Cortisone Treatment Research Articles

Synergism between Thymocytes and Lymph Node Cells in the Graft-Versus-Host Response. Effect of Cortisone Treatment of the Thymus Cell Donor

Abstract Combinations of thymic cells from 1-month-old and lymph node cells from 6-month-old C57BL mice were tested for their capacity to give a synergistic effect in the graft-versus-host reaction (G-v-H) when injected into young A/Sn × C57BL F1-hybrids. No clear synergism was observed between normal thymic cells and lymph node cells. Two days after cortisone treatment of the thymus cell donors the cell number in the thymus had dropped to 5% of its original value and the relative G-v-H reactivity exhibited a 15-fold increase. There was no evidence, however, of an enrichment of cells capable of amplifying the G-v-H reaction. On day 12 after steroid treatment the G-v-H reactivity of the organ had decreased, but there was a marked tendency of the cell population to act synergistically with lymph node cells. After another 8 days the thymus cell population had regained its G-v-H reactivity and diminished its “amplifying” capacity. The transformation of amplifying cells into G-v-H reactive cells is a possible explanation of this phenomenon.

IMMUNOLOGIC PROPERTIES OF MOUSE THYMUS CELLS

The functional attributes of minor subpopulations of mouse thymus cells derived by bovine serum albumin density gradient centrifugation, cortisone treatment, or selective depletion by anti-TL or anti-theta treatment have been examined. A subpopulation derived in each fashion contains the cells required to evoke graft-versus-host reactions in neonatal F(1) hybrid recipients and to be stimulated by alloantigens in vitro in one-way mixed lymphocyte cultures and by phytohemagglutinin. The functions of this subpopulation are abrogated by treatment with anti-H-2 plus complement and by high concentrations of anti-theta. A tentative ordering of the various thymus cell subpopulations, on the basis of these and other data, is described.

The Effect of Porcine Calcitonin on Osteoporosis Induced by Adrenal Cortical Steroids

Effects of porcine calcitonin (five MRC units per kilogram per day) on development of osteoporosis induced by cortisone (fifteen milligrams per kilogram per day) have been investigated in adult rabbits. Measurements of surface undergoing resorption and formation were determined from cross sections of femoral mid-diaphyses, femoral metaphyses, ribs, and vertebral bodies using the quantitative microradiographic method of Jowsey. Intact femora and vertebral bodies were evaluated for gross rarefaction by high resolution macnoradiography. Bone mass per unit area was determined and mineral content of femora, ribs, and vertebrae was esimated by ashing. Cortisone treatment alone: (1) decreased bone formation and increased bone resorption at all skeletal sites evaluated, (2) decreased the amount of bone mass per unit area in both cortical and cancellous specimens, (3) caused gross macroradiographic rarefaction of femora and vertebral bodies, and (4) reduced the ash weight of ribs and vertebrae. Calcitonin treatment alone: (1) increased bone formation in cortical specimens and reduced bone resorption in vertebral bodies, (2) caused increased density of metaphyseal zones of vertebral bodies as shown by macroradiognaphy, and (3) increased the ash content of femora, ribs, and vertebrae. When compared with specimens removed from animals receiving only cortisone, specimens removed from animals receiving both hormones exhibited: (1) reduction in bone resorption rates in the cancellous specimens, (2) increased rates of bone formation in femoral diaphyses, (3) increased mass per unit area in both cortical and cancellous bone, (4) less macroradiographic rarefaction of femora and ventebral bodies, and (5) increased ash content of vertebral bodies. These results support the possibility that exogenous calcitonin may be capable of retarding some of the detrimental effects of the adrenal cortical steroids on osseous tissue, especially cancellous bone.

Long-term Recovery of Chondrocytes in the Tibial Epiphyseal Plate in Rats after Cortisone Treatment An Electron Microscopic Study

Long-term Recovery of Chondrocytes in the Tibial Epiphyseal Plate in Rats after Cortisone Treatment An Electron Microscopic Study

Changes of the PHA-responding pool of cells in the thymus after cortisone or X-ray treatment of mice. Evidence for an inverse relation between the production of cortical and medullary thymocytes

Approximately 5% of the lymphocytes in the mouse thymus are immunologically reactive and respond to PHA in vitro. This cell population seems to be located in the thymic medulla, whereas the rest of the cells are located in the cortex. The present investigation was undertaken primarily to study the changes of the medullary population during depletion and subsequent regeneration of the thymus after treatment of mice with cortisone or exposure to X-rays. The results show that the PHA-responding pool of cells decrease during increase of the nonresponding cell population. Conversely, an increase of the absolute PHA-response of the organ could be demonstrated under certain conditions when the nonresponding pool of the cells was depleted. The results indicate that there exists a feedback mechanism between the production of cortical and medullary thymocytes. The implications of the findings are discussed.

Dependence of hypothalamic obesity on insulin, the pituitary and the adrenal gland.

ABSTRACT. The obesity which follows destruction of the ventromedial nucleus (VMN) of the hypothalamus of rats is accompanied by hyperphagia and hypersecretion of insulin. The effects of weight gain after ventromedial lesions were examined after hypophysectomy, after adrenalectomy and in rats in which the secretory function of the (3-cells had been destroyed with streptozotocin. Mature female rats received streptozotocin (65 mg/kg) intravenously: a) prior to hypothalamic injury; b) 7 days following hypothalamic injury; or c) after the rats had already become obese following hypothalamic damage. Weight gain of lesioned rats was not impaired by hypophysectomy or adrenalectomy. Treatment of lesioned-hypophysectomized rats with growth hormone prevented most of the increase in weight. Cortisone treatment of adrenalectomized rats with lesions had no significant effect. Both lesioned and control rats lost weight following treatment with streptozotocin until supplemental insulin was given. Body weight of all anima...

Corticosteroids and the Development of Intrinsic Factor-Mediated Vitamin B12 Absorption in the Rat

The changes which occur in vitamin B12 absorption from birth to weaning were studied in unanesthetized rats. The absorption of an oral dose of Co57-labeled vitamin B12, decreased 15 days after birth, at the same time that intrinsic factor (IF) in the stomach rose rapidly to weanling levels. The transition to IF-mediated absorption occurred at an earlier age in rats which were treated with cortisone. Absorption of the vitamin by 12-day-old rats which had received a subcutaneous injection of cortisone 8 days after birth was similar to that in animals which had just been weaned. Saturation of the absorptive mechanism was demonstrated when the dose of vitamin was increased. IF levels increased 6-fold following cortisone treatment. Repeated injections of adrenocorticotropin also resulted in elevated IF levels and in an earlier decrease in the absorption of the vitamin. The time of onset of the IF mechanism may therefore be related to the effects of endogenous corticosterone on gastric and intestinal epithelial cell function.

Cell migration and cortisone induction of sucrase activity in jejunum and ileum.

The increase of sucrase activity in homogenates of jejunum and ileum of suckling rats after cortisone administration has been investigated. Serial tissue sections of villi and crypts were also assayed for sucrase activity and these results were compared with the migration of cells labelled with [(3)H]thymidine along the villus. By using a low dose of cortisone (0.5mg/day per 100g body wt.) it was found that the sensitivity of the small intestine producing system to cortisone stimulation increased during the suckling period. On the other hand, 5mg of cortisone/day per 100g body wt. produced practically the same increase of sucrase during the entire suckling period. Sucrase activity in homogenates of the entire small-intestinal wall was first detected 24h after the first injection of cortisone (5mg/day per 100g body weight) to 9-day-old animals and maximum activity both in the jejunum and ileum was reached by 120h. Jejunal activity was greater than ileal activity, but the rate of the increase was similar. The half-time of the increase was 23-27h, whereas enterocytes migrate from the base to the tip of the villi in approximately 72h. Comparison of sucrase activity in serial tissue sections of villi and crypts at various times after cortisone treatment showed that the leading edge of sucrase activity proceeds toward the tip of the villi at the same rate as the advancing edge of newly formed cells. Sucrase activity increased in the newly induced cells as they migrated to the tip of the villi. It was concluded that the increase of sucrase activity in suckling rats after cortisone stimulation is due to at least three factors: (1) increase of activity in newly differentiating cells, (2) increased percentage of villus cells with sucrase activity and (3) continued production or activation of sucrase activity as the cells migrate along the villi.

Effect of anti-ulcer drugs on gastric mucous hexosamine in rats subjected to several ulcerogenic conditions.

Hexosamine content of pyloric tissue of the stomach in rats exposed to fasting, water immersion and restraint stress, and cortisone treatment was determined. Water immersion and restraint stress, and cortisone treatment resulted in the decreased hexosamine content. Anti-ulcer drugs were administered to these animals orally. In the water immersion and restraint stress the hexosamine content of pyloric tissue of the rats was increased by tyrosine, threonine, glutamine, gefarnate, synthetic aluminum silicate and sodium copper chlorophylline. Glutamine, gefarnate and sodium copper chlorophylline also induced the increase in hexosamine content of the rat pyloric tissue treated with cortisone acetate.

Effects of Tumor-Bearing, Phenylhydrazine and Cortisone on Thymidine Kinase and Other Enzymes in Rat Hematopoietic Organs

In rats carrying Walker carcinomas transplanted subcutaneously, splenomegaly (a 2- to 5-fold increase in spleen weight) is associated with striking increases (5- to 30-fold/g spleen) in the concentration of thymidine kinase. This may reflect active erythropoiesis since thymidine kinase is also at unusually high levels in the spleen of 4- to 5-day-old rats and in adult rats after phenylhydrazine treatment. Cortisone treatment did not affect the thymidine kinase concentration of host spleen or normal bone marrow, but in thymus it caused a drastic fall. The most prominent changes among five other enzymes studied were the increase of hexokinase and the decrease of glutamyltransferase in the spleen, and also in bone marrow and liver, of tumor-bearing rats.

The effect of cortisone treatment on the weight and nitrogen content of the salivary glands in the rat

The effect of cortisone treatment on the weight and nitrogen content of the salivary glands in the rat

Significance of cleft palate induced by chemicals in the rat and mouse

Five chemicals administered to pregnant rats and/or mice produced from 0–100% incidence of cleft palate in individual litters. Chlorcyclizine, one of six benzhydrylpiperazines already shown to produce a common syndrome in the rat, was found also to produce most of the responses in the mouse. In further studies on chlorcyclizine in the rat, the form of cleft palate in individual foetuses varied from unrotated palatine processes (vertical (V) type) through several horizontal (H) forms. Thorax enlargement, previously shown to be due to oedema of overlying tissue, subsided, was about constant or increased as the incidence of cleft palate increased. On average, the foetuses with cleft palate in individual litters had slightly larger thoraxes. When chlorcyclizine administration began 2 days later in gestation (on day 15), the thorax enlargement developed later and cleft palate did not result, and both the cleft-palate incidence and the degree of thorax enlargement were less when rats were co-treated with either SKF-525A or triamterene. Growth of the foetus, as determined by length, was only slightly retarded on most days of gestation and at most levels of cleft-palate incidence. In other studies, chlorcyclizine given to mice produced H and V forms of cleft palate and mild growth retardation but no thorax enlargement, β-aminopropionitrile produced in the rat and mouse both H and V forms of cleft palate but no growth retardation, and only transient, mild thorax enlargement was seen in the mouse. Only horizontal forms of cleft palate resulted from cortisone treatment of mice or triamcinolone treatment of rats or mice, and while the foetuses in all these cases showed severe growth retardation, thorax enlargement occurred only in the rats. Treatment of rats with N-nitroso- N-methylurea led to V-type cleft palates, severe growth retardation and a transient reduction in thorax area. Thus the teratological significance of cleft palate occurring in safety tests cannot be determined merely from the level of incidence without consideration of other findings. The multiple techniques used in this study should help in relating altered foetal metabolism and physiology to malformation and various other anomalies.

Effects of x-irradiation and cortisone treatment of albino rats on infections with Brucei-complex trypanosomes.

Abstract X-ray irradiation and treatment with cortisone acetate were used to suppress the immune response of rats to infection with brucei -complex trypanosomes. Low doses of cortisone acetate produced a transient enhancement of parasitaemia, but high doses of cortisone acetate, or exposure to a single dose of x-irradiation produced prolonged enhancement. Agglutinating antibodies were absent from the irradiated rats for 17 days after infection and there was no change in antigenicity of the trypanosomes in the irradiated rats. In the rats whose defence mechanisms had been damaged, morphological transformation proceeded as in intact controls. It appears that the production of antibody by the host is not the main factor influencing pleomorphism, and it is possible that other host factors are important.

Developmental aspects of uridine diphosphate galactose 4-epimerase in rat intestine.

Kinetic and developmental characteristics of rat intestinal UDP-galactose 4-epimerase activity have been examined. The enzyme in the adult rat had a V(max.) value 2-3 times higher than that of the newborn animal, but the K(m) values for the enzyme in the newborn and adult rat were the same (0.17mm). No differences in epimerase activity were found along the length of the jejuno-ileum of adult animals, but higher activity was detected in the lower portion of the villi and crypts. The specific activity of the enzyme in the newborn rat began to rise at about 17 days of age, reaching a peak at 29 days of age, and then became constant at adult values. Total epimerase activity in the newborn rat liver was 2-5 times higher than the total activity in the intestine, and total epimerase activity in the adult intestine was 3-4 times higher than the total activity in the liver. Cortisone injection did not enhance the increase of epimerase normally seen during development, but caused a decrease in activity of this enzyme in the jejunum in rats up to 17 days of age. After 17 days, cortisone treatment had no effect on epimerase activity.

The action of cortisone acetate on cell-mediated immunity to infection. Suppression of host cell proliferation and alteration of cellular composition of infective foci.

Pulse labeling with tritiated thymidine shows that the response in the mouse to infection with L. monocytogenes includes a large increase in the division of lymphoid cells in the spleen, an increase in the division of macrophages in the liver, and an accumulation of monocyte-derived macrophages at infective foci in the tissues. A single 2.5 mg dose of cortisone acetate given at the beginning of infection greatly delays and suppresses these three components of the host response. The unrestricted bacterial multiplication which follows cortisone treatment is ultimately because of a failure of monocyte-derived macrophages to accumulate at infective foci where they normally express immunity. The accumulation of polymorphs at these sites, in contrast, is enhanced. It is argued that cortisone acetate prevents the accumulation of monocytes at infective foci indirectly by suppressing the production in the spleen of immunologically-committed lymphocytes which are needed to mediate the cellular events at infective foci.

Cortisone stimulation of nucleolar RNA polymerase activity.

Four hours after intraperitoneal injection of cortisone acetate into rats, hepatic nuclei had an enhanced ability to incorporate labeled nucleoside triphosphates into RNA in vitro. When the nuclei were further fractionated into nucleolar and extranucleolar (nucleoplasmic) fractions, it was found that this hormonal effect was localized exclusively in the nucleolar fraction. This increased transcriptive activity potentially could be due to either (a) an increased availability of the DNA template or (b) an increase in the amount or catalytic efficiency of the RNA polymerase, or both. In order to distinguish between these possibilities, actinomycin D was used to inhibit the template function of endogenous nucleolar DNA and a synthetic template, polydeoxycytidylate, which is insensitive to actinomycin D and codes for polyriboguanylate synthesis, was used to evaluate RNA polymerase activity. These studies indicate that the increased RNA synthesis evident in nucleoli isolated from livers of rats four hours after cortisone treatment is largely a consequence of elevated levels of RNA polymerase.

Differential sensitivity of nuclear and mitochondrial DNA synthesis to suppression by cortisone treatment

The administration of cortisone to young rats is known to result in a prompt suppression of liver DNA synthesis. The present study demonstrates that this suppression represents a selective inhibition of thymidine incorporation into nuclear DNA, and that after a single dose of cortisone to weanling animals the ratio of thymidine incorporated into nuclear DNA to that incorporated into mitochondrial DNA falls to 10–15 % of the ratio in control animals. The persistence of mitochondrial DNA synthesis in these animals despite nearly total suppression of nuclear DNA synthesis provides another example of mitochondrial autonomy. In older rats incorporation of thymidine into nuclear DNA is shown to be considerably less sensitive to inhibition than it is in more rapidly growing animals; even in the larger animals, however, it continues to be more easily suppressed than incorporation into mitochondrial DNA.

Radiographic and autoradiographic study on the effects of cortisone on bone growth in young albino rats

A group of sixty male rats, aged 21 days, received cortisone acetate in the diet (CA diet, 0.2 mg of cortisone per g of food) for 15 days, then recovered on regular food (R diet) for 35 days. Another group of sixty male rats, aged 21 days, were fed with R diet for 50 days (pair-feeding). Tibias and mandibular condyles were studied radiographically, histologically and autoradiographically. Appearance of dense sclerotic metaphyses during cortisone treatment period, due to continuous matrix formation and cessation of resorption was noted. In recovery, appearance of “cortisone bone” in the diaphyses and rami was observed.

Studies on spermatogenesis in rats. 3. Effects of hormonal treatment on differentiation kinetics of the spermatogenic cycle in regressed hypophysectomized rats.

The general hormonal requirements for the restoration of spermatogenesis in regressed hypophysectomized rats were investigated. With the aid of the Staput fractionation technique, it was established that thymidine-3H was readily incorporated into spermatogonia and resting spermatocytes. Labeled cells did not progress to form appreciable numbers of primary spermatocytes or spermatids in the absence of hormonal replacement. The inhibition of formation of pachytene primary spermatocytes in hypophysectomized rats was overcome by administration of follicle-stimulating hormone (FSH), luteinizing hormone (LH), or testosterone, but a combination of either FSH plus LH, or FSH plus testosterone, was required for the progression of pachytene primary spermatocytes to spermatids and spermatozoa. Carnitine acetyltransferase (CAT) measurements in testes from various groups of animals provided ancillary evidence consistent with the conclusion that either FSH, LH, or testosterone was required for the normal restoration of pachytene-diplotene spermatocyte formation. However, one or more additional blocks in spermatogenesis existed in hypophysectomized animals, since elevation of depressed testicular CAT levels in hypophysectomized rats to normal levels required FSH plus LH, or FSH plus testosterone. Cortisone and thyroxin treatment had no measurable effects on testicular function in hypophysectomized rats.

Effect of cortisone treatment on the active transport of calcium by the small intestine.

It is generally recognized that glucocorticoid administration may diminish calcium absorption in vivo as well as the active transport of calcium by the intestine in vitro. Recent studies by others have emphasized the possibility of an alteration in the metabolism of vitamin D to 25-hydroxycholecalciferol in accounting for the steroid effects on calcium absorption. The results obtained in the present studies fail to support this hypothesis. The present studies confirm that the administration of cortisone or other glucocorticoids to the rat interferes with the active transport of calcium by duodenal gut sacs in vitro. This abnormality is not due to an alteration in the permeability of the intestine to calcium, and it cannot be corrected by the administration of either massive doses of vitamin D(2) or modest doses of 25-hydroxycholecalciferol. Experiments concerned with the effects of cortisone on the level of the vitamin D-dependent duodenal calcium-binding protein, the amount of bioassayable vitamin D activity in the mucosa, and the distribution and metabolism of (3)H-vitamin D(3), did not provide evidence in favor of a harmone-related defect in either the localization of vitamin D or its metabolism to 25-hydroxycholecalciferol. Alterations in the transport of iron and D-galactose, not dependent on vitamin D, suggest that cortisone treatment may be responsible for more than a simple antagonism to the effects of vitamin D. The results of the present studies indicate that cortisone administration affects the cellular mechanisms mediating calcium transport in a manner that is opposite to the effects of vitamin D, but seems to be independent of any direct interaction with the parent vitamin or its metabolites. If a disorder in vitamin D metabolism is at all involved, it is at a step subsequent to 25-hydroxylation.