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Biomedical subjects

B Noble

Publications and source records attributed to B Noble.

At least 55 records · Page 3Linked to original sources
PubMed1991

Glomerular macrophage proliferation in experimental immune complex nephritis.

In immune complex nephritis, glomerular hypercellularity is known to result from the proliferation of intrinsic cells and from the infiltration of mononuclear cells, primarily macrophages. An immunohistochemical double-labeling procedure was used to determine whether macrophages were among the cells which may undergo mitosis within the glomerular tuft. The monoclonal antibody ED1 served as a macrophage marker; cells in the S-phase of mitosis were recognized by uptake of bromodeoxyuridine. Glomerular proliferation was studied in chronic serum sickness of LEW rats, an animal model of immune complex nephritis for which the relationship between immunopathology and pathophysiology has been well described. In normal glomeruli, resident mesangial macrophages accounted for an unexpectedly large proportion (greater than or equal to one-third) of the total mitotic activity. In immune complex glomerulonephritis, the rate of glomerular macrophage proliferation increased rapidly just at the onset of proteinuria and remained high throughout the remaining course of disease. Glomerular macrophages from rats with proliferative nephritis also divided more vigorously than normal in short term culture in vitro, while persistently expressing abnormal surface marker phenotypes. The proliferation of mesangial macrophages appears to be a prominent feature of the normal process of glomerular cell renewal. In hypercellular glomeruli, vigorous local proliferation could greatly amplify the potential of macrophages to cause damage.

Animals↗
PubMed1991

Progressive glomerular injury after recovery from acute glomerulonephritis in rats.

To determine if an acute immunologic injury resembling poststreptococcal nephritis could lead to chronic renal injury, rats with immune-complex glomerulonephritis produced with cationic human gammaglobulin were followed for 48 weeks. During Week 1, animals developed severe proteinuria, hypoalbuminemia, and a diffuse proliferative/exudative glomerulitis. Substantial recovery, characterized by a significant decline in urinary protein excretion and normalization of plasma albumin concentration, occurred by Week 4. Subsequently, rats developed significantly elevated blood pressures and increasing proteinuria. Glomerular histology at Week 48 revealed minimal inflammation, significant hypertrophy, and considerable sclerosis. We conclude that chronic, progressive renal disease can evolve after apparent recovery from an acute immunologic insult. Further study of this model should provide clinically relevant information about the mechanisms underlying this process.

Acute Disease↗
PubMed1990

Persistent proximal tubule dysfunction late in Heymann nephritis.

To determine whether proximal tubule function returned to normal after cessation of active immunological injury in Heymann nephritis, we compared kidney function in an acute stage of the disease, when antibodies were being deposited on the brush border, to a later, chronic stage. Renal blood flow measurements via a flow probe, along with clearance and micropuncture techniques, were used to measure renal plasma flow, glomerular filtration rate, protein and albumin excretion, organic ion (PAH and TEA) extraction and tubule fluid inulin concentration. Proximal tubule fluid reabsorption, which was depressed in the acute stage of injury, returned to normal in chronic Heymann nephritis, but both PAH and TEA extraction continued to be depressed. PAH extraction was also decreased in isolated perfused kidneys from rats with Heymann nephritis. A three fold increase in PAH content of these perfused kidneys indicated that there was a defect in luminal PAH transport. Reconstitution of the proximal tubule brush border in chronic Heymann nephritis was not accompanied by functional recovery of secretory processes.

Animals↗
PubMed1990

Mononuclear cells in glomeruli and cytokines in urine reflect the severity of experimental proliferative immune complex glomerulonephritis.

Immunohistochemical methods were used to investigate the role of macrophages in the progression of proliferative immune complex glomerulonephritis. The mononuclear cell component of glomerular inflammation was analysed in three different stages of chronic serum sickness, each of which was clearly distinguished by criteria of kidney function. Urinary excretion of the macrophage secretory products interleukin-1 and tumour necrosis factor was also evaluated in relation to the functional severity of kidney disease. T lymphocytes and macrophages began to accumulate in glomeruli at the onset of proteinuria, but not before. Urinary excretion of interleukin-1 also began with proteinuria. Proteinuria increased in direct correlation with increases in the number of glomerular macrophages. Development of the most severe stage of glomerulonephritis, characterized by cachexia, declining kidney function, and necrotizing glomerular pathology, was accompanied by the disappearance of T cells from glomeruli and the expression of highly abnormal phenotypes by most macrophages. In addition, there was a switch from urinary excretion of interleukin-1 to excretion of tumour necrosis factor. The progression of proliferative immune complex glomerulonephritis was associated with qualitative as well as quantitative changes in glomerular macrophage populations. Differentiation and/or activation of those glomerular macrophages may have resulted from local T cell-mediated immunoregulation. Measurements of urinary cytokine excretion provided a reliable means of monitoring disease progression. The local action of tumour necrosis factor probably contributed to declining kidney function in the most severe stage of disease.

Animals↗
PubMed1990

Enalapril and renal injury in spontaneously hypertensive rats.

Rats of the spontaneously hypertensive strain develop kidney damage that resembles the nephropathy seen in some cases of human essential hypertension. Previous studies with a triple drug antihypertensive regimen indicated that proteinuria and glomerular histopathology in spontaneously hypertensive rats might develop despite long-term effective control of systemic blood pressure. To investigate further the relation between hypertension and kidney disease, a group of spontaneously hypertensive rats were treated with enalapril at 15 weeks of age. Blood pressure, protein excretion, and kidney function were measured in those rats at regular intervals during the next year and a half and were compared with untreated spontaneously hypertensive rats and the normotensive Wistar-Kyoto parent strain. Kidney tissue samples from all three groups, collected at autopsy, were stained by immunohistochemical and conventional methods to assess the relative severity and nature of kidney damage. Although enalapril therapy was completely effective in controlling the blood pressure of spontaneously hypertensive rats, it only postponed the onset of kidney disease. Enalapril-treated spontaneously hypertensive rats eventually exhibited albuminuria as severe as that found in hypertensive rats. Kidney vessel pathology was completely prevented with enalapril, but the abnormal accumulation of mononuclear cells in tubulointerstitial and periglomerular sites was the same as in untreated spontaneously hypertensive rats. We have concluded that elevated protein excretion in rats of the spontaneously hypertensive rat strain is not a secondary consequence of systemic hypertension. Structural abnormalities of renal vessels also do not appear to contribute significantly to the pathogenesis of albuminuria in spontaneously hypertensive rats. Other explanations must be sought to account for the close link between spontaneous hypertension and kidney damage in this animal model. The clear dissociation of kidney disease from systemic hypertension exhibited by spontaneously hypertensive rats may also be relevant for human disease.

Albuminuria↗
PubMed1989

Glomerular leukotriene synthesis in Heymann nephritis.

The glomerular synthesis of LTB4 was assessed in glomeruli isolated from rats with passive Heymann nephritis (PHN). PHN was induced by a single intravenous administration of proteinuric doses of immune sera raised in sheep against rat brush border tubular fraction Fx1A. At various time points following induction of the disease glomeruli were isolated and LTB4 synthesis was assessed under basal and phospholipase A2 activation conditions. LTB4 was measured by high pressure liquid chromatography and radioimmunoassay and was identified by UV spectroscopy. The role of complement system in mediating glomerular LTB4 synthesis was also assessed in a group of decomplemented rats using cobra venom factor and at various time points following administration of immune serum. Following induction of PHN, enhanced glomerular LTB4 synthesis was observed as early as one hour, peaked at five hours and returned toward control levels over the subsequent four days. The peak in glomerular LTB4 synthesis did not correlate with changes in glomerular neutrophiles or macrophages. A second increment of LTB4 synthesis occurred at the onset of heavy proteinuria (day 5). Complement depletion reduced proteinuria and the enhancement in LTB4 synthesis at day 5 but had no effect at earlier time points. The observations indicate that in non-inflammatory forms of glomerular immune injury the glomerular arachidonate 5-lipoxygenation is enhanced. This phenomenon has no apparent relationship with increased glomerular permeability to protein and may reflect the presence or activation of a leukotriene producing cell following intraglomerular interactions of Fx1A antigen, anti-Fx1A antibody and complement.

Animals↗
PubMed1989

Sudden onset of proteinuria in chronic serum sickness in rats.

1. Daily intravenous administration of bovine serum albumin (BSA) to rats produces chronic serum sickness glomerulonephritis, an immune-complex-mediated renal disease that is eventually always fatal. We have performed a detailed study of the onset of proteinuria in chronic serum sickness in order to assess the long-term consequences of discontinuing daily BSA injections precisely at that very early and well-defined stage of disease. 2. Urine and plasma samples from rats receiving daily BSA injections were collected and analysed daily before the onset of proteinuria, at which time the rats were divided into three groups. Group 1 continued to receive daily BSA injections, in group 2 injections were stopped on the first, and in group 3 on the third, day of proteinuria. Proteinuria began suddenly and was not preceded either by microalbuminuria or abnormalities of plasma composition. The sudden expression of proteinuria was accompanied by an equally rapid development of hypoalbuminaemia and hypercholesterolaemia. Development of the characteristic glomerular histopathology of serum sickness coincided with, but did not precede, the onset of proteinuria. Despite the discontinuation of antigen injections at the onset of proteinuria, basement membrane thickening was evident 8 weeks later; proteinuria persisted and hypercholesterolaemia increased. 3. In this model of immune complex glomerulonephritis, changes in kidney function and immunopathology were abrupt and closely linked, precluding the use of those criteria to predict when proteinuria would begin. Furthermore, extremely brief periods of active immunological injury to the peripheral capillary wall were sufficient to produce persistent abnormalities of glomerular structure and function.

Animals↗
PubMed1989

Dietary protein restriction and renal injury in the spontaneously hypertensive rat.

We examined the influence of a low-protein diet on the course of the renal injury in spontaneously hypertensive rats (SHR) and SHR given antihypertensive drug therapy (SHRD). Antihypertensive drug treatment was hydralazine, reserpine, and chlorothiazide. Wistar-Kyoto (WKY) rats served as normotensive controls. SHR, SHRD, and WKY were each placed on a 24, 14, and 10% protein diet at 5 wk and followed to 80-90 wk of age. Untreated SHR showed a steady rise in protein excretion from 5 to 70 wk regardless of dietary protein content. Protein excretion in SHRD on a 24% protein diet was similar to untreated SHR. However, SHRD on a 14 or 10% diet had a more moderate increase in protein excretion. Glomerular, tubular, and vascular pathology in untreated SHR was not influenced by dietary protein intake. Despite successful antihypertensive therapy, kidney pathology in SHRD on a 24% diet was not significantly different from untreated SHR. In contrast, SHRD on 14 or 10% protein diets had less segmental glomerulosclerosis and vascular pathology than untreated SHR. The results indicate that dietary protein restriction does not influence the course of renal injury in untreated SHR. However, the combination of antihypertensive drug therapy with protein restriction in SHR delays and may arrest progression of glomerulosclerosis and proteinuria.

Animals↗
PubMed1989

Immunopathology of experimental bronchiectasis.

In human bronchiectasis, the bronchial wall is the seat of abnormal mononuclear cell infiltration, which suggests the presence of a cell-mediated immune reaction. The histopathology of a recently devised animal model of experimental bronchiectasis resembles that of the human disease. We have investigated its immunohistology to validate the similarity to that of human bronchiectasis in order to provide a model for the study of cellular immune aspects of the pathogenesis of bronchiectasis. The immunohistology of the bronchial wall mononuclear cell population in experimental rat bronchiectasis was compared with that in control and normal rats. The control rats did not develop bronchiectasis, and the composition and distribution of mononuclear cells in the bronchial wall were similar to those of normal animals. In the rats developing bronchiectasis, there was infiltration of T lymphocytes, macrophages, and dendritic cells (as defined by monoclonal antibodies) in all compartments of the lung, particularly in the bronchial wall and around vessels. The bronchus-associated lymphoid tissue was disrupted by heavy infiltration of T cells, and follicular aggregates of T lymphocytes were seen deeper in the lung parenchyma. Expression of Ia antigen increased in the bronchial epithelium and in large numbers of mononuclear cells throughout the lung. These findings suggest that a cell-mediated immune response appears during the development of experimental bronchiectasis in this rat model. This cellular immune response is similar to that described in human bronchiectasis and may enable this animal model to be used in defining the role of cellular immunity in the pathogenesis of bronchiectasis.

Animals↗
PubMed1989

The distribution of phenotypically distinct macrophage subsets in the lungs of patients with cryptogenic fibrosing alveolitis.

Monoclonal antibodies that identify phenotypically distinct macrophage subsets were used to analyse the macrophages in lung biopsy specimens and bronchoalveolar lavage fluid from patients with cryptogenic fibrosing alveolitis. Among the antibodies were RFD1, an interdigitating cell marker, RFD7, a marker for mature tissue macrophages, and RFD9, which identifies epithelioid cells as well as germinal centre macrophages. The lavage fluid was found to contain abnormally high numbers of cells staining with each of the antibodies, a finding that could be explained, at least in part, by an increased frequency of cells expressing more than one marker. In lung tissue macrophage phenotypes within the interstitium were found to differ significantly from those in the alveolar space. Most strikingly, cells bearing the antigen recognized by RFD9 were entirely absent from the interstitial macrophage population, whereas the vast majority in the alveolar lumen were RFD9-positive. The discrete compartmentalization of phenotypically different macrophages within the lung suggests that macrophages may contribute differently to lung pathology in each microenvironment. The functional capacity of the unusual RFD9-positive alveolar macrophages remains to be determined, but their close association with the process of alveolar occlusion indicates a role in the fibrotic process.

Aged↗
PubMed1988

Studies on cell proliferation and tracer localization in the kidneys of guinea pigs with experimental autoimmune anti-tubular basement membrane nephritis.

The mitotic activity in kidneys of guinea pigs with experimental autoimmune anti-tubular basement membrane (TBM) nephritis was investigated using autoradiographic techniques to determine the uptake of [3H]thymidine by actively dividing cells. It was observed in these animals that cells of proximal tubules, distal tubules, cortical and medullary interstitium, medullary collecting ducts, and loops of Henle took up significantly greater amounts of [3H]thymidine when compared with normal animals. In addition, the behaviour of horseradish peroxidase (HRP) and goat anti-HRP IgG in extraglomerular sites in the kidneys of these animals was studied. Contrary to what was expected, these tracers appeared to be less concentrated in the tubules and interstitium of animals with anti-TBM disease, with tracer movement restricted in areas of disrupted TBM. The significance of these observations is discussed.

Animals↗
PubMed1988

Antibody-mediated proliferation of proximal tubule cells requires cross-linking of antigenic determinants.

In Heymann nephritis, the deposition in vivo of divalent anti-brush border antibodies on the luminal plasma membrane of proximal tubules leads to both epithelial cell proliferation and clumping and loss of microvilli. The passive transfer of divalent rat, sheep or rabbit anti-brush border antibodies to proteinuric recipients has a similar effect. To determine whether cross-linking of antigenic determinants in the plasma membrane was required to produce pathology, monovalent and divalent antibodies were compared for their ability to stimulate the incorporation of 3H-thymidine into kidney cells and to damage the brush border. Proximal tubule immunopathology was also evaluated in recipients treated with chlorpromazine, a drug which blocks the redistribution of plasma membrane molecules that may follow antibody-mediated cross-linking. Monovalent Fab fragments of anti-brush border antibodies failed to stimulate proximal tubule cell proliferation, and they appeared to block the proliferation induced by divalent antibodies. Destruction of microvilli also required the deposition of divalent antibodies. Chlorpromazine treatment prevented both the cell proliferation and the brush border loss produced by divalent antibodies, although clumping of microvilli was not prevented. Antibody-mediated cell proliferation and membrane shedding, resembling aspects of the normal B-cell response to ligands of the antigen receptor, might also account for tissue damage in autoimmune diseases affecting other epithelia.

Animals↗
PubMed1988

Antibody-mediated proliferation of proximal tubule cells.

We have proposed that the deposition in vivo of anti-brush border antibodies on proximal tubule cells in Heymann nephritis stimulates those cells to divide. To evaluate that hypothesis, we have investigated the temporal relationship between antibody deposition and kidney cell proliferation, using autoradiography to detect dividing cells in rats with Heymann nephritis and in age-matched controls treated with Freund's adjuvant alone. To assess the possible stimulation of proximal tubule cell proliferation by factors associated with proteinuria and/or nephrotic syndrome, kidney cell proliferation was measured in rats with chronic serum sickness glomerulonephritis. Proteinuric rats with chronic serum sickness also served as recipients of anti-brush border antibodies in passive transfer experiments. Cell division rates were not altered by adjuvant treatment or ageing. In both active Heymann nephritis and passive transfer experiments, a highly elevated stimulation of 3H-thymidine incorporation, reflecting mitotic activity, was detected in the proximal tubule epithelium immediately following the deposition of antibodies on the brush border. Significant enhancement of cell division was not noted in other nephron segments. A much smaller increase in proximal tubule cell proliferation accompanied proteinuria in chronic serum sickness. A similar small elevation compared to controls was also detected in late stages of Heymann nephritis when the proximal tubules were free of immunoglobulin deposits. It appears that the reaction of divalent antibodies with plasma membrane antigens can produce proliferative pathology of the proximal tubule epithelium. Furthermore, a significant, if less dramatic, enhancement of cell proliferation may be secondary to proteinuria and/or other manifestations of the nephrotic syndrome.

Animals↗
PubMed1987

Kidney immunopathology and pathophysiology in rats immunized with proximal tubule cell brush border or basolateral membrane vesicles.

Proximal tubule pathology in Heymann nephritis has been attributed to anti-brush border antibodies, but antibodies with other specificities might also be important. To determine whether injury to the basolateral membranes of proximal tubules could occur independently of brush border injury, LEW rats were immunized either with partially purified basolateral or brush border membrane vesicles. Both immunogens produced glomerular immunopathology and pathophysiology identical in magnitude and time course to that seen in Heymann nephritis. Antibodies eluted from the kidneys of rats immunized with either antigen preparation stained the brush border in vitro. However, circulating anti-brush border antibodies were in significant titers only in rats immunized with brush border vesicles, whereas antibodies that stained the cytoplasm of both proximal and distal tubules predominated in rats immunized with basolateral membranes. With the onset of proteinuria, rats immunized with brush border membranes developed the proximal tubule pathology of Heymann nephritis. In rats immunized with basolateral membranes, the brush border and apical aspect of proximal tubule cells remained essentially normal. However, defects of basolateral membrane transport function were present, indicating that those defects need not necessarily be secondary to brush border damage. The dissociation of brush border damage from glomerular injury suggests that different antibody populations may account for each. Furthermore, anti-brush border antibodies may not account for all aspects of proximal tubule pathology in Heymann nephritis.

Animals↗
PubMed1987

Relationship of the quality and quantity of circulating anti-BSA antibodies to the severity of glomerulonephritis in rats with chronic serum sickness.

Chronic serum sickness glomerulonephritis, induced in hyperimmunized rats by daily intravenous administration of bovine serum albumin, occurs in three stages, mild, moderate and severe, with abrupt onsets and distinctive features of kidney pathophysiology and immunopathology. We have studied the relationship between circulating anti-BSA antibodies and the severity of glomerulonephritis at each stage. The total amount of antibodies declined gradually during the course of disease, to low concentrations in the most severe stage of kidney inflammation. High levels of immune complexes were present in the circulation while precipitating antibodies were maintained, and rats remained in the mill stage of disease, exhibiting no abnormalities of kidney function and only mesangial immunopathology. The start of the moderate stage of chronic serum sickness, identified by proteinuria and the accumulation of immune deposits along the glomerular basement membrane, was associated with the disappearance of precipitating antibodies from circulation. With the onset of the severe stage of disease, marked by depressed glomerular filtration and sodium excretion, circulating antibodies of high affinity were no longer detected and circulating immune complex levels were only marginally elevated above normal. The experiments reported here demonstrate that, in chronic serum sickness glomerulonephritis of rats, transitions from one stage of kidney disease to another can be inferred from changes in the population of circulating antibodies. Kidney histopathology, therefore, can be predicted reliably from serological data alone.

Animals↗
PubMed1986

Pathogenesis of passive Heymann glomerulonephritis: chlorpromazine inhibits antibody-mediated redistribution of cell surface antigens and prevents development of the disease.

Two hypotheses were tested: first, that in LEW rats the interaction of sheep (or rabbit) anti-brush border antibodies with antigens (Heymann antigens) expressed on the plasma membrane of glomerular visceral epithelial cells is characterized by initial redistribution of immune complexes on the cell surface and by subsequent shedding of immune complexes in the subepithelial part of the capillary wall; and secondly, that this interaction is inhibited by chlorpromazine, a drug that displaces calcium ions from binding sites linking the plasma membrane to the cytoskeleton, and which blocks the redistribution of IgG on the surface of B lymphocytes exposed to anti-IgG antibodies. The studies were performed in vitro on cultured LEW glomerular epithelial cells and in vivo in LEW rats. In cultured glomerular epithelial cells exposed at 37 degrees C to anti-brush border IgG, chlorpromazine prevented, in a dose-dependent manner, the redistribution ("capping") of Heymann antigens and the fixation of complement. The renal glomeruli of chlorpromazine-treated LEW rats examined 6 and 48 hr after transfer of anti-brush border antibodies had punctate and, later, punctate and diffuse deposits of sheep (or rabbit) IgG on glomerular epithelial cells, but not similar deposits of rat C3. Moreover, granular subepithelial deposits of sheep (or rabbit) IgG and rat C3, characteristic of passive Heymann glomerulonephritis, did not develop, although deposits of sheep IgG were detected by immunoelectron microscopy on the microvilli of glomerular epithelial cells. Comparative studies on rats with similar reductions in glomerular filtration rates, produced by high doses of chlorpromazine or with renal artery stenosis, showed that the findings were not the consequence of insufficient delivery of antibody to glomerular epithelial cells. The results are consistent with the interpretation that Heymann glomerulonephritis is induced by mechanisms of redistribution of cell surface antigens comparable to those that govern the interaction of surface antigens (or receptors) with appropriate ligands in B lymphocytes and other classical in vitro systems.

Animals↗