PubMed Health⌕ Search

Biomedical subjects

M R Boyd

Publications and source records attributed to M R Boyd.

At least 235 records · Page 13Linked to original sources
PubMed1985

Isolated total lung perfusion as a means to deliver organ-specific chemotherapy: long-term studies in animals.

The objectives of this study were to develop a surgical procedure that would allow for bilateral isolated lung perfusion in vivo as a means of delivering organ-specific chemotherapy and to evaluate the influence of the procedure on certain pulmonary physiologic parameters. The sterile surgical procedure that was carried out in dogs involved the setting up of two separate perfusion circuits. Once standard systemic cardiopulmonary bypass was established, a second circuit was devised to perfuse the lungs by placing an inflow cannula into the main pulmonary artery and collecting venous effluent in the left atrium. Cross-contamination between perfusion circuits was determined in acute studies with labeled plasma protein or red blood cells and was found to be in an acceptable range if the aorta was cross-clamped and the heart arrested. Only about 0.4 ml/min of pulmonary perfusate leaked into the systemic circulation, indicating that systemic toxicity should not be a major concern when chemotherapy agents are added to the pulmonary perfusate. Chronic studies demonstrated that hemodynamic parameters, lung water, pulmonary endothelial serotonin extraction, and histologic findings all showed minimal changes after 50 minutes of isolated lung perfusion. Five days after perfusion, lung dynamic compliance and peak serotonin extraction showed significant decreases. However, all of the measured parameters had returned toward baseline levels by the end of the 8-week postoperative study period. The procedure offers significant advantages over the previously described single lung perfusion and may provide a method of delivering immediate high-concentration adjuvant chemotherapy to coincide with resection of primary or metastatic lung tumors.

Animals↗
PubMed1985

Effects of buthionine sulfoximine on the nephrotoxicity of 1-(2-chloroethyl)-3-(trans-4-methylcyclohexyl)-1-nitrosourea (MeCCNU).

Administration of 1-(2-chloroethyl)-3-(trans-4-methylcyclohexyl)-1 1-nitrosourea (MeCCNU; 50-500 mg/kg) to male F344 rats caused a time- and dose-related decrease of glutathione (GSH) preferentially in the liver, but not in the kidney. A 500-mg/kg dose of MeCCNU decreased liver, lung and kidney GSH by 69, 15 and 3%, respectively, 2 hr after dosing. However, MeCCNU had no effect on the ratio of GSH/oxidized GSH or on GSH reductase activity in any tissue tested. A single i.p. dose of DL-buthionine-SR-sulfoximine, an inhibitor of GSH biosynthesis, caused tissue GSH levels to decrease at a rate which reflected the biological half-life of GSH in the respective organs. The T 1/2 for GSH in kidney, liver and lung was found to be 1.5, 5 and 9 hr, respectively. MeCCNU administered s.c. to DL-buthionine-SR-sulfoximine-pretreated rats resulted in a depletion of hepatic and renal GSH concentrations which was additive to the effects of either of these treatments alone. DL-Buthionine-SR-sulfoximine also markedly increased the nephrotoxicity of MeCCNU and resulted in a hepatotoxicity not ordinarily seen when MeCCNU was administered alone. These results suggest that a reactive electrophilic intermediate may be involved in the mechanism of MeCCNU nephrotoxicity. Moreover, that renal GSH may play a protective role against MeCCNU-induced nephrotoxicity.

Animals↗
PubMed1984

Reactive metabolites from the bioactivation of toxic methylfurans.

An important mechanism of toxicity of furans involves the cytochrome P-450 monooxygenase-catalyzed bioactivation of the compound in situ directly within the target tissues to highly reactive electrophilic products. The unsaturated aldehydes acetylacrolein and methylbutenedial have been identified as the principal reactive intermediates of 2- and 3-methylfuran, respectively, that are produced and bound covalently to tissue macromolecules in hepatic and pulmonary microsomal systems in vitro.

Animals↗
PubMed1984

The effect of 3-methylfuran inhalation exposure on the rat nasal cavity.

The acute inhalation toxicity of 3-methylfuran (3MF) was investigated in female CD/CR rats. Animals were killed 1, 3, 6, 9, 12, 15 and 30 days following a 1-h exposure to 148 mumol 3MF/1. Relatively selective 3MF-induced necrosis of the olfactory epithelium was seen at day 1 post exposure. Subsequent resolution of the acute olfactory necrosis was not complete and resulted in partial occlusive fibrosis of the nasal cavity as seen at 30 days. Pretreatment of the animals with piperonyl butoxide (PB) did not block 3MF-induced olfactory epithelial necrosis although it prevented Clara cell necrosis when given at a dose of 800 mg/kg intraperitoneally 1 h before exposure to 3MF.

Animals↗
PubMed1984

Acute inhalation toxicity of 3-methylfuran in the mouse: pathology, cell kinetics, and respiratory rate effects.

The acute inhalation toxicity of 3-methylfuran (3MF) was investigated in male BALB/c mice by morphologic examination of animals killed at varying timepoints following a 1-hr exposure to an initial chamber concentration of 14 to 37 mumol/liter (343 to 906 ppm). In addition, respiratory rate measurements and cell kinetics were used to assess quantitatively pulmonary damage and repair. Necrosis of nonciliated bronchiolar epithelial (Clara) cells was seen 1 day following exposure and was followed by regeneration, which was virtually complete, within 21 days. Cell kinetic studies showed peak bronchiolar cell proliferation at 3 days with a labeling index (LI) of 5.0% compared to 0.4% in controls. An increase in parenchymal cell proliferation was also noted coincident with a mild interstitial pneumonitis. This parenchymal proliferation, peaking at 10 days with an LI of 1.4% compared to 0.2% in controls, consisted primarily of type II epithelial and endothelial cell proliferation indicating possible delayed damage and repair of type I epithelial and endothelial cells. The respiratory rate showed an initial transient increase followed by a more prolonged decrease with eventual return to control levels. 3MF toxicity was also evidenced by a necrotizing suppurative rhinitis, centrilobular hepatic necrosis, lymphocyte necrosis in the thymus and spleen, sialoadenitis, and otitis media.

Air Pollutants↗
PubMed1984

Immune characteristics of the beige-nude mouse. A model for studying immune surveillance.

Double immunodeficient mice, homozygous for both the beige and the nude genes, were developed on C57BL/6N-beige and N:NIH(S)-nude background through five steps of mating. The animals were healthy and had a life span comparable to that of regular nude mice. Beige and regular nude mice showed a significant difference in natural killer (NK) activity, with mean +/- SE values of 6 +/- 1.0% and 25 +/- 2.8%, respectively. The response to the T-cell mitogens phytohaemagglutinin and concanavalin A was similar in beige and NIH mice of the same genotypes for the nude genes. Both groups of nu/nu mice also showed some response in these assays, as well as in the plaque-forming cell assay, indicating that nude mice are not completely devoid of functional T or T-like cells. The nude genes were found to increase the response to the B-cell mitogen lipopolysaccharide in both the beige and NIH animals, whereas the response was reduced in mice of the beige genotypes. The viable, low NK beige-nude mice here reported on may be a valuable tool for studying factors involved in host defence against tumours. Interestingly, no spontaneous tumours have so far been observed in such mice.

Animals↗
PubMed1984

Metabolic basis for the pulmonary Clara cell as a target for pulmonary carcinogenesis.

The furan compound, 4-ipomeanol, is activated in lung tissue by cytochrome P-450 dependent oxidation to a highly reactive, electrophilic product that binds covalently to tissue macromolecules. Although the reactive metabolite(s) of 4-ipomeanol have not yet been definitively identified, recent studies with 3-methylfuran have indicated that a highly reactive, unsaturated dialdehyde is formed from microsomal oxidation and ring-opening of the furan nucleus. Metabolic experiments with 4-ipomeanol in intact lungs, lung slices, lung cells, lung microsomes and purified lung cytochromes P-450, supported the conclusion that the Clara cell is an important locus of cytochrome P-450 monooxygenase activity in lung. In vivo, 4-ipomeanol was bound covalently and caused necrosis preferentially in the pulmonary Clara cells of laboratory animals. Similarly, N-nitrosamines require metabolic activation mediated by the cytochrome P-450 monooxygenase system in the host organism. A number of nitrosamines which are lung carcinogens in rats and hamsters have been shown to bind preferentially to bronchial and bronchiolar Clara cells in these species. Early pathological changes occurred specifically in Clara cells and lung tumors that developed under continuous nitrosamine treatment originated from such altered Clara cells. The well-differentiated counterparts of these tumors clearly retained their ability to bind the nitrosamine that had induced their formation. Thus, the studies on these two different classes of compounds together supported the view that metabolism may be a factor critical to the progenitor role of the Clara cell in chemically-induced bronchogenic lung cancer.

Animals↗
PubMed1984

Metabolic activation and lung toxicity: a basis for cell-selective pulmonary damage by foreign chemicals.

The lungs may be exposed to potentially toxic metabolites that are either formed in situ or which are present in the circulation. Therefore, pulmonary injury may be a prominent effect of certain classes of chemicals that undergo bioactivation in the body. The specific types of lung cells damaged may depend upon factors such as preferential exposure or accumulation of parent compounds and/or metabolites, differences in cellular defense mechanisms, or the specific mechanism of activation of the toxicant. Prior knowledge about the metabolism, disposition and mechanism of bioactivation of a particular compound may allow prediction of the type of lung cell damage it is likely to produce. Conversely, morphological observations of characteristic types of cell-specific injury in the lung may suggest a likely biochemical mechanism of toxicity for the particular chemical involved.

Animals↗
PubMed1984

Lack of correlation between natural killer activity and tumor growth control in nude mice with different immune defects.

To elucidate the in vivo role of natural killer (NK) cells, the growth of several murine and human tumors was studied in four variants of athymic, nude mice with different levels of NK activity. Beige-nude mice, homozygous for both the beige and the nude genes, had very low levels of NK activity, and their response to the B-cell mitogen, bacterial lipopolysaccharide, was lower than that of high-NK, adult NIH nude mice. Young and adult NIH nudes had different NK levels and showed different response in assays for K-cell, T-cell, and B-cell activity. The B-cell-defective NIH-II mice had slightly lower NK levels than adult NIH animals, but much lower response in the antibody-dependent cell-mediated cytotoxicity assay. No correlation was found between host NK activity and the s.c. growth of various human (LOX, CEM, K562) and murine (YAC-1) tumor cells. Low NK activity was not associated with increased lung colony formation in a metastasis model using i.v.-injected human (LOX) and murine (B16F10) melanoma cells. No relationship was found between host NK activity and the rate of elimination of i.v.-injected 5-iodo-2'-deoxyuridine-labeled LOX, B16F10, and YAC-1 cells from lungs, liver, or spleen. The results fail to support the view that NK cells exert significant direct effects on tumor cells in vivo.

Animals↗
PubMed1984

Pharmacokinetics of doxorubicin in isolated lung of dogs and humans perfused in vivo.

The pharmacokinetics of doxorubicin was investigated in the lungs of dogs and three pulmonary cancer patients perfused in situ. In the dogs, doxorubicin uptake increased with time but was saturable at perfusate concentrations above 20 nmol/ml. After 50 min, tissue levels were consistently higher than blood perfusate levels. The kinetics of doxorubicin uptake were well described by a simple diffusion model. Changes in the estimated kinetic model parameters suggested that the saturation of doxorubicin accumulation at higher concentrations was due to a decrease in the relative rate of uptake rather than a change in the rate of efflux. In the three human patients studied, doxorubicin accumulation in the perfused lung was considerably slower compared to dog lung, and the level of drug measured in human lung tumor biopsies was consistently less than surrounding tissue. The present study has shown that lung perfusion is technically feasible and may represent a means of delivering cytotoxic drugs to unresectable pulmonary tumors in humans.

Animals↗
PubMed1984

Preferential effects of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) on pulmonary glutathione reductase and glutathione/glutathione disulfide ratios: possible implications for lung toxicity.

Single doses (8-80 mg/kg) of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) inhibited lung glutathione disulfide (GSSG) reductase in a dose- and time-dependent manner. The loss of enzyme activity persisted up to 8 days after 20 mg of BCNU per kg. A multiple dosing regimen consisting of 5 mg of BCNU per kg/week for 6 weeks decreased lung reductase activity by at least 70%. Recovery was very slow, still remaining well below (68%) control activity for 2 weeks after cessation of BCNU treatment. In contrast, liver GSSG reductase was only slightly decreased by the multi-dose BCNU regimen and rapidly returned to control levels. Pulmonary GSSG concentrations were increased to about 300% of control. This elevation persisted up to 2 weeks after BCNU treatment was completed. There was no effect on total pulmonary glutathione levels during or after BCNU treatment. BCNU administration did not alter hepatic GSSG, although there was a delayed elevation of total liver glutathione. The multi-dose BCNU regimen used in this study leads to the delayed onset of striking pulmonary damage which develops in severity over several weeks after the BCNU treatment is completed. The present results, therefore, suggest that a relatively preferential destruction of lung GSSG reductase by BCNU may precede the development of severe lung toxicity. Considering the probable importance of GSSG reductase in maintaining normal lung homeostasis, this biochemical lesion merits further attention as to its possible role in the pathogenesis of BCNU-induced lung disease.

Animals↗
PubMed1983

Effects of bis-chloronitrosourea (BCNU) on pulmonary and serum angiotensin converting enzyme activity in rats.

The anticancer drug bis-chloronitrosourea (BCNU) causes potentially life-threatening lung injury in a high percentage of patients. Because changes in the activities of pulmonary and serum angiotensin converting enzyme (ACE) have been reported previously to reflect toxic pulmonary damage by certain agents, we have investigated the effects of BCNU on pulmonary and serum ACE of rats. In vitro, BCNU had a direct inhibitory effect on both serum ACE and pulmonary ACE. In vivo, a large single dose of BCNU (80 mg/kg, i.p.) did not alter pulmonary ACE nor cause histologically observable acute lung damage. However, serum ACE dropped by 25% within 1 hr after drug. A multi-dose regimen, consisting of 5 mg BCNU/kg once per week for 6 weeks, caused marked pulmonary injury, which continued to develop in severity over several weeks following the completion of dosing. Lung ACE after four doses (total of 20 mg BCNU/kg) was depressed by 40% and remained low until dosing was completed. Following the final dose, lung ACE returned to control within 2 weeks. However, after an additional 2 weeks both lung and serum ACE had decreased by 35 and 25% respectively. It appears that ACE may provide a useful biochemical monitor for BCNU-induced pulmonary toxicity, but careful attention must be given to the time-course of changes in the enzyme activity.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1983

Isolated lung perfusion with Adriamycin. A preclinical study.

Isolated in vivo single-lung perfusion with an Adriamycin-containing whole-blood perfusate was performed in three groups of dogs after establishing adequate controls. The procedure, performed through a left thoracotomy, was followed two weeks later by a contralateral pneumonectomy. Survival following pneumonectomy was used as the ultimate end point in assessing perfusion toxicity. Groups I and II had high mortality rates but provided valuable information concerning perfusion methods, venous drainage techniques, drug dosage schedules, and perfusate flow rates. The group III study consisted of five dogs perfused for 45 minutes at flow rates sufficient to maintain mean pulmonary artery pressure at 12-15 mm Hg. An initial Adriamycin (Adr) dosage of 0.5 micrograms/ml in the plasma perfusate resulted in mean peak Adr lung tissue levels of 3.8 +/- 1.06 micrograms/g. All animals survived right pneumonectomy 19 +/- 4 days later. Three dogs have been killed and histologic examination showed only mild focal pleural and subpleural interstitial fibrosis. Based on these studies it is concluded that isolated single-lung perfusion is a reproducibly safe technique and that a dosage of Adr has been identified which produces no apparent toxity in a large animal model. A clinical trial is currently in progress.

Animals↗
PubMed1983

Pathology of acute inhalation exposure to 3-methylfuran in the rat and hamster.

The acute inhalation toxicity of 3-methylfuran (3MF) was investigated in SPF Fischer-derived and CD/CR rats, and golden Syrian hamsters by determination of the 2-week LC50, and by histologic examination of animals killed 1, 3, and 14 days following a 1-hr exposure to 148 and 322 mumole 3MF/liter for CD/CR rats and hamsters, respectively. The Fischer-derived rat was more sensitive to 3MF-induced lethality than the CD/CR rat with an LC50 in the male rat of 81 mumole/liter-1 hr as compared to 222 mumole/liter-1 hr. No sex difference was found. The hamster was relatively resistant with no lethality at 322 mumole 3MF/liter-2 hr. Pulmonary damage was present in both species. In the hamster, selective necrosis of nonciliated bronchiolar epithelial (Clara) cells was seen at 1 day with virtually complete regeneration by 14 days whereas in the rat the bronchiolar epithelial damage was more extensive and was followed by scattered peribronchiolar fibrosis and epithelial mucous metaplasia suggestive of "small airway disease" of man. Relatively selective 3MF-induced necrosis of olfactory epithelium occurred in the nasal mucosa of both species. Resolution of this lesion was seen by 14 days in the hamster. In the rat, however, the necrosis was much more extensive and was followed by partially occlusive fibrosis of the nasal cavity as seen at 14 days. 3MF also induced centrilobular hepatic necrosis in both species. In the rat, lymphocyte necrosis in the thymus and spleen, and esophageal necrosis was also seen.

Acute Disease↗
PubMed1983

Effects of 3-methylcholanthrene on covalent binding and toxicity of 4-ipomeanol in inducible and non-inducible (B6D2) mice.

The effects of 3-methylcholanthrene (MC) on the covalent binding and toxicity of 4-ipomeanol (1-(3-furyl)-4-hydroxypentanone, IPO) were studied in (C57BL/6N)(DBA/2N)F1 X DBA/2N backcross (B6D2)D2) mice previously segregated into relatively "inducible" or "non-inducible" groups based on zoxazolamine (2-amino-5-chlorobenzoxazole, ZOX) paralysis times following MC treatment. MC decreased the covalently bound IPO metabolite(s) both in the lungs and in the kidneys of "inducible" and "non-inducible" mice when compared to controls not pretreated with MC. On the other hand, concentrations of covalently bound IPO metabolite(s) in liver were increased in "inducible" mice and decreased in "non-inducible" mice by MC pretreatment when compared to non-pretreated heterogenous mice. Associated with MC pretreatment was a significant decrease in the acute lethality of IPO both in the "inducible" and in the "non-inducible" mice when compared to nonpretreated control animals (LD50: 213 +/- 2, 140 +/- 14 and 14 +/- 4 mg/kg, respectively). Hepatic necrosis occurred frequently in the "inducible" mice and occasionally in the "non-inducible" mice given large IPO doses near the respective LD50-values. Hepatic necrosis was never observed in non-pretreated mice receiving near lethal doses of IPO. These results support previous studies indicating that reactive IPO metabolites binding to extrahepatic tissues are formed in situ and do not reflect binding of blood-borne metabolites formed in the liver.

Animals↗