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Biomedical subjects

R C Atkins

Publications and source records attributed to R C Atkins.

At least 91 records · Page 5Linked to original sources
PubMed1996

De novo CD44 expression by proliferating mesangial cells in rat anti-Thy-1 nephritis.

CD44 is the major cell-surface receptor for hyaluronan, and cell-matrix interactions mediated by the CD44/hyaluronan receptor-ligand pair are involved in a variety of cellular functions, including cell migration. The aim of the study presented here was to examine the expression of CD44 and hyaluronan in the mesangial proliferative response in rat anti-Thy-1 nephritis. In normal rat kidney, CD44 is expressed by medullary tubules, some distal tubules and thick ascending limbs of Henle, dendritic-like cells around Bowman's capsule, and some interstitial cells. However, only occasional CD44+ cells were found within the glomerular tuft. In experimental nephritis, there was an early glomerular influx of CD44+ macrophages, which peaked on Day 4 after anti-Thy-1 antibody injection. A striking finding was de novo CD44 expression by mesangial cells. This CD44 expression was restricted to the transient period of mesangial cell proliferation as shown by double-staining with an antibody against the proliferating cell nuclear antigen. Immunohistochemistry staining also demonstrated hyaluronan deposition within segmental areas of proliferating CD44+ cells, suggesting a functional interaction between the CD44/hyaluronan receptor-ligand pair during mesangial cell proliferation. In vitro, rat mesangial cells were shown to express mRNA and protein for the 90-kd isoform of CD44. In addition, hyaluronan-dependent aggregation of CD44+ mesangial cells was specifically inhibited by an anti-CD44 antibody, demonstrating a functional interaction between hyaluronan and the CD44 expressed on the surface of rat mesangial cells. In conclusion, these data suggest that cell-matrix interactions mediated by the CD44/hyaluronan receptor-ligand pair are involved in mesangial cell proliferation in rat anti-Thy-1 nephritis.

Animals↗
PubMed1996

De Novo renal expression of macrophage migration inhibitory factor during the development of rat crescentic glomerulonephritis.

Macrophage migration inhibitory factor (MIF), a key mediator of the delayed-type hypersensitivity response, was originally thought to be produced by activated T cells. However, recent studies have found that MIF is produced in many cell types including monocytes/macrophages and anterior pituitary cells. The current study has examined MIF expression in normal and diseased kidney using in situ hybridization, immunohistochemistry, and Northern blotting. MIF mRNA and protein are constitutively expressed in normal kidney, being largely restricted to tubular epithelial cells and some glomerular visceral and parietal epithelial cells. During the development of rat anti-glomerular basement membrane glomerulonephritis, a model of macrophage-mediated renal injury, there was marked de novo expression of MIF by intrinsic kidney cells including endothelium and glomerular and tubular epithelial cells. Up-regulation of MIF expression correlated with macrophage accumulation within the glomerulus (P < 0.001) and tubulointerstitium (P < 0.001). Of significance, the accumulation of macrophages was exclusively localized to areas of strong MIF expression, contributing to focal glomerular and tubulointerstitial lesion formation. In addition, up-regulation of MIF expression by parietal epithelial cells was associated with macrophage accumulation within Bowman's space and crescent formation. Combined in situ hybridization and immunostaining also demonstrated MIF expression by macrophages, T cells, and fibroblast-like cells within renal lesions. In conclusion, these data provide the first demonstration that renal epithelial cells are a major source of MIF in both normal and diseased kidney. Furthermore, the up-regulation of MIF expression may play an important role in macrophage accumulation and progressive renal injury in rat crescentic glomerulonephritis.

Animals↗
PubMed1996

Total body protein status assessed by different estimates of fat-free mass in adult peritoneal dialysis patients.

OBJECTIVE: To assess the usefulness of fat-free mass (FFM) as an index of total body protein (TBPr) status in continuous ambulatory peritoneal dialysis (CAPD) patients. DESIGN: TBPr was measured by in vivo neutron activation analysis (IVNAA) and expressed as a standardised protein index (PI). FFM was estimated by dual energy X-ray absorptiometry (DXA), whole body counting of total body potassium (TBK), and creatinine kinetics (CK), and expressed as a standardised FFM index (FFMI). FFM was also determined by a criterion method based on four compartment model (4CM) which is defined as the sum of total body water determined by D2O dilution, TBPr determined by IVNAA, bone mineral determined by DXA, and glycogen estimated to be 4.4% of TBPr. Each patient was measured within a four hour period by all methods. SETTING: Body Composition Laboratory, Monash Medical Centre. SUBJECTS: Six male and twelve female CAPD patients (33-77 years). RESULTS: FFMI assessed by DXA and by TBK agreed with measurements of PI on identifying the mean TBPr status of the CAPD group as significantly below a comparable normal reference population (mean Z score: PI = -1.01 (P < 0.05); FFMI by DXA = -0.50 (P < 0.05); FFMI by TBK = -1.24 (P < 0.05)). In contrast, FFMI assessed by CK did not reveal a significantly reduced TBPr status (mean Z score: -0.70 (NS)). Furthermore, significant linear correlations were noted between PI and FFMI estimated by DXA and by TBK (r = 0.57 (P < 0.05) vs r = 0.69 (P < 0.05)) however no significant correlation was observed between PI and FFMI estimated by CK (r = 0.36 (NS)). Moderate variation in FFM hydration did not compromise the ability of DXA, TBK or CK to differentiate between protein deleted, normal and enriched patients. Comparison of FFM estimates between the criterion method and either DXA, TBK or CK revealed no significant bias (+ 1.8 kg vs -2.0 kg vs +0.8 kg) and respective SEE values of 3.8 kg (8.3%), 5.9 kg (14.3%) and 9.6 kg (21.7%). CONCLUSION: The findings of this study indicate that FFM estimated by either DXA or the whole body counting of TBK is a useful index of TBPr status in CAPD patients. However, FFM assessed by CK does not appear to be an appropriate index of TBPr status in CAPD patients.

Absorptiometry, Photon↗
PubMed1996

Interleukin-1 receptor antagonism.

Interleukin-1 (IL-1) is a pro-inflammatory cytokine that exerts a wide range of biological effects. The recently identified IL-1 receptor antagonist (IL-1ra) has provided a tool for blocking IL-1 activity in vivo, leading to a detailed understanding of the role of this cytokine in the inflammatory response. The importance of IL-1 production in glomerulonephritis has been shown by the ability of IL-1ra treatment to suppress the induction and progression of experimental crescentic glomerulonephritis. Although further studies are required, IL-1ra treatment is an attractive adjunct therapy for patients with progressive glomerulonephritis.

Animals↗
PubMed1995

Interleukin-1 receptor antagonist halts the progression of established crescentic glomerulonephritis in the rat.

The pathogenic role of interleukin-1 (IL-1) in the progression of established rat crescentic glomerulonephritis was investigated by administration of the interleukin-1 receptor antagonist (IL-1ra). Passive accelerated antiglomerular basement membrane (GBM) disease was induced in three groups of six rats. One group was killed on day 7 with no treatment. The other groups received a constant infusion of IL-1ra or saline from day 7 until being killed on day 21. All animals developed moderate glomerular injury, a significant loss of renal function and marked histological damage including crescent formation by day 7. Saline treated animals showed a significant deterioration in these parameters over days 7 to 21. In contrast, animals treated with the IL-1ra over this period showed stabilization of glomerular injury (protein-uria; P < 0.001) and a recovery of normal renal function (creatinine clearance; P < 0.05). Histologically, IL-1ra treatment suppressed glomerular cell proliferation (PCNA expression; P < 0.001) and significantly inhibited crescent formation (P < 0.005), glomerular sclerosis (P < 0.005), tubular atrophy (P < 0.05) and interstitial fibrosis (P < 0.05). A key finding was that IL-1ra treatment not only stopped renal leukocyte accumulation over days 7 to 21 (P < 0.01), but that treatment also suppressed immune activation of the infiltrate (P < 0.01). In conclusion, this study provides direct evidence that IL-1 plays a key role in the progressive/chronic phase of renal injury in experimental crescentic glomerulonephritis and indicates that IL-1ra treatment may be of therapeutic benefit in human rapidly progressive crescentic glomerulonephritis.

Analysis of Variance↗
PubMed1995

ICAM-1 and VCAM-1 in human renal allograft rejection.

Light microscopy studies have demonstrated heightened ICAM-1 and VCAM-1 expression in renal allograft rejection in experimental animals and in humans, and administration of ICAM-1 blocking antibodies has been shown to prolong graft survival in nonhuman primates. We used a precise ultrastructural immunogold localization technique to identify the exact sites of expression of ICAM-1 and VCAM-1 in both normal human kidney and in renal allograft rejection. In the normal kidney ICAM-1 is moderately strongly expressed in glomeruli, on the endothelium and parietal epithelium and in the interstitium, on the endothelium of peritubular capillaries, arterioles and small arteries, on fibroblast-like interstitial cells and on the brush border of proximal tubules. In contrast, in normal kidney, VCAM-1 expression is restricted to the parietal epithelium and the basolateral surfaces of a few proximal tubule cells. In allograft rejection, although ICAM-1 expression appears to be increased, its pattern of distribution is similar to that seen in the normal kidney. However, VCAM-I in allograft rejection is widely expressed on the endothelium of peritubular capillaries and arterioles in association with adhesion of mononuclear leukocytes within these vessels. The tubular expression of VCAM-1, although still focal in nature, is increased on the basolateral surfaces in association with lymphocytic infiltration of tubules.(ABSTRACT TRUNCATED AT 250 WORDS)

Biopsy↗
PubMed1995

Kt/V in CAPD by different estimations of V.

This study compared the measurements of total body water (TBW) by 58% body weight (TBW58%), the Watson equation (TBWWV) and bioelectric impedance (TBWBIA) with the gold standard, Deuterium oxide (TBWD2O) dilution method in twenty continuous ambulatory peritoneal dialysis (CAPD) patients. TBW volumes were highest when calculated as TBW58% (42.6 +/- 9.4 liter) and lowest when calculated from TBWWV (34.6 +/- 6.8 liter). TBWBIA underestimated TBW when compared to TBWD2O, although the difference was not statistically significant (37.1 +/- 9.8 liter and 38.8 +/- 9.3 liter, respectively). In fact, TBWBIA correlated strongly with TBWD2O (r = 0.8, P < 0.0001). These discrepancies resulted in significant differences when Kt/V week-1 derived from the four methods were compared. To determine the effect of percent fat mass on the estimation of TBW by each method, we compared TBW and Kt/V week-1 derived from the four methods in nine CAPD patients who had normal percent fat mass (Non-Obese) and 11 CAPD patients who had greater than normal % fat mass (Obese). In the Non-Obese group, there was close correlation of TBWBIA, TBWWV and TBW58% when compared with TBWD2O (r = 0.93, P < 0.001, r = 0.89, P < 0.01 and R = 0.86, P < 0.01, respectively. Also, Kt/V week-1 derived from TBWBIA, TBWWV and TBW58% correlated strongly with Kt/V week-1 from TBWD2O (r = 0.93, P < 0.0005, r = 0.83, P < 0.01 and r = 0.8, P < 0.01, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Body Composition↗
PubMed1995

Local macrophage proliferation in the progression of glomerular and tubulointerstitial injury in rat anti-GBM glomerulonephritis.

The aim of this study was to examine the contribution of local proliferation in the development of macrophage accumulation and macrophage-mediated injury in rat anti-GBM glomerulonephritis. Using double immunohistochemistry staining of monocyte/macrophages plus the proliferating cell nuclear antigen (PCNA) or bromodeoxyuridine (BrdU) incorporation, we found that the initial accumulation of ED1+ macrophages in the kidney on day 1 of disease was due to an influx of circulating monocytes. However, large numbers of proliferating macrophages (ED1+PCNA+cells), including mitotic macrophages, were present within the glomerulus and interstitium during disease progression (days 7 to 21), accounting for up to 62% of the total macrophage population and giving an excellent correlation with total macrophage accumulation (glomerulus, r = 0.92; interstitium, r = 0.94; both P < 0.001). These proliferating cells had a monocyte phenotype (ED1+ED2-ED3-), but this marked proliferative activity was restricted to the diseased kidney since no PCNA expression or BrdU incorporation was evident within circulating blood monocytes. Proliferating macrophages were almost exclusively localized in areas of severe tissue damage and they correlated significantly with glomerular and tubulointerstitial lesions (P < 0.001), proteinuria (P < 0.001) and creatinine clearance (P < 0.01). In marked contrast, glomerular PCNA- macrophages failed to correlate with these parameters. In conclusion, this study has demonstrated that local macrophage proliferation is the major mechanism of macrophage accumulation during the progression of rat anti-GBM glomerulonephritis. Furthermore, it suggests that proliferating macrophages are potent local effector cells in the mediation of progressive renal injury in this disease.

Animals↗
PubMed1995

The role of T-cells in inflammatory kidney disease.

The fundamental role of cell-mediated immunity in inflammatory disease of the kidney has been established for some time. This review focusses on the recent advances in our understanding of the role of T-cells in the pathogenesis both of glomerulonephritis and interstitial nephritis. In particular, the increasing experimental evidence for a functional role for T-cells in promoting disease initiation and progression is examined. The ever increasing variety of T-cell-effector functions and their relevance are also discussed.

Animals↗
PubMed1995

A novel, simple, reliable, and sensitive method for multiple immunoenzyme staining: use of microwave oven heating to block antibody crossreactivity and retrieve antigens.

We report a simple and reliable method for detection of two or more antigens within tissue sections by indirect immunoenzyme staining using mouse monoclonal antibodies (MAbs). This technique involves treating sections with two 5-min microwave (MW) oven heatings between sequential rounds of three-layer immunoenzyme staining (mouse MAb, goat anti-mouse IgG, and mouse PAP or mouse APAAP) and color development. Discrete staining of cell surface, cytoplasmic, and nuclear antigens was evident within individual cells. This technique has a number of advantages over those currently available. First, MW treatment denatures bound antibody molecules, thereby completely blocking crossreactivity between sequential rounds of staining. This allows the use of primary (and other) antibodies raised in the same species and the use of a sensitive three-layer staining method. Second, antigen retrieval after MW treatment markedly increases the sensitivity of cytoplasmic and nuclear antigen detection. Third, inactivation of peroxidase and alkaline phosphatase enzymes present in PAP and APAAP complexes prevents inappropriate color development. Finally, this method can be used in both paraformaldehyde-fixed cryostat sections and formalin-fixed paraffin tissue sections. In conclusion, this is a simple, reliable, and sensitive technique that will be useful in many areas of diagnosis and research.

Animals↗
PubMed1995

Deoxyspergualin inhibits mesangial cell proliferation and major histocompatibility complex class II expression.

It has previously been shown that the immunosuppressive drug deoxyspergualin can inhibit renal injury in experimental glomerulonephritis. This study examined whether deoxyspergualin can modulate the mesangial cell response to glomerular injury. Antiglomerular basement membrane glomerulonephritis was induced in primed rats. Groups of five animals were treated with deoxyspergualin (5 mg/kg per day) or saline from Day 0 until being euthanized on Day 1, 7, 14, or 21. Deoxyspergualin treatment significantly inhibited mesangial cell proliferation (proliferating cell nuclear antigen expression) over the disease course as assessed by double immunohistochemistry staining (P < 0.001 versus saline treated) and reduced glomerular major histocompatibility complex (MHC) class II expression. To demonstrate if this was a direct action of deoxyspergualin, an in vitro system was studied. The addition of deoxyspergualin caused a time- and dose-dependent inhibition of [3H]thymidine uptake by cultured rat mesangial cells. Of particular interest was the finding that deoxyspergualin inhibited the de novo cell surface expression of MHC class II antigens after interferon-gamma stimulation. However, deoxyspergualin did not prevent the cytoplasmic accumulation of MHC class II molecules, indicating that the drug interfered with a posttranslational event in MHC class II processing and/or assembly. Deoxyspergualin was not a general inhibitor of mesangial cells, and it had no effect on constitutive or lipopolysaccharide-induced transforming growth factor beta 1 expression. In conclusion, deoxyspergualin has been shown to inhibit the mesangial cell response to glomerular injury. This novel mode of action may provide an additional therapeutic benefit in the treatment of proliferative forms of glomerulonephritis.

Animals↗
PubMed1995

Local macrophage proliferation in multinucleated giant cell and granuloma formation in experimental Goodpasture's syndrome.

Granuloma is a specialized form of inflammatory reaction featuring focal macrophage and T-cell accumulation and multinucleated giant cell formation. It is widely held that macrophage accumulation within granulomatous lesions results from recruitment of blood monocytes, whereas proliferation of monocyte/macrophages makes little contribution to this process. The present study of macrophage proliferation within immunologically induced granulomas in rat experimental Goodpasture's syndrome challenges the conventional view. In this disease, granulomatous lesions in the kidney and lung contained 60 to 70% macrophages of an ED1+ED2-ED3-blood monocyte phenotype. However, double immunohistochemistry showed that up to 75% of ED1+ macrophages within granulomatous lesions were proliferating on the basis of proliferating cell nuclear antigen expression and bromodeoxyuridine incorporation. In contrast, no proliferating cell nuclear antigen expression or bromodeoxyuridine incorporations was detected in blood monocytes, indicating that proliferation of ED1+ED2-ED3- cells was a localized event within granulomatous lesions. A second finding of note was that almost all ( > 95%) nuclei within multinucleated giant cells were positive for proliferating cell nuclear antigen, but these nuclei lacked bromodeoxyuridine incorporation. This suggests a novel mechanism of multinucleated giant cell formation involving fusion of macrophages in G1 phase, which then halts progression into S phase of the cell cycle. In conclusion, this study has found that local macrophage proliferation plays an important role in the pathogenesis of granuloma formation.

Animals↗