min after the intratracheal instillation of silica, a significant reduction also was demonstrated in the silica-induced elevations in BALF total protein, beta-glucuronidase activity, and influx of PMNs 1 d after the instillation exposures. In an attempt to protect silica-exposed lungs over a longer period of time, Survanta was instilled into the lung 15 min after the silica instillation, and then every other day over a 7-d treatment period. Twenty-four hours after the last Survanta instillation, slight but significant decreases in the silica-induced elevations in BALF total protein and beta-glucuronidase activity were observed. The Survanta treatment, however, had no effect in preventing the infiltration of PMNs into the airspaces of the lungs. The results of this study indicate that artificially coating the silica with surfactant phospholipid offers short-term protection against its toxicity under both in vitro and in vivo conditions.

Analysis of Variance↗
PubMed1994

Acute silica toxicity: attenuation by amiodarone-induced pulmonary phospholipidosis.

Exposure to the toxic mineral dust silica has been shown to produce an acute inflammatory response in the lungs of both humans and laboratory animals. Coating silica with phospholipids reduces its toxicity when studied with in vitro systems. The drug amiodarone increases phospholipid within the cells, airways, and alveoli of the lungs. This increase in phospholipid is due to amiodarone's ability to inhibit phospholipase activity within alveolar macrophages (AMs) and whole lung. The purpose of this study was to determine whether the amiodarone-induced increase in pulmonary phospholipid would protect the lungs from acute damage caused by the intratracheal instillation of silica. Treatment of male Fischer 344 rats with amiodarone for 14 days caused an increase in phospholipid content in bronchoalveolar lavage fluid and AMs compared to vehicle-treated controls. The rats were then instilled with silica or saline vehicle. At both 1 and 14 days after silica exposure, pulmonary phospholipidosis was associated with a marked reduction in acute silica-induced pulmonary damage as assessed by biochemical parameters in bronchoalveolar lavage fluid, however, the influx of neutrophils into the airspaces was not reduced. Four times more phospholipid was bound to the silica recovered from amiodarone-treated rats compared to controls. The results of these in vivo experiments indicate that pulmonary phospholipidosis attenuates the acute damage associated with the intratracheal instillation of silica in rats. By using an in vitro cell culture system, we demonstrated that, in contrast to control AMs, phospholipidotic AMs were significantly more resistant to the cytotoxicity of surfactant-coated silica.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Disease↗
PubMed1994

Introduction of luminol-dependent chemiluminescence as a method to study silica inflammation in the tissue and phagocytic cells of rat lung.

The inhalation of silica has been shown to produce a dramatic inflammatory and toxic response within the lungs of humans and laboratory animals. A variety of cellular and biochemical parameters are used to assess the silica-induced lung injury. The purpose of this paper is to introduce the use of luminol-dependent chemiluminescence as a new method to study inflammation in both phagocytic cells and lung tissue recovered from silica-exposed animals. Chemiluminescence, or the emission of light, accompanies the release of reactive forms of oxygen when phagocytic cells are challenged. In this study, male Fischer 344 rats were intratracheally instilled with either silica (10 mg/100 g bw) or saline vehicle. One day after the instillations, a marked increase in the chemiluminescence was observed in the lung tissue and bronchoalveolar lavage cells recovered from the silica-treated animals when compared with the saline controls. The light reaction was markedly decreased by either superoxide dismutase of N-nitro-arginine methyl ester hydrochloride. Superoxide dismutase is involved in the enzymatic breakdown of superoxide anion, while N-nitro-L-arginine methyl ester hydrocholoride, a nitric oxide synthase inhibitor, prevents the formation of nitric oxide. When superoxide anion and nitric oxide react, they form the highly oxidizing substance peroxynitrite. This study then implicates peroxynitrite as an agent that may be responsible for some of the oxidant lung injury that is associated with silica exposure. The use of luminol-dependent chemiluminescence may prove valuable as a method to measure the earliest events in the inflammatory process, and may be an adjunct in studying the mechanisms that produce inflammation.

Animals↗
PubMed1994

A toxicologic approach for evaluating cases of sick building syndrome or multiple chemical sensitivity.

The nonspecificity of symptoms and exposures commonly reported as "sick building syndrome" is very similar to that reported for the condition termed "multiple chemical sensitivity (MCS)." In many instances health care practitioners are divided on the reality of the latter. As in all scientific cases of possible cause-and-effect relationships, an organized, dispassionate approach should be used to evaluate each claim of MCS. Most obviously, known medical conditions must be ruled out before chemical "sensitivity" is proposed. Also, several questions on the toxicology of the chemical exposure must be addressed. Although temporality may be apparent (toxicity followed exposure), the time frame for the appearance of symptoms must be appropriate to the exposure conditions and chemical(s) involved. The chemical(s) must have known or reasonably inferred properties to cause the claimed effect. The dose(s) received must be adequate to effect a response (dose-response characteristics). Alternate causation must be evaluated thoroughly, that is, are there other more logical explanations for the symptoms? In contrast to single-chemical exposures, exposure to mixtures of chemicals, as commonly found in sick buildings, is very difficult to evaluate. However, a rational, scientific approach to cause-and-effect questions will help avoid erroneous and subjective decision making.

Air Pollution, Indoor↗
PubMed1993

X-ray microanalysis of cultured alveolar macrophages with phospholipidosis.

When administered to humans and animals, the iodine-containing drug amiodarone can cause pulmonary toxicity. As part of the pulmonary response to amiodarone, the drug and its principal metabolite, desethylamiodarone, accumulate in alveolar macrophages. Little is known about the susceptibility of lungs with preexisting damage to amiodarone administration. A number of chemicals can cause pulmonary phospholipidosis in humans and animals. To study the effect of a preexisting phospholipidosis on the intracellular accumulation of amiodarone and desethylamiodarone, rats were treated with chlorphentermine to induce a phospholipidosis in alveolar macrophages. The cells were recovered from the lungs by pulmonary lavage and placed in cell culture. They were then exposed to the same concentration of either amiodarone or desethylamiodarone. The intracellular distribution of each drug was quantified by measuring the associated iodine signal using X-ray microanalysis of freeze-dried cryosections of cells. Both drugs accumulated in lipid-rich amorphous bodies which correspond to lysosomally derived lamellar structures observed in conventional plastic sections. The level of desethylamiodarone exceeded that of amiodarone in the amorphous bodies. With both drugs, a higher concentration of iodine was present at the outer edges of the amorphous bodies compared to that in the center core. This suggests that the drugs are unable to freely penetrate the performed structures. By monitoring the concentrations of sodium and potassium ions within the nucleus, it was determined that chlorphentermine treatment disrupted the ionic distribution in the cells. Exposure to amiodarone, but not desethylamiodarone, resulted in further changes in sodium and potassium levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Amiodarone↗
PubMed1992

Effects of amiodarone administration during lactation in Fischer-344 rats.

The antiarrhythmic drug, amiodarone, was administered (35 mg/kg, p.o.) once daily to lactating Fischer-344 rats for either the first 7 days of lactation, the first 14 days of lactation, or for the full 24-day lactational period. Treatment with amiodarone resulted in a decrease in maternal weight gain compared to pair-fed vehicle-treated controls, however, neonatal weight gain was not affected. The concentration of amiodarone in the maternal milk was approx. 6-fold higher than its primary metabolite, desethylamiodarone. Plasma levels of amiodarone and desethylamiodarone were higher in maternal rats compared to neonates. Both amiodarone and desethylamiodarone were distributed to neonatal tissues through lactational transfer. The levels of desethylamiodarone were higher in neonatal lung compared to liver at all treatment times. They were also elevated above amiodarone in neonatal lung at all treatment times. The amiodarone levels in neonatal lung and liver were similar.

Amiodarone↗
PubMed1992

Retrograde extrapolation of blood alcohol data: an applied approach.

Retrograde extrapolation is a mathematical process, based on sound scientific principles, that is used routinely in pharmacology, toxicology, and clinical medicine. This process may be applied to the situation of ethyl alcohol consumption with reliability when reasonable assumptions are made concerning absorption rates, elimination rates, and patterns of alcohol consumption, including drinking duration and volume consumed. By utilizing an established range of values for the elimination rate of alcohol of 0.015-0.020 g/dl/h, a relatively narrow range of extrapolated blood alcohol concentrations (BACs) can be determined in situations where the time frame in question is after peak alcohol absorption into the blood. A wider range of elimination rates of 0.01-0.03 g/dl/h may be applied and will satisfy the possibility of nonlinear kinetics within an individual; however, this wider range will have little practical effect on the predicted BACs. When the time point in question is prior to peak absorption, a wider range of predicted BAC values will result. The extent of this range will be influenced by the amount of information available concerning the temporal pattern of alcohol consumption. Reported drinking volumes are notoriously inaccurate and, in fact, are of little practical use. Given the parameters of body weight and time duration between initiation of drinking and determination of the BAC, the number of "drinks" consumed may be reliability calculated. Retrograde extrapolation is applicable in the forensic setting with scientific reliability when reasonable and justifiable assumptions are utilized.

Absorption↗
PubMed1991

Accumulation of amiodarone and desethylamiodarone by rat alveolar macrophages in cell culture.

Amiodarone is a clinically effective antiarrhythmic drug shown to cause lung damage in humans and animals. While the mechanism of this pulmonary toxicity is unknown, it may be associated with the accumulation of amiodarone and its principal metabolite, desethylamiodarone, by alveolar macrophages. In the present study, characteristics of the uptake of these drugs by rat alveolar macrophages in vitro were examined. The alveolar macrophages were collected by pulmonary lavage from male Fischer 344 rats. Amiodarone and desethylamiodarone were incubated separately (2.5 microM) with the cells in culture for 1, 2, 4 and 18 hr. High performance liquid chromatography was used to measure drug uptake. At 1 and 2 hr, the uptake of desethylamiodarone by alveolar macrophages was significantly greater (P less than 0.05) than that of amiodarone, but over time, the accumulation of amiodarone began to approach that of desethylamiodarone and was not significantly different by 4 hr. To simulate a more physiological situation, plasma levels achieved in the adult male rat after 1 week of amiodarone treatment (150 mg/kg) were used. Amiodarone (1.95 micrograms/mL) and desethylamiodarone (0.80 microgram/mL) were added together into the cell culture. At 1 and 18 hr, the ratio of desethylamiodarone/amiodarone uptake was significantly greater (P less than 0.05) than in incubation medium containing no cells, indicating an enhanced uptake of desethylamiodarone. Metabolic inhibitors (KCN, 2,4-dinitrophenol, and ouabain) and other cationic, amphiphilic drugs (chlorcyclizine, chlorphentermine, and imipramine) were added individually to the cell cultures containing amiodarone or desethylamiodarone. During 1 hr of incubation, these agents had no effect in blocking the accumulation of amiodarone and desethylamiodarone in the cells. The efflux of amiodarone or desethylamiodarone was measured from cells following incubation for 4 hr with each drug. After this time, the medium was replaced with drug-free medium, and the cells were incubated for another 24 hr. Sixty-three percent of amiodarone was lost as compared to only 31% of desethylamiodarone over the 24-hr period (P less than 0.05). The results of this study are suggestive of a preferential uptake and retention of desethylamiodarone as compared to amiodarone. The accumulation of the drugs appears not to be due to active transport or associated with any carrier protein involved in the transport of other structurally-related compounds.

Amiodarone↗
PubMed1991

Effects of amiodarone administration during pregnancy in Fischer 344 rats.

Amiodarone is a class III anti-arrhythmic compound that is iodinated, cationic and amphiphilic in nature. The clinical use of amiodarone may be associated with various side-effects, including pulmonary and hepatic toxicity. Use of this compound during pregnancy may therefore place the fetus at risk through in utero exposure. This study was designed to observe any gross developmental effects that may be caused by the administration of amiodarone to Fischer 344 rats during pregnancy, investigate the placental transfer of amiodarone and its principal metabolite, desethylamiodarone and determine the levels of amiodarone and desethylamiodarone in the maternal and newborn lung, liver and plasma. To conduct this study, 35 mg/kg of amiodarone was administered daily to pregnant rats for either the last 7 days of pregnancy, the last 14 days of pregnancy, or for the full 22 days of pregnancy. Drug treatment had no effect on the length of gestation or litter size. Maternal weight gain was decreased only when amiodarone was administered during the last 7 days of gestation. The birthweights of the offspring were decreased, however, crown to rump length was unaffected. Both amiodarone and desethylamiodarone accumulated in the offspring through placental transfer. The levels of both compounds were greater in maternal and newborn lung when compared to maternal and newborn liver, respectively. The maternal lung and liver concentrations of both compounds were significantly higher than the respective newborn concentrations. The newborn plasma concentrations of amiodarone and desethylamiodarone were significantly lower than maternal levels indicating that the placenta may not be totally permeable to the two drugs.

Amiodarone↗
PubMed1991

Influence of a pre-existing phospholipidosis on the accumulation of amiodarone and desethylamiodarone in rat alveolar macrophages.

Amiodarone is an antiarrhythmic drug that concentrates in the lungs and can cause pulmonary damage in humans. The purpose of the present study was to examine the influence of a pre-existing lung pathology on the pulmonary accumulation of amiodarone and its primary metabolite, desethylamiodarone. To study this problem, male Fischer 344 rats were administered chlorphentermine to induce a phospholipidosis in the alveolar macrophages of the lungs. The accumulation of amiodarone and desethylamiodarone in phospholipidotic alveolar macrophages was measured following 5 weeks of amiodarone administration. When calculated on a per cell basis, the levels of both drugs were increased over 10-fold in phospholipid-laden macrophages compared to cells from control rats in which a phospholipidosis was not present. When phospholipidotic macrophages were exposed to amiodarone and desethylamiodarone in vitro, both drugs were accumulated to a higher level than occurred in cells from control rats. The results of this study demonstrate that the presence of a pre-existing phospholipidosis results in an enhanced accumulation of amiodarone and desethylamiodarone in rat alveolar macrophages.

Amiodarone↗
PubMed1990

Response of alveolar macrophages to amiodarone and desethylamiodarone, in vitro.

Administration of the antiarrhythmic drug amiodarone to humans or animals may result in lung damage. Amiodarone is metabolized to desethylamiodarone and other minor metabolites. Because amiodarone and the metabolites accumulate in the lungs, it is not possible to ascertain the role of each of these compounds in the induction of toxicity. In the present study, we utilized primary cell cultures of rat alveolar macrophages to study the actions of amiodarone and desethylamiodarone individually and in combination. Neither drug species was metabolized by the cells over 42 h in culture thereby permitting assessment of the actions of each. Both drugs induced the formation of lamellar inclusions, indicative of the development of cellular phospholipidosis. Desethylamiodarone appeared to induce formation of the structures in a shorter period of time than did amiodarone, although given adequate exposure, the two drugs produced similar responses. At shorter times of exposure and lower concentrations, desethylamiodarone was more cytotoxic than amiodarone as assessed by the release of lactate dehydrogenase. The two in combination resulted in cytotoxicity that was more than additive. The results of this study indicate that in vitro cultures of alveolar macrophages may be quite useful in studying the role these cells play in the pulmonary toxicity associated with amiodarone therapy. Additionally, this study supports the idea that a significant portion of the toxicity may result from the actions of desethylamiodarone.

Amiodarone↗
PubMed1990

Application of X-ray microanalysis to the study of drug uptake in cell culture.

X-ray microanalysis has been used previously to study the accumulation of iodine in alveolar macrophages of rats treated with the iodinated drug, amiodarone. Due to metabolism of the drug in vivo, primarily to desethylamiodarone, it was not possible to identify the source of the iodine signal. In the present study we have utilized primary cell cultures of alveolar macrophages to study the intracellular accumulation of each of these drug species in vitro. Neither drug is metabolized by these cells in culture, permitting characterization of the accumulation of each independent of the other. Cells were incubated with equimolar concentrations of either amiodarone or desethylamiodarone for 42 hr, and X-ray microanalysis of freeze-dried cryosections of cells was used to quantify accumulation by monitoring the iodine signal associated with each drug. For both drug exposures, the highest iodine content was present in amorphous bodies and dense granules, consistent with the pattern following in vivo exposure. Higher levels of desethylamiodarone, compared to amiodarone, were measured in all compartments of the cells. The results of the in vitro investigation further demonstrate the utility of X-ray microanalysis in the study of the cellular response to amiodarone and desethylamiodarone.

Amiodarone↗
PubMed1990

Quantitative X-ray microanalysis of alveolar macrophages after long-term treatment with amiodarone.

Treatment with the iodine-containing antiarrhythmic drug, amiodarone, can cause pulmonary toxicity. Alveolar macrophages are particularly susceptible to formation of lipidrich lamellar bodies in amiodarone-treated animals. Amiodarone and several of its metabolites accumulate in the cell. Previously, we have reported that the technique of X-ray microanalysis is useful in monitoring the distribution of iodine in freeze-dried cryosections of alveolar macrophages from Fischer 344 rats 24 hr after a single dose of amiodarone. In the present study, we examine the effects of longer term amiodarone treatment of 1 or 9 weeks. Substantial changes in iodine distribution occur in the cells with increasing length of drug treatment. High concentrations of iodine are found early in the lamellar bodies. The iodine levels in the nuclei slowly increase with the length of treatment, and after 9 weeks of treatment, approach those found in the lamellar bodies. It is possible that this accumulation of iodine in the nuclei is due to the presence of polar metabolites. In addition, the potassium concentration in the cell decreases and the sodium increases with treatment duration. These changes in cations are most likely due to altered ion transport in the macrophages by the inhibition of membrane Na-K-ATPase by the drug and its principal metabolite, desethylamiodarone.

Amiodarone↗
PubMed1990

Bone marrow stromal cell bioactivation and detoxification of the benzene metabolite hydroquinone: comparison of macrophages and fibroblastoid cells.

Bone marrow stroma consists predominately of two cell types, macrophages and fibroblastoid stromal cells, which regulate the growth and differentiation of myelopoietic cells via the production of growth factors. We have previously shown that macrophages are more sensitive than fibroblastoid stromal cells (LTF cells) to the toxic effects of the benzene metabolite hydroquinone. In this study, the role of selective bioactivation and/or deactivation in the macrophage-selective effects of hydroquinone was examined. LTF and macrophage cultures were incubated with 10 microM [14C]hydroquinone to examine differential bioactivation. After 24 hr, the amount of 14C covalently bound to acid-insoluble macromolecules was determined. Macrophages had 16-fold higher levels of macromolecule-associated 14C than did LTF cells. Additional experiments revealed that hydroquinone bioactivation to covalent-binding species was hydrogen peroxide dependent in macrophage homogenates. Covalent binding in companion LTF homogenates was minimal, even in the presence of excess hydrogen peroxide. These data suggest that a peroxidative event was responsible for bioactivation in macrophages and, in agreement with this, macrophages contained detectable peroxidase activity whereas LTF cells did not. Bioactivation of [14C]hydroquinone to protein-binding species by peroxidase was confirmed utilizing purified human myeloperoxidase in the presence of hydrogen peroxide and ovalbumin as a protein source. High performance liquid chromatographic analysis of incubations containing purified myeloperoxidase, hydroquinone, and hydrogen peroxide showed that greater than 90% of hydroquinone was removed and could be detected stoichometrically as 1,4-benzoquinone. 1,4-Benzoquinone was confirmed as a reactive metabolite formed from hydroquinone in macrophage incubations using excess GSH and trapping the reactive quinone as its GSH conjugate, which was measured by high performance liquid chromatography with electrochemical detection. The activity of DT-diaphorase, a quinone reductase that has been invoked as a protective mechanism in quinone-induced toxicity, was 4-fold higher in LTF cells than macrophages. These data suggest that the macrophage-selective toxicity of hydroquinone results from higher levels of peroxidase-mediated bioactivation and/or lower levels of DT-diaphorase-mediated detoxification.

Animals↗