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Biomedical subjects

R E Edwards

Publications and source records attributed to R E Edwards.

At least 19 recordsLinked to original sources
PubMed1992

The immunotoxicity of tributyltin oxide (TBTO) does not increase the susceptibility of rats to experimental respiratory infection.

1. The dietary exposure of rats to tributyltin oxide at a concentration of 150 ppm for 6 weeks is known to lead to a significant reduction in relative thymic weight. 2. To determine whether this reduction in thymic weight also leads to an impairment of function sufficient to alter the host response to micro-organisms, we have examined the development of virus- and mycoplasma-induced pneumonia in TBTO-exposed rats. 3. Using a quantitative histopathological method for measuring both the extent and duration of lung lesions in TBTO-exposed rats, no statistically significant increase in the extent or persistence of virus-induced lung lesions was found in rats exposed chronically to TBTO. 4. The susceptibility of rats to Mycoplasma pulmonis infection, alone, or in conjunction with viral pneumonia, was also not increased by dietary exposure to TBTO.

Animals↗
PubMed1992

Intrapleural administration of fibres induces mesothelioma in rats in the same relative order of hazard as occurs in man after exposure.

1. The dose-response data for the induction of mesothelioma, in rats, by the intrapleural administration of the fibrous zeolite, erionite, has been compared to the published data for the crocidolite and chrysotile forms of asbestos. Erionite is more than two orders of magnitude more carcinogenic than either of the two forms of asbestos examined. 2. The relative sensitivity of the intrapleural and intraperitoneal routes of injection were also examined. The sensitivity of the intraperitoneal over the intrapleural route of administration was considerably greater for all the forms of asbestos examined but not for erionite. 3. The relationship for different fibres, between the number of fibres required to give animals mesothelioma, at the 50% or 10% observable tumour effect level (OTEL) was examined, and a ranking of relative carcinogenicity was made. 4. This showed that the data derived from the dose responses obtained by the intrapleural administration of fibres to rats ranked the relative carcinogenicity of erionite, crocidolite and chrysotile in accord with the known clinical mesothelioma induction in man after exposure to these fibres. Examination of the carcinogenicity ranking from data derived from intraperitoneal injections of fibres was not in accord with the known clinical mesothelioma induction in man for the various asbestos types examined.

Animals↗
PubMed1991

Hepatic fibrosis and iron accumulation due to endotoxin-induced haemorrhage in the gerbil.

This study reports the findings of hepatic fibrosis and the accumulation of iron in the livers of 12 gerbils. The primary lesion was a haemorrhagic necrosis of the liver that was identical to that produced experimentally in the gerbil by administration of E. coli endotoxin lipopolysaccharide. The resulting extravasation of blood caused focal histiocytic reactions. The number of lesions increased with age, eventually resulting in a micronodular cirrhosis after 9 to 12 months owing to repeated episodes of endotoxin-induced haemorrhages in the liver. The accumulation of iron occurred in perisinusoidal cells, Kupffer cells and hepatocytes. The perisinusoidal cells were responsible for the subsequent hepatic fibrosis. The fibrosis associated with this condition appears to result from iron accumulation in the liver, following haemorrhage caused by endotoxin lipopolysaccharide. The gerbil is the first recorded rodent species to develop hepatic fibrosis in response to hepatic iron overload.

Animals↗
PubMed1991

Increased susceptibility of aged rats to haemorrhage and intravascular hypercoagulation following endotoxin administered in a generalized Shwartzman regime.

Ageing rats are known to have an increased incidence of myocardial fibrosis and dyspnoea caused by pulmonary intravascular coagulation. In order to determine whether endotoxin can be responsible for such responses in ageing rats we have exposed rats of differing ages (2 months, 16 months and 24 months) to single or repeated (two doses 24 h apart; generalized Shwartzman regime) intravenous doses of endotoxin (E. coli 0111 B4). Only the 2-year-old rats reacted adversely. Two doses of endotoxin produced death, with focal myocardial necrosis, haemorrhage and pulmonary and hepatic intravascular coagulation. The increased susceptibility of aged rats to the toxic effects of endotoxin explains some of the changes found in the tissues of old rats. The sporadic nature of both cardiac failure and dyspnoea as a cause of morbidity and mortality in ageing rats may be related to the need for two endotoxin episodes in a period of 24 h to provoke a generalized Shwartzman reaction, an occurrence likely to be relatively uncommon under natural conditions.

Aging↗
PubMed1991

Rapid induction of hepatic fibrosis in the gerbil after the parenteral administration of iron-dextran complex.

The parenteral administration of iron-dextran complex to gerbils caused hepatic hemosiderosis and fibrosis after 6 wk. Type I and III collagen synthesis in the liver developed from perisinusoidal stellate cells that are often referred to as myofibroblasts. Immunohistologically these cells were shown to have large intracellular deposits of ferritin. The hepatic fibrosis appeared to be associated with aggregates of these cells rather than the aggregates of Kupffer cells, which also occur in hemosiderosis in the liver. No appreciable necrosis of hepatocytes to trigger the fibrotic response was found, so that the fibrosis appeared to be related to the accumulation of ferritin in the perisinusoidal stellate cells. In contrast, rats and mice did not accumulate ferritin in their perisinusoidal cells or develop hepatic fibrosis in response to parenterally administered iron, although they accumulated similar or greater amounts of total iron in their livers. The rapid induction of hepatic fibrosis in gerbils in response to parenterally administered iron will provide a model to investigate the mechanism of induction of collagen deposition in response to iron overload and a means of quickly evaluating therapeutic treatments for iron overload-induced fibrosis in vivo using iron-chelating drugs.

Animals↗
PubMed1990

The preparation of highly enriched fractions of binucleated rat hepatocytes by centrifugal elutriation and flow cytometry.

A procedure is described for the isolation of highly enriched fractions of binucleated hepatocytes from rat liver. Liver cells isolated by EGTA and collagenase perfusion were initially subjected to centrifugal elutriation and second to flow cytometry coupled with Hoechst 33342 staining. The elutriation step yielded hepatocyte fractions which contained almost entirely mononuclear diploid cells and fractions enriched in binucleate hepatocytes. The fractions with the highest proportion of binucleated hepatocytes contained between 50 and 56% of these cells. Subsequent flow cytometric cell sorting yielded fractions which contained greater than 80% binucleated cells. These cells were viable in culture as demonstrated by the immunohistochemical detection of bromodeoxyuridine incorporation.

Aneuploidy↗
PubMed1990

Characterization and accumulation of ferritin in hepatocyte nuclei of mice with iron overload.

After a single subcutaneous dose of iron-dextran (600 mg of iron/kg), iron overload developed in C57BL/10ScSn mice. At 4, 24 and 78 wk liver nonheme iron concentrations were 67-, 42- and 21-fold higher than controls, respectively. Much of the iron was in macrophages, but hepatocytes were also strongly positive for Perls' stainable iron. One feature was the development of iron-positive nuclear inclusions in hepatocytes. After a delay of at least 8 wk when no stainable iron was evident, a maximum of 37% of periportal hepatocytes contained inclusions by 24 wk. Although this proportion remained constant for the remainder of the study, the size of the inclusions (which were not membrane-limited) increased to greater than 3 microns in diameter, occupying greater than 25% of the nuclear volume. The presence of iron in the inclusions was confirmed by energy dispersive x-ray microanalysis. Immunocytochemical studies showed that the iron was present as aggregates of ferritin. Quantitation of nonaggregated ferritin molecules by image analyses after electron microscopy demonstrated that within 4 wk ferritin levels in cytoplasm and nucleoplasm had greatly increased but that there was a concentration gradient of approximately one order of magnitude across the nuclear envelope. These findings are consistent with the hypothesis that in iron-loaded mouse hepatocytes there is a slow passage of ferritin-molecules through the nuclear pores; the gradient is maintained by the continual aggregation of ferritin within the nucleus. Intranuclear ferritin may provide a source of iron for catalyzing hydroxyl radical formation in nuclei during some toxic, carcinogenic and aging processes.

Animals↗
PubMed1990

Phenotypic stability and metastatic behaviour of serially xenografted rat mesotheliomas.

Mesotheliomas induced in rats by intrapleural injection of the fibrous zeolite, erionite, were serially transplanted in nude mice for up to ten generations. The cell phenotypes (epithelial or sarcomatous) were well maintained during passaging, as determined morphologically and by the expression of the cytokeratin markers demonstrated in normal mesothelial cells. Some of the tumours occasionally produced metastasis in nude mice. In contrast, a cloned epithelial cell mesothelioma and sarcomatous cell mesothelioma, the original cells of which were isolated in tissue culture, both produced regular multiple metastases when passaged in nude mice. These metastases were frequently found on the visceral pleura, rather than in the lung parenchyma, in nude mice. The high metastatic rate of the xenograph mesotheliomas derived by in vitro isolation of cells from mesotheliomas is atypical of the usual behaviour of xenografts of mesotheliomas.

Aluminum Silicates↗
PubMed1990

Immunotoxic effects of hexachlorobenzene on the pathogenesis of systemic, pneumonic and hepatic virus infections in the mouse.

A quantitative histopathological method has been developed for the evaluation of the effects of hexachlorobenzene (HCB) on the pathogenesis of three virus infections in the mouse. Hexachlorobenzene was selected because a substantial amount of immunotoxicological data already exists with which we could compare our results. To establish the validity of the method a systemic virus infection (mouse cytomegalovirus, MCMV), a pneumonia causing virus (pneumonia virus of mice, PVM) and a hepatitis virus (mouse hepatitis virus, MHV) were used. We have compared the existing data with the actual pathological effects of hexachlorobenzene on virus disease processes, to gain a more realistic idea of the value of the risk assessment to be derived from extrapolating the in-vitro data in particular, to the in-vivo situation. The results show that the data derived from previous studies on the immunotoxicity of HCB were accurate in predicting the exacerbation of the viral hepatitis, especially in immunodeficient athymic 'nude' mice. It is proposed that this histopathological technique could be a useful technique in the evaluation of host resistance changes following exposure to potentially immunotoxic compounds, but caution will have to be exercised in interpretation in relation to human disease.

Animals↗
PubMed1990

Early changes in the pleural mesothelium following intrapleural inoculation of the mineral fibre erionite and the subsequent development of mesotheliomas.

Changes in the pleura of rat lungs after intrapleural inoculation of the fibrous zeolite, erionite, have been examined from the earliest stages of reaction through to the eventual development of mesotheliomas. The initial changes involve haemorrhaging and pleural inflammation and proliferation with localized destruction of the elastic membrane under the visceral pleura. This allows cell proliferation into the lung parenchyma with fibres being able to penetrate into the lung. The chronic stimulation of the pleura by erionite eventually leads to the development of mesotheliomas which are invasive or compressing. The tumours are derived from the epithelial cells of the mesothelium (as shown by cytokeratin staining) or the subserosal cells beneath the mesothelium. Both types of mesothelioma can be invasive and some show an unusual property of 'tracking' along the blood vessels in the parenchyma as they invade. In dose-response terms for mesothelioma formation, erionite is over 200 times more tumourogenic than crocidolite (blue) asbestos.

Aluminum Silicates↗
PubMed1989

Dyspnea in aging rats due to disseminated intravascular coagulation (DIC).

During an 18-month oncogenicity study using rats, approximately 10% of the animals developed a form of respiratory distress very similar to that seen in the terminal stages of chronic respiratory disease, commonly associated with Mycoplasma pulmonis infection. Investigation of the lungs of the affected rats revealed not only that they did not have the consolidation usually associated with chronic respiratory disease, but they also appeared macroscopically normal. Further investigation of a number of cases revealed systemic intravascular thrombus formation of the type usually referred to as disseminated intravascular coagulation. Using an antiserum to fibrin we have demonstrated the presence of intravascular fibrin deposits in the lungs of the affected rats and have shown them to be the same as experimentally induced intravascular fibrin deposits induced in rat lungs by the administration of thrombin after blocking the fibrinolytic system. This is the first example of such a phenomenon being recorded in aging rats.

Aging↗
PubMed1989

Cytokeratin expression in cells of the rodent bile duct developing under normal and pathological conditions.

A polyclonal anti-cytokeratin antibody has been used to examine the expression of this intermediate filament both during normal development in the rat and in a variety of pathological states in the rat and mouse. Bile duct proliferation induced by the administration of alpha-naphthylisothiocyanate (ANIT) as well as the oval cell proliferation induced by 3'-methyl-4-dimethylaminoazobenzene (3-MeDAB) have been used to examine the expression of the rodent cytokeratins in the proliferating cells regarded as being of bile duct origin. Examples of cholangiofibrosis and cholangiocarcinomas were also examined for evidence of cytokeratin expression using this antibody, as well as proliferations of a morphological intermediate type between epithelial and mesenchymal. In all cases we have been able to demonstrate continuity of phenotypic expression of the cytokeratins recognized by this antibody in cells which are recognized as bile duct in origin, even where their morphological appearance does not resemble an epithelial cell type. Because this antibody can be used on formalin-fixed, paraffin-processed tissues, after trypsin treatment, it is proposed that it can be used routinely in the toxicological evaluation (even retrospectively) of bile duct related proliferations and tumours.

1-Naphthylisothiocyanate↗
PubMed1985

The use of vimentin antibodies in the diagnosis of malignant mesothelioma.

An immunohistochemical investigation of vimentin, an intermediate filament, was carried out on formalin fixed paraffin embedded sections of 44 malignant mesotheliomas of the pleura and 24 pulmonary adenocarcinomas, in order to assess its value in differential diagnosis. Seventy-five percent of the malignant mesotheliomas showed positive staining for vimentin. An unexpected finding was the presence of vimentin in 46% of the pulmonary adenocarcinomas. In either case there was no correlation between the presence of vimentin and the histological types or grades of differentiation. The overall level of vimentin staining was significantly greater in the malignant mesotheliomas than in the pulmonary adenocarcinomas but no single antibody dilution was found to provide clear cut separation of the two groups. Vimentin does not appear to be a simple discriminatory marker of malignant mesothelioma.

Adenocarcinoma↗
PubMed1984

Cell population and histochemistry of asbestos related lesions of rat pleural cavity after injection of various inorganic dusts.

Rats injected intrapleurally with either crocidolite or chrysotile asbestos or silica or saline, were killed at intervals up to 2 years of age. The pleural cavities were washed out immediately after death and the washing used for enumerating cells. In addition tissue from granulomas and mesotheliomas was sectioned and stained for lysosomal enzymes. The total cellular response to silica found in the washout showed a pronounced increase when compared with either asbestos dust or controls; crocidolite gave a decreased response in an early group of the individual cells studied. The most important finding was a decrease in the number of mast cells found to be associated with the injection of both types of fibres. Crocidolite induced granulomas showed the presence of lysosomal enzymes and non-specific esterase in mononuclear cells and giant cells, even two years after injection. With chrysotile, giant cells were only present up to three to four months, and few positively staining cells were noted after 18 months. While the response of cells in the pleural cavity does not differ greatly between the two types of fibres, that in the granulomas highlights the longer lasting action of crocidolite.

Animals↗
PubMed1984

Mast cells and inhalation of asbestos in rats.

Mast cell counts were performed on sections taken from the lungs of rats exposed by inhalation to different UICC samples of asbestos fibres for periods ranging from a few days to two years. A comparison of mast cell counts with grades of fibrosis showed that there is a sevenfold increase when there is interlobular linking of the fibrotic lesions (grade 5). Submesothelial mast cells showed a trend of increasing numbers with increasing exposure and with increasing subpleural thickening. Each type of asbestos produced a steady increase in mast cell numbers with increasing exposure. Two samples from animals exposed to chrysotile and two from animals exposed to amphiboles (crocidolite and amosite respectively) had 10 times as many cells as the control group after six and 24 months' exposure. Another amphibole, anthophyllite, produced 50 times more cells than were present in the control specimen appropriate for the heaviest exposure. These results are briefly discussed in relation to further exposure, smoking, and characteristics of the dusts.

Animals↗
PubMed1984

Pluripotential nature of mesotheliomata induced by inhalation of erionite in rats.

Mesotheliomata can be induced more rapidly and more frequently by inhalation of erionite than by asbestos inhalation. Erionite-induced tumours have in general a similar ultrastructural appearance to inoculum-induced pleural and peritoneal mesotheliomata. Unusual features of these tumours were the presence of dense-cored vesicles and cells staining positively for neuron-specific enolase which indicated the presence of endocrine cells. In addition, one tumour showed differentiation towards bone-forming cells. The expression of both epithelial and mesodermal characteristics demonstrates the pluripotential nature of mesothelial cells under certain circumstances.

Aluminum Silicates↗
PubMed1979

Sequential immunological studies on an asbestos-exposed population. I. Factors affecting peripheral blood leucocytes and T lymphocytes.

Peripheral blood leucocyte counts, and E binding rosettes were measured on 138 men on five separate occasions. Little effect was seen from age, or length of asbestos exposure. Overall the most marked effect was that obtained from smoking. Most relevant was an increase in percentage of E-rosettes read after 1 1/2 hrs, which was obtained in the group of those with radiological evidence of fibrosis who smoked. Restricted to subjects with small opacities, those who smoke have a significantly higher (P less than 0.05) percentage E 1 1/2 hr rosettes than those who do not smoke. (Percentage E rosettes read overnight remained unaltered by smoking or X-ray). This increase was found on each occasion that it was measured. Since the absolute number of T lymphocytes rosetting at 1 1/2 hr did not increase, it is suggested that there is either no stimulation of the central pool of T lymphocytes or a decrease in the absolute number of T lymphocytes which could only rosette overnight.

Adult↗