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Biomedical subjects

W Bursch

Publications and source records attributed to W Bursch.

At least 55 records · Page 3Linked to original sources
PubMed1992

Cell death by apoptosis and its protective role against disease.

The involvement of cell death in control of tissue growth has long been neglected, but the description of apoptosis as cellular 'suicide', the functional opposite of mitosis, is now attracting more attention to this phenomenon. Physiologically unwanted cells are removed by apoptosis, and toxic chemicals and drugs may enhance or inhibit this type of cell death. These findings are providing new insights into the pathophysiology of a variety of diseases, and suggesting new therapeutic strategies.

Animals↗
PubMed1992

Programmed cell death and its protective role with particular reference to apoptosis.

Apoptosis is a type of programmed cell death involved in growth control of tissues. It is considered as a cellular suicide functionally opposite to mitosis. It may serve to remove "unwanted" damaged or dangerous, e.g. precancerous, cells. Chemical compounds can interfere with the regulatory network which controls apoptosis and can thereby stimulate or prevent cell death. Both induction or inhibition of apoptosis may result in various diseases such as of the immune system, malformation or tumor development. The protective role of apoptosis against carcinogenesis is described in some detail. Tumor formation seems to occur through several stages, namely initiation, promotion, progression, and involves formation and growth of premalignant cell populations. At least in some model systems initiated cells and premalignant cell populations have been found to exhibit enhanced cell replication, but also enhanced apoptotic activity as compared to the normal tissue. Therefore, initiated cells may be eliminated by apoptosis. Tumor promoters can inhibit apoptosis in putative preneoplastic cells and thereby accelerate tumor development. Furthermore, in hormone-dependent cancers malignant cells may undergo massive apoptosis in response to hormone withdrawal or antihormone treatment. Finally, the regulation of apoptosis will be addressed. Our results suggest that transforming growth factor beta 1, a negative regulator of epithelial tissue growth, is a signal inducing apoptosis of liver cells.

Apoptosis↗
PubMed1991

Effect of transforming growth factor beta on cell death of cultured rat hepatocytes.

We investigate mechanisms of regression of liver hyperplasia which occurs after induction of growth by hepatomitogens and their subsequent withdrawal. We hypothesized that transforming growth factor beta 1 (TGF-beta 1) might be involved in the control of regression. Therefore we studied the effect of this agent on DNA synthesis and death of hepatocytes cultured in vitro. Both the low basal rate of DNA synthesis of untreated cells and its increase by epidermal growth factor (10 ng/ml) were suppressed by TGF-beta 1 at concentrations higher than 0.01-0.1 ng/ml. At the same range of concentrations of TGF-beta 1, the DNA content of the cultures declined significantly and numerous dead cells could be seen in the monolayer. Time course studies showed that TGF-beta 1 (1 ng/ml) decreased DNA content in the cultures linearly to 41 +/- 7% of controls during a period of 48 h. A similar decrease occurred with vital hepatocytes in hematoxylin and eosin stained monolayers. These changes were accompanied by an extensive release of lactate dehydrogenase which began at 20 h and was 70% of the total lactate dehydrogenase content of the cultures at 40-48 h. Little formation of guanidine hydrochloride resistant bodies and no fragmentation of DNA, indicators of apoptotic cell death, were detected after TGF-beta 1 (1 ng/ml) treatment. Time lapse cinematography revealed an active detachment of the cells from the underlying collagen gel. These studies show that inhibition of DNA synthesis by TGF-beta 1 is associated with enhanced cell death in cultured hepatocytes.

Animals↗
PubMed1991

Control of cell death (apoptosis) by diethylstilbestrol in an estrogen-dependent kidney tumor.

The role of cell death as a determinant for tumor growth and regression was studied using an estrogen-dependent, transplantable kidney tumor designated H301. H301 cells were injected s.c. into diethylstilbestrol(DES)-treated male Syrian hamsters and developed solid tumors of 1-2 g within 2-3 weeks. Upon withdrawal of estrogen the tumors regressed by 80-90% within 4 days. Mitoses, necrotic areas and single-cell death indicated by small, condensed cell residues, were counted in hematoxylin and eosin stained histological sections of the tumors. Coincident with tumor regression after DES withdrawal, mitotic activity decreased by approximately 90%; the rate of single-cell death increased (by approximately 2-fold at its maximum). The incidence of necrotic areas was not affected by DES withdrawal. DES re-treatment resulted in reduction of single-cell death by 80% within 8 h. Mitotic activity increased within 24 h to the level observed before DES withdrawal. Again, the incidence of necrotic areas did not change. As a result, tumors re-grew to their previous size within 2 days after resumption of DES treatment. These results led to the following conclusions: (i) DES treatment inhibits and DES withdrawal enhances single-cell death of H301 tumor cells. (ii) Both this functional property and its morphology characterize single-cell death in the tumors as apoptosis. (iii) Estrogen-dependent cell death determines, in addition to mitosis and necrosis, the growth rate of H301 tumors. (iv) This experimental model may provide a useful tool to study the interaction of potential anti-tumor drugs with apoptosis in neoplasia.

Animals↗
PubMed1990

DNA synthesis, apoptosis, and phenotypic expression as determinants of growth of altered foci in rat liver during phenobarbital promotion.

Carcinogenesis was initiated in female rat liver by a single dose of N-nitrosomorpholine; subsequently phenobarbital (PB) was administered via the diet at a daily dose of 50 mg/kg body weight for up to 49 weeks. Subgroups of rats were left untreated after 10 or 28 weeks on PB. PB produced the following changes: (a) accelerated appearance of neoplastic nodules and hepatocellular carcinoma (from 28 weeks onwards); (b) phenotypic changes in altered foci such as a shift from clear to eosinophilic appearance, enhanced expression of gamma-glutamyltranspeptidase and other markers, and more distinct borders from surrounding liver; (c) an increase in foci number; and (d) accelerated foci enlargement. The increase in foci number was found to be due to increased phenotypic expression of foci. DNA synthesis was measured by [3H]thymidine labeling at multiple time points. The rate of DNA synthesis was always approximately 10-fold higher in foci than in surrounding liver tissue. Despite this, after N-nitrosomorpholine alone foci grew little before 18-24 weeks. Continuous treatment with PB did not produce a persistent further increase of DNA synthesis in foci, although it accelerated foci growth. Furthermore, at early stages small and larger foci showed similar DNA synthesis activity. These findings indicate that the rate of cell replication as measured by DNA synthesis is not the only determinant of the growth rate of foci. Further studies showed that foci with indistinct borders (reflecting weak expression of the altered phenotype) grew much less than foci with distinct borders; this was at least in part due to an increased rate of cell death by apoptosis found in foci with indistinct borders. In conclusion, besides cell replication, apoptosis and the extent of phenotypic expression (remodeling) determine the growth rate of foci. Foci with weak phenotypic expression predominated after N-nitrosomorpholine alone; in these, a high incidence of apoptosis counterbalanced cell replication. In contrast, during PB treatment foci with strong phenotypic expression predominated; in these, apoptotic activity was lower and the high replicative activity could manifest itself. Finally, all effects of PB on foci were largely although not completely reversible upon cessation of treatment; as a result phenotypic expression declined, and "remodeling" foci with high apoptotic activity predominated again.

Animals↗
PubMed1990

Effects of hypolipidemic drugs nafenopin and clofibrate on phenotypic expression and cell death (apoptosis) in altered foci of rat liver.

Phenotypically altered liver foci were produced in female Wistar rats by a single dose of N-nitrosomorpholine followed by promotion with phenobarbital (PB) for 20 or 28 weeks. Then treatment was changed to either hexachlorocyclohexane (HCH), or cyproterone acetate (CPA), or nafenopin (Naf) or clofibrate (Clof), two hypolipidemic drugs. Foci were identified by a positive reaction for gamma-glutamyl-transpeptidase (GGT) and other cytological markers. HCH and CPA could substitute for PB as foci promoters; in contrast, Naf and Clof decreased expression of GGT in foci resulting in a decline of number and area of detectable foci, effects particularly pronounced with Naf. Immunohistochemical investigations of serial sections revealed that Naf also reduced expression of the altered phenotype when cytochrome P450-PB and pyruvate kinase (type L) were used as foci markers, but not when glutathione-S-transferase B (GST-B) was used. Thus, the number of foci with enhanced GST-B did not decline significantly after the change from PB to Naf treatment. Furthermore, the reduction of GGT and the decrease of foci number during Naf treatment were not associated with increased evidence of cell death by apoptosis in foci, in contrast to the situation after PB withdrawal. These findings strongly suggest that the disappearance of GGT-positive foci after Naf is due to a phenotypic change resulting in a suppression of GGT expression rather than to physical elimination of foci.

Animals↗
PubMed1990

Determination of the length of the histological stages of apoptosis in normal liver and in altered hepatic foci of rats.

Apoptosis is a form of cell death involved in the regulation of cell number in various organs and tumors. Quantitative determination of cell loss through apoptosis in histological sections requires, in addition to counts of apoptotic cells, information on the duration of the histologically visible stages of apoptosis. Here we describe a method to determine the duration of apoptosis in (i) normal and (ii) putative preneoplastic tissue of the liver. (i) Female rats were treated with high doses of the hepatomitogen cyproterone acetate (CPA) to induce liver hyperplasia. After stopping CPA treatment, the hyperplasia partially regressed and excessive hepatocytes were eliminated by apoptosis. CPA was given to block the initiation of apoptosis, and thereafter the time course of elimination of apoptotic cell residues (apoptotic bodies, ABs) from the liver was studied. The mean duration of the histological stages of apoptosis was found to be approximately 3 h. (ii) Phenotypically altered cell foci in rat liver were produced by a single dose of N-nitrosomorpholine and subsequent promotion for 39 weeks with phenobarbital (PB). PB was withdrawn to stop foci growth and to stimulate apoptosis. Then rats were retreated with PB to block initiation of apoptosis in foci. The results indicate that the majority of apoptotic bodies in foci disappeared within 4 h after PB, suggesting that the stages of apoptosis are as short in foci as in normal liver. Finally a simple formula is given to calculate the cell loss rate by apoptosis. The method presented may provide data for quantitative cancer risk assessment from mathematical models of carcinogenesis.

Animals↗
PubMed1989

Histochemical and biochemical studies on the effect of the prostacyclin derivative iloprost on CCl4-induced lipid peroxidation in rat liver and its significance for hepatoprotection.

In the present study, it was investigated whether the prostacyclin derivative Iloprost would protect hepatocytes against CCl4-induced liver injury and which mechanism(s) of hepatocellular pathogenesis might be affected by it. Rats were treated with a single oral dose of CCl4 (2 ml per kg); Iloprost was infused continuously from 2 to 4 hr before intoxication until killing. The following results were obtained. The CCl4-induced release of AST, lactate dehydrogenase and alkaline phosphatase into the serum was reduced by 50 to 70% in rats treated with doses of 0.1 and 0.5 micrograms Iloprost per kg per min. Infusion of 0.02 and 0.004 micrograms Iloprost per kg per min did not affect the CCl4-induced enzyme release into the blood. CCl4 induced the occurrence of aldehydes (products of lipid peroxidation), which were detected by histochemical and biochemical means. At 12, 48 and 72 hr after CCl4, the aldehyde-positive liver section area was about 58, 69 and 16% in rats treated with CCl4 alone, but only about 18, 13 and less than 1% in rats treated additionally with Iloprost. The aldehyde-positive hepatocytes were located predominantly in the centrilobular zone of the liver. At 24 hr the extent of the aldehyde-positive section area was the same in rats with or without Iloprost treatment (about 90%). Biochemical determination, however, revealed that at this time point the malondialdehyde content after Iloprost in rats was about 70% lower than without Iloprost treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Alkaline Phosphatase↗
PubMed1989

Effects of non-genotoxic hepatocarcinogens phenobarbital and nafenopin on phenotype and growth of different populations of altered foci in rat liver.

Non-genotoxic hepatocarcinogens share the ability to induce liver growth in rodents. Phenobarbital (PB), as one prototype compound, promotes the development of liver tumors; altered cell foci of the clear-eosinophilic phenotype, also identified by gamma-glutamyltransferase expression, appear to be precursor lesions. These foci seem to over-respond to the growth-inducing effect of PB. In contrast, the question as to whether peroxisome inducers are also tumor promoters is still unsettled. We will present evidence which strongly suggests that the peroxisome inducer, nafenopin (Naf), promotes tumor development in rat livers by stimulating selective growth of a hitherto undescribed subtype of altered foci. This subtype is characterized by weak diffuse cytoplasmic basophilia of its hepatocytes. Initiation in rats by aflatoxin B1 followed by promotion with Naf produced numerous adenomas and carcinomas; their morphology resembled that of the weakly basophilic foci. Both clear-eosinophilic and weakly basophilic foci appear "spontaneously" in the liver of aging rats. Promotion of such lesions by PB-type compounds or peroxisome inducers may explain cancer formation by these non-genotoxic agents.

Aging↗
PubMed1988

Quantitative structure-activity studies on effects of sixteen different steroids on growth and monooxygenases of rat liver.

Sixteen steroids with different endocrine activities were administered to female rats for 6 or 7 days, in a broad range of doses. Liver growth was recorded by measuring weight and DNA contents and monooxygenase activity by assaying the turnover of five different substrates. According to their effects on these parameters steroids were assigned into one of the following three groups: (a) Estrogens estradiol and ethinylestradiol, as well as the progestins norethynodrel and norethisterone (norethindrone) which have estrogenic activity in rats. These agents induced pronounced liver growth and excessive DNA increase which was not associated with major monooxygenase induction. (b) A different type of response consisted of liver growth and DNA increase associated with a pronounced induction of monooxygenase(s) in a characteristic pattern. This response was elicited by pregnenolone-16 alpha-carbonitril, by progestins progesterone, cyproterone acetate, and medroxyprogesterone (but not gestoden and levonorgestrel), by the antimineralocorticoid spironolactone and by the glucocorticoids cortisol and dexamethasone. Apparently, this response pattern was not related to any specific endocrine action but to certain structural features, in particular to the presence of a saturated, at least two-membered alkyl substituent at C17 of the steroid ring system. (c) No or small effects were observed after gestoden, levonorgestrel and the androgens testosterone and methyltestosterone. Dose-response stuides revealed that estrogens estradiol and EE2 induced hepatic effects more potently by four orders of magnitude than progestins. The response patterns observed may be relevant to the tumor-promoting activity of some of the steroids tested.

Animals↗
PubMed1986

Growth, regression and cell death in rat liver as related to tissue levels of the hepatomitogen cyproterone acetate.

Previous studies have shown that "xenobiotic" compounds such as the environmental pollutant alpha-hexachlorocyclohexane (alpha-HCH) and the synthetic sex steroid cyproterone acetate (CPA) induce growth of rat liver by hypertrophy and hyperplasia. After withdrawal of the growth stimuli, liver hypertrophy was usually found to be readily reversible. Conflicting observations were made concerning the fate of liver hyperplasia: hepatic hyperplasia persisted when induced by alpha-HCH but was found to be partially reversible when induced by CPA. The present study confirms the reversibility of hepatic hyperplasia induced by CPA in rats: about 30% of liver DNA present at maximal liver enlargement disappeared within 6 days after cessation of CPA treatment. Simultaneously, a dramatic increase in the rate of cell elimination by apoptosis was found. Glutamate-pyruvate transaminase and alkaline phosphatase in serum did not show major increases, suggesting that cell death was not due to lytic membrane damage. Furthermore, if treatment with CPA was continued or resumed, the enhanced DNA content persisted and the number of apoptotic bodies was greatly reduced. These observations suggest that the occurrence of cell death is due to withdrawal of the growth stimulus CPA. It may reflect a regulatory phenomenon serving to maintain homeostasis of cell number. Further studies showed that CPA is rapidly eliminated from rat liver and serum: t 1/2 in the liver is about 11 h. In contrast, alpha-HCH was previously found to be eliminated more slowly: t 1/2 approximately 144 h. The present study revealed that alpha-HCH, CPA and nafenopin lower the number of apoptotic bodies. This suggests that inducers of liver growth can inhibit hepatocellular death by apoptosis.(ABSTRACT TRUNCATED AT 250 WORDS)

Alanine Transaminase↗
PubMed1986

Cytoprotective effect of the prostacyclin derivative iloprost against liver cell death induced by the hepatotoxins carbon tetrachloride and bromobenzene.

It was investigated whether the prostacyclin derivative Iloprost (Schering, Berlin) protects rat hepatocytes against lethal damage induced by carbon tetrachloride (CCl4) and bromobenzene (BB). Iloprost was tested in whole animal experiments (intoxication with 2 ml CCl4/kg) and with primary hepatocyte cultures (intoxication with 1.6 mM BB). Cell damage was estimated by light microscopic examination of hepatocellular morphology and by the release of hepatocellular enzymes (glutamic-pyruvic transaminase, GPT; glutamic-oxalacetic transaminase, GOT; lactic dehydrogenase, LDH) into the blood or culture medium. In both experimental set-ups, Iloprost (0.1 micrograms/kg/min in whole animal experiments and 10(-9)-10(-12) M in primary hepatocyte cultures) largely preserved normal hepatocellular morphology after intoxication. Furthermore, the toxin-induced release of hepatocellular enzymes into the blood (GOT, GPT) or into the culture medium (LDH) was reduced by 50%-70% in the presence of Iloprost. It is concluded that the prostacyclin derivative Iloprost possesses cytoprotective activity on rat hepatocytes against lethal injury by CCl4 or BB.

Alanine Transaminase↗
PubMed1985

Quantitative histological and histochemical studies on the occurrence and stages of controlled cell death (apoptosis) during regression of rat liver hyperplasia.

Hyperplasia of the rat liver can be induced by cyproterone acetate (CPA). The fate of this hyperplasia after cessation of CPA treatment has been studied and the following findings were obtained: Liver DNA content decreased by about 25% within a few days after CPA withdrawal. In histological sections some hepatocytes showed degenerative changes. Among these, small membrane bounded bodies ("apoptotic bodies"; ABs) with or without chromatin were most numerous. Their incidence coincided with the phase of DNA elimination. Inflammatory reactions were not observed. Their small size and occurrence in clusters suggests that many of these ABs are formed by fragmentation of dying hepatocytes. Liver DNA was prelabelled with 3H-thymidine. Autoradiographic evaluation showed that many hepatocytes contained labelled nuclei, but unlabelled ABs. This finding strongly suggests that ABs, after the fragmentation stage, can be phagocytized by intact hepatocytes. About 80% of all ABs were found within hepatocytes. Extracellular ABs (early stage) contained no or very few active lysosomes. Intracellular ABs were sometimes surrounded by lysosomes, while others were in various stages of digestion. These observations suggest that the lysosomes of the phagocytizing hepatocytes degrade intracellular ABs, whereas intraapoptotic lysosomes seem to be inactive until the late stages of this degradation. Hepatocytes that did not replicate during CPA-induced liver growth appear to die off preferentially after CPA withdrawal. Retreatment with CPA greatly reduced the number of ABs within 4 h. Phenobarbital, another stimulus of liver growth, had the same effect. These findings suggest that the present type of cell death can be inhibited by growth stimuli and is therefore a controlled event serving to eliminate an excess of cells, rather than a manifestation of toxic injury to hepatocytes. The findings also suggest that this type of cell death and elimination is a rapid process completed within a few hours. It is concluded that cell death under the present experimental conditions probably occurs through apoptosis.

Animals↗
PubMed1984

Controlled death (apoptosis) of normal and putative preneoplastic cells in rat liver following withdrawal of tumor promoters.

Numerous drugs, hormones and environmental pollutants induce liver growth by hypertrophy and/or hyperplasia, and promote preferential growth of putative preneoplastic foci in the liver. In the present study the regression of hyperplasia after cessation of inducer/promoter treatment was studied in normal liver and in liver foci. High doses of cyproterone acetate (CPA), a synthetic sex steroid, were administered to rats and produced a doubling of liver size; after cessation of treatment liver size declined, and 27% of the total liver DNA disappeared within 6 days. In histological sections from the involuting liver no necroses, but numerous apoptotic bodies (ABs) were found; retreatment with CPA interrupted the formation of ABs. These findings suggest that elimination of excess liver DNA after cessation of CPA treatment is due to controlled cell death by apoptosis. In a further series of experiments putative preneoplastic foci were produced by a single dose of N-nitrosomorpholine and subsequently stimulated to grow by 10 or 28 weeks of phenobarbital (PB) treatment. After withdrawal of PB numerous ABs were present in normal liver and in the foci; in both, retreatment with PB decreased the appearance of ABs. It appears that inhibition of cell death by PB may contribute to tumour promotion. Under all conditions tested more ABs were found in the foci than in non-focal parts of the liver, suggesting an enhanced cell turnover in foci. The apparent sensitivity of foci to mechanisms controlling cell death might eventually provide a means for elimination of preneoplastic lesions.

Animals↗