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Biomedical subjects
J D O'Shea
Publications and source records attributed to J D O'Shea.
Unusual concretions in the hepatocyte rough endoplasmic reticulum of sheep given tunicamycin.
Unusual concentric laminar bodies in the RER of ovine hepatocytes treated with tunicamycin are described. These bodies are probably proteinaceous in nature and related to inhibition of protein glycosylation by tunicamycin in the RER.
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Effect of tunicamycin on the blood-brain barrier and on endothelial cells in vitro.
In guinea-pigs given 400 micrograms per kg of tunicamycin, the toxin responsible for the disease known as annual ryegrass toxicity, alterations in blood-brain barrier permeability were assessed with vascular tracers of differing particle size. The toxin caused loss of integrity of the barrier to the smallest diameter tracer, horseradish peroxidase, but the cerebral endothelium was able to retain larger particles of ferritin and colloidal gold in the circulation. The effect of tunicamycin on cultured endothelial cells was characterized by dose-dependent lethal damage to these cells, marked dilatation of cisternae of RER, severe cytoplasmic vacuolation and a reduced incidence of mitosis in surviving endothelial cells. It was concluded that tunicamycin is able to damage directly endothelial cells, with a resultant increase in cerebral vascular permeability.
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Ultrastructural cytology of the cyclic corpus luteum of the cow.
Corpora lutea (CL) from cows on day 12 of the oestrous cycle were studied by electron microscopy to investigate whether, and how, different subpopulations of luteal cells can be identified in tissue sections. Tissues from 6 CL were examined, and nucleated profiles of luteal cells were classified as large, medium or small on the basis of their areas in electron micrographs. Cut-off points for area categories for large, medium and small-sized cells were based on diameters of greater than 25, 20-25 and less than 20 microns, respectively, if the measured areas were converted to a circular shape after correction for shrinkage. The only qualitative features which distinguished cells of large size from those of small size were the presence of clusters of secretory granules, and of exocytosis of these granules, in large cells only. However, these features were observed in only 59% of large cells, probably primarily due to sampling limitations in single sections. Other qualitative features which have been regarded as diagnostic of large or small luteal cells were observed in cells in all size categories. It was concluded that large and small luteal cells in the cyclic CL of the cow are distinguishable by their ultrastructural features. However, these data do not support the recent suggestion that the mid-cycle CL of the cow contain two subpopulations of large luteal cells in approximately equal numbers.
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Cellular composition of the cyclic corpus luteum of the cow.
The cellular composition of CL from 6 cows on approximately Day 12 of the oestrous cycle, after synchronization with cloprostenol, was studied by ultrastructural morphometry. Point-count measurements of volume density (mean +/- s.d.) showed that large luteal cells occupied 40.2 +/- 7.0% of the luteal tissue, and small luteal cells 27.7 +/- 6.3%. Of the total of 393.4 +/- 52.0 x 10(3) cells per mm3 of luteal tissue, large luteal cells made up only 3.5% and small luteal cells 26.7%, a ratio of 1:7.6. Endothelial cells/pericytes, at 52.3%, were the most numerous cell type. The mean volume per large luteal cell was 29.6 +/- 6.3 x 10(3) microns 3, while that of small luteal cells was 2.7 +/- 0.4 x 10(3) microns 3. In spherical form, these volumes would represent mean diameters of 38.4 microns and 17.2 microns respectively, and are consistent with published measurements on dispersed luteal cells. However, the values for cell numbers are much higher than published values based on luteal tissue dispersion, suggesting that dispersion may result in substantial and possibly selective losses of luteal cells.
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Acute hepatotoxicity with resultant pulmonary and cerebral embolism in guinea pigs given tunicamycin.
The hepatotoxicity of tunicamycin was studied in 8 to 10-week-old guinea pigs. Acute hepatic damage was produced consistently in guinea pigs given a single dose of 400 micrograms/kg of tunicamycin and observed at intervals up to 72 h post-injection. Significant elevations occurred in serum levels of liver enzymes and ammonia, while concentrations of serum proteins were lowered. A periportal pattern of hepatocellular damage, with death of many hepatocytes, was consistently observed by 72 h. Severe vacuolation of hepatocytes resulted from lipid accumulation and dilatation of cisternae of rough endoplasmic reticulum, and bile ductule hyperplasia was also observed. Swollen hepatocyte cytoplasm protruded into many hepatic blood vessels, and detached portions of hepatocytes produced emboli in pulmonary and cerebral capillaries, thus contributing to capillary occlusion in the brains of treated guinea pigs.
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Expression of leucocyte antigens by cells from the metrial gland of the pregnant rat.
The function of the metrial gland of the rat, and particularly of its characteristic population of granulated cells, remains unknown. However, several lines of evidence suggest that the granulated cells may derive from lymphocytes, and play a role in the immunology of pregnancy. In this study, antigen expression by granulated and other cell populations from the metrial glands of rats at Days 13 and 14 of pregnancy was studied by an indirect immunoperoxidase method. Acetone-fixed frozen sections, and cytocentrifuge preparations of collagenase-dispersed metrial gland tissue in which numbers of granulated cells had been increased by density-gradient centrifugation, were used. The primary antibodies used recognised, inter alia, B lymphocytes (MRC OX-3, MRC OX-6, MRC OX-12), T lymphocytes (MRC OX-8, W3/25, MRC OX-19), neutrophils (MRC OX-42) and cells of the monocyte/macrophage series (MRC OX-3, MRC OX-6, MRC OX-42, MRC OX-43). The majority of the granulated cells, including smaller, "immature" forms, were unlabelled by any of these antibodies. Some lymphocytes, and varying numbers of larger, non-granulated cells, were labelled by OX-6, OX-12, W3/25, OX-42 and OX-43. In addition to lymphocytes, labelled cells included neutrophils (OX-42), endothelial cells (OX-43), and probably some macrophages (OX-6, OX-43). OX-12, which recognises the kappa chain of rat IgG, labelled some large cells which may have been stromal cells. These findings do not support the concept that the granulated cells are derived from lymphocytes.
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Pathological and pathogenetic changes in the central nervous system of guinea pigs given tunicamycin.
Guinea pigs were injected with tunicamycin and the sequential morphological alterations in the brain examined to investigate further the pathogenesis of cerebral lesions in this experimental model of annual ryegrass toxicity, a central nervous system disease of livestock caused by members of the tunicamycin group of antibiotics. Brain damage was most commonly observed in the cerebellum, and the important alterations in the development of degenerative parenchymal lesions appeared to be largely referrable to changes in small blood vessels. Endothelial damage, with increased vascular permeability, resulted in capillary obstruction leading to localised ischaemia and hypoxic neuronal damage. There was evidence for several possible mechanisms which may have contributed to vascular occlusion.
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Weight, composition, mitosis, cell death and content of progesterone and DNA in the corpus luteum of pregnancy in the ewe.
Changes in luteal weight from about Day 20 to near term, and in quantitative histology as assessed by ultrastructural morphometry and light microscopic counts of mitosis and cell death on Days 30, 60, 100 and 142, were studied in 168 pregnant ewes. Luteal weight (mean +/- s.d.) remained constant at 0.56 +/- 0.11 g until Day 120, and fell thereafter to reach 0.31 +/- 0.11 g after Day 140 (P less than 0.01). Up to Day 100, quantitative aspects of the composition of the luteal tissue showed no significant change, and values for volume density, cytoplasmic:nuclear ratio, cell number/mm3 and cell volume were comparable to values previously obtained for corpora lutea (CL) of the cycle. By Day 142 structural evidence of luteal regression was present, but regressive changes were much more marked in some CL than others. Mitosis was seen in a few cells (0.02-0.04%) on all of the days studied, but never in large luteal cells. Cell death was rarely seen up to Day 100, but had increased in incidence by Day 142 (P less than 0.01). Luteal progesterone content, 55.2 +/- 15.9 nmol/g on Day 30, was not significantly changed on Days 60, 100 or 142. It is concluded that (1) structural regression of the CL of pregnancy does not begin until much later than the time (about Day 50) when pregnancy ceases to depend on the CL; (2) structural luteal regression begins before parturition, but its time of onset and/or rate of progression vary widely between animals; and (3) large and small luteal cells remain as distinctive populations throughout pregnancy, and their numbers at all stages can be accounted for by survival of the cells which differentiate during the genesis of the CL.
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Morphometric estimation of the numbers of granulosa cells in preovulatory follicles of the ewe.
Several lines of evidence suggest that follicular granulosa cells give rise to the large luteal cells of the corpus luteum in the sheep. To further investigate this suggestion, numbers of granulosa cells in preovulatory follicles were estimated by morphometric methods for comparison with a previous estimate of numbers of large luteal cells (9.6 +/- 0.9 x 10(6)). Preovulatory follicles from five Corriedale ewes were obtained after synchronization of the oestrous cycle with the prostaglandin analogue cloprostenol. Morphometry was undertaken using light microscopy of plastic-embedded tissue sectioned at 1 micron. Mitotic index in the membrana granulosa was 0.05 +/- s.e.m. 0.05%. Mean follicular diameter was 6.25 +/- 0.25 mm and there were 7.68 +/- 0.53 x 10(6) granulosa cells per follicle. These results demonstrate a similarity between the number of granulosa cells per follicle and the number of large luteal cells per corpus luteum and thus support the hypothesis that large luteal cells are derived from granulosa cells.
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Heterogeneous cell types in the corpus luteum of sheep, goats and cattle.
Data on the structure, quantitation, origins and functions of the large luteal (LL) and small luteal (SL) cells of sheep, goats and cattle are reviewed. Both LL and SL cells show ultrastructural features consistent with a steroidogenic function. However, in addition to differences in size and shape, LL cells differ from SL cells primarily in possessing large numbers of secretory granules, suggesting an additional protein/polypeptide synthetic and secretory function. In sheep, morphometric estimates show that the corpus luteum (CL) contains approximately equal to 10 X 10(6) LL cells and approximately equal to 50-60 X 10(6) SL cells: individual LL cells are approximately equal to X 6 greater in volume than SL cells. During formation of the CL, granulosa and theca cells are incorporated, and evidence suggests that granulosa cells give rise to LL cells and theca cells to SL cells. However, SL cells, or cells of thecal origin, may also give rise to some LL cells. Both LL and SL cells produce progesterone in vitro. On a per cell basis, LL cells produce more progesterone than do SL cells, but SL cells show a much greater progesterone-secretory response to LH. Oxytocin is synthesized, and secreted in granule form, only by the LL cells, and relaxin, whose presence has been demonstrated convincingly only in cattle, also appears to be produced only by LL cells. The two types of luteal cell in ruminants therefore show major differences in function: the occurrence of any significant functional interaction remains to be established.
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Cellular composition of the sheep corpus luteum in the mid- and late luteal phases of the oestrous cycle.
Corpora lutea (CL) from naturally cycling Corriedale ewes were obtained in the mid- and late luteal phases of the oestrous cycle (Days 9 and 13; 5 ewes per group). The cellular composition of these CL was compared by ultrastructural morphometry to determine whether there were changes in numbers of large and small luteal cells consistent with differentiation of some small luteal cells to large luteal cells during the last part of the luteal phase. No differences between Days 9 and 13 were detected in luteal volume, plasma progesterone concentration, or volume density of any component of the luteal tissue. Large luteal cell numbers (mean +/- s.e.m.) were lower per unit volume of luteal tissue on Day 13 than on Day 9 (14.1 +/- 0.5 vs 18.4 +/- 1.3 X 10(3)/mm3, P less than 0.05). Mean volume of the individual large luteal cells was greater on Day 13 than on Day 9 (19.65 +/- 0.72 vs' 15.60 +/- 1.34 micrograms 3 X 10(3), P less than 0.05). However, there were no significant differences in numbers or volumes of small luteal cells between Days 9 and 13, and total numbers of large luteal cells per CL were not different between these two days. These results provide no support for the hypothesis that small luteal cells differentiate into large luteal cells during the oestrous cycle of the sheep.
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Regression of the corpus luteum of pregnancy following parturition in the ewe.
Corpora lutea (CL) of pregnancy from single-lambing ewes were examined by light and electron microscopy within 24 h and at 8, 15, 23, 31 and 41 days after parturition (2 ewes per stage). Within 24 h of parturition the structure of the CL was well preserved and both large and small luteal cells, characteristic of this species, were present in substantial numbers. However, both types of luteal cell contained numerous cytoplasmic lipid droplets, and smooth endoplasmic reticulum and secretory granules in large luteal cells were less prominent than in normal functional CL of cyclic ewes. Leucocytic infiltration, and death of some luteal and endothelial cells, were also observed at this stage. Further regression of the CL progressed slowly, and lipid-rich large luteal cells were still readily recognisable 15 days after parturition. The size of the CL declined progressively, and the proportion of tissue occupied by intercellular substances increased. Corpora albicantia approximately equal to 3-4 mm in diameter were still recognisable 41 days after parturition. It was concluded that luteal regression post partum progresses much less rapidly than at the end of the oestrous cycle.
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Do small and large luteal cells of the sheep interact in the production of progesterone?
Corpora lutea from cyclic ewes were dissociated by collagenase and trypsin/EGTA treatments, and enriched fractions of small and large luteal cells were prepared on gradients of Ficoll. These fractions were incubated separately or remixed before incubation. Colchicine, cytochalasin B and the calcium channel-blocker verapamil significantly reduced progesterone production by both small and large luteal cell fractions, while isoprenaline stimulated an increase in progesterone production by large luteal cell fractions only. When fractions of small and large luteal cells were remixed, no more and no less progesterone was produced than would have been predicted from equivalent fractions incubated separately. There was therefore no evidence of synergism between small and large luteal cells in the production of progesterone. Prostaglandin F-2 alpha, which can inhibit LH-stimulated progesterone production by ovine luteal tissue in vitro, had no effect on LH-stimulated progesterone production by small luteal cell fractions, but significantly inhibited that by enriched fractions of large luteal cells. Since large luteal cell fractions were contaminated with small luteal cells, which are probably responsible for the progesterone-secretory response of these fractions to LH, it was concluded that the inhibition of LH-stimulated progesterone production by small luteal cells is dependent on the presence of large luteal cells. Oxytocin added to large and small luteal cell fractions did not affect progesterone production by either fraction. It was therefore concluded that the inhibitory action of PGF-2 alpha on LH-stimulated progesterone production may require the interaction of large and small luteal cells, but that oxytocin is not likely to be an intermediary in this interaction.
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Morphometry of the functional and regressing corpus luteum of the guinea pig.
A morphometric study of functional and regressing corpora lutea (CL) of guinea pigs (n = 5 per day) was performed on days 9, 12, and 16 of the estrous cycle. On day 9 the functional CL contained congruent to 750,000 cells, which included 565,200 +/- 56,700 (S.D.) endothelial cells or pericytes and 137,300 +/- 7,700 luteal cells. Between days 9 and 12 the only significant change suggesting the onset of regression was a reduction in vascular luminal surface area. During this time the number of luteal cells per CL increased to 204,400 +/- 34,800 (P less than .05), with an accompanying reduction in luteal cell volume from 19.8 +/- 1.8 to 14.4 +/- 2.4 pl/cell (P less than .01). The increase in cell numbers was explicable by cell division, with mitotic indices of 0.83% and 0.97% on days 9 and 12, respectively. Luteal volume was unaltered. Between days 12 and 16, the mean volume of a single CL fell from 3.98 +/- 0.2 to 1.42 +/- 0.3 mm3 (P less than .01) and luteal cell volume was reduced to 5.3 +/- 1.1 pl/cell (P less than .01). Between these 2 days the number of endothelial cells per CL fell from 539,900 +/- 75,500 to 144,400 +/- 63,300 (P less than .01), with an accompanying reduction in vascular luminal surface area and in the volume occupied by vascular lumina. The total number of luteal cells per CL was not reduced significantly. It was concluded that luteal cell numbers in the guinea pig increase up to the time of onset of luteal regression, and that during regression up to day 16, shrinkage of luteal cells is the major cause of loss of luteal volume. During regression, endothelial cell loss occurs much more rapidly than loss of luteal cells.
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Involution and regeneration of the endometrium following parturition in the ewe.
Involution and regeneration of the endometrium after parturition in the ewe, were studied by light- and electron microscopy. The luminal epithelium in intercaruncular regions of the endometrium remained intact at all stages, but degeneration and death of many glandular epithelial cells were observed on the day after parturition. Glandular regeneration had commenced by 8 d post partum, and the glands were substantially regenerated by 15 d. Caruncular epithelial cells on the maternal side of the placentomes, between the bases of the maternal septa, persisted during the period of degeneration of the foetal and maternal tissues of the placentomes. Epithelial cells from this source contributed to the regeneration of the caruncular epithelium following shedding of plaques of degenerate placental tissue from the caruncles, which commenced after 8 d and was completed before 31 d. Thus, ingrowth of epithelium from the edges of the caruncles, as previously proposed, was not the sole source of new caruncular epithelium. The additional source of regenerating epithelium identified here may account for the rapidity with which epithelium appears in the centres of some caruncles, several millimetres in diameter, during endometrial regeneration. However, in some caruncles, regeneration of the epithelium was not completed until after 31 d post partum.
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A congenital vascular naevus in a foal.
This paper describes a case of a congenital vascular malformation in the skin of a colt. The lesion arose at the coronary border of the right hind leg. The microscopic structure of a biopsy suggested that the lesion, consisting of multiple foci of closely-packed convoluted small vessels in the dermis, represented a marked exaggeration of glomi which normally occur in considerable numbers in this region of the skin. On the basis of the clinical, macroscopic and histological findings, this lesion was considered to be an hamartoma, rather than a true tumour, and was therefore termed a congenital vascular naevus. The foal is remaining under observation to determine the eventual outcome of the lesion.
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Morphometric analysis and function in vivo and in vitro of corpora lutea from ewes treated with LHRH during seasonal anoestrus.
Ovulation was induced by 3 X 30 micrograms LHRH i.v. at 90-min intervals in anoestrous Corriedale ewes. Plasma LH surges occurred in all of 31 ewes given LHRH, but ovulation occurred in only 16 of these ewes. Luteal weight and plasma progesterone concentration were lower in ewes in which ovulation was induced during anoestrus than in cyclic control ewes in the breeding season, and when data from induced and control ewes were pooled luteal weight was strongly correlated with plasma progesterone concentration (r = +0.612, P less than 0.01). Five mature corpora lutea (CL) resulting from ovulation induced during anoestrus were compared by morphometric methods with 5 CL from cyclic control ewes. When data from induced and control CL were pooled, luteal volume was positively correlated with total number of cells per CL (r = +0.869, P less than 0.01) but negatively correlated with number of cells per mm3 luteal tissue (r = -0.676, P less than 0.05), i.e. smaller CL contained fewer cells, but more cells per unit volume. Relative numbers of large to small luteal cells, at approximately equal to 1:6, were similar in LHRH-induced and cyclic control CL. Large and small luteal cells were smaller in induced CL than in control CL, but cytoplasmic:nuclear ratio did not differ between induced and control CL. Basal and LH-stimulated progesterone production by dispersed luteal cells in vitro were lower for CL from LHRH-treated ewes than from controls. However, percentage increase in progesterone production in response to LH was not different between LHRH-treated and control ewes at any dose rate of LH used. It is concluded that the small size of CL induced by LHRH is due primarily to the low numbers and small volumes of the luteal cells in these CL, and that subnormal luteal weight and subnormal progesterone production per luteal cell contribute to the low plasma progesterone concentrations in ewes treated with LHRH during seasonal anoestrus.
Anestrus↗