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Biomedical subjects

R C Atkins

Publications and source records attributed to R C Atkins.

At least 109 records · Page 6Linked to original sources
PubMed1994

Control of post-transplant erythrocytosis by enalapril.

OBJECTIVE: To assess the erythropoietin response in patients with erythrocytosis after renal transplantation who were treated with enalapril. PATIENTS: Fourteen patients with stable renal transplants (creatinine clearance, 74.4 +/- 24.6 mL/min) and a packed cell volume of 51% or more over six months and who had no other cause for their erythrocytosis. METHODS: Patients were treated with enalapril for six months. Serum erythropoietin levels, creatinine clearance and packed cell volume were measured before and during the study; patients were reviewed each month. RESULTS: All patients had erythropoietin levels inappropriate for their packed cell volume. After six months' therapy with enalapril their mean erythropoietin concentration of 21.3 +/- 5.0 U/L fell to 7.4 +/- 1.3 U/L (P < 0.02) although the concentration increased in two patients. The mean packed cell volume fell from 52.7% +/- 0.5% to 44.4% +/- 1.0% (P < 0.0001). There was no change in renal function. CONCLUSION: Low-dose enalapril controls post-transplant erythrocytosis, at least in part, by lowering serum erythropoietin levels.

Adult↗
PubMed1994

Deoxyspergualin suppresses local macrophage proliferation in rat renal allograft rejection.

Deoxyspergualin (DSP) is a potent immunosuppressive drug that is able to both prevent and reverse acute allograft rejection. Although there is good evidence that DSP can inhibit T and B lymphocyte responses, the effect of this drug upon monocyte function is controversial. In the current study, substantial local proliferation of inflammatory macrophages (41.6 +/- 5.5% of ED1+ cells) within acutely rejecting rat renal allografts was identified by expression of the proliferating cell nuclear antigen. Treatment of animals with DSP not only reduced macrophage accumulation within the tissue, but it also significantly inhibited local proliferation of macrophages within the graft (26.4 +/- 5.6% of ED1+ cells, P < 0.05 vs. untreated). This appeared to be, at least in part, a direct effect of DSP upon macrophages since the drug also inhibited growth of 2 monocytic cell lines (RC-2A and U937) in vitro. However, DSP treatment had no effect upon LPS-induced monocyte IL-1 beta, TNF alpha, and IL-6 mRNA and protein production, indicating that this drug is not a general inhibitor of monocyte function. In conclusion, this study has demonstrated that local proliferation of macrophages within the kidney is a prominent feature of acute allograft rejection and that inhibition of this response is one mechanism whereby DSP exerts its potent immunosuppressive actions.

Animals↗
PubMed1994

Regulation of human renal adenocarcinoma cell growth by retinoic acid and its interactions with epidermal growth factor.

Retinoic acid (RA) is a natural derivative of vitamin A which regulates the growth and differentiation of epithelia. We have previously proposed that RA participates in compensatory kidney growth and reported that RA inhibits rat mesangial cell growth. This paper describes the effects of RA on a human renal adenocarcinoma cell line (PAD) under different growth conditions, and its interactions with epidermal growth factor (EGF). PAD cells were shown to express RA receptors alpha and beta by Northern blot analysis. In serum free cultures, addition of RA (10(-7) M) markedly increased thymidine incorporation by PAD cells (155 +/- 7% mean +/- SE vs. control in 6 separate experiments; P < 0.0001). RA also caused a significant increase in thymidine incorporation by PAD cells under conditions of rapid growth in serum supplemented medium (115 +/- 2% vs. control; P < 0.001). RA by itself was unable to reverse contact inhibition of PAD cell growth (NS vs. control), but it synergistically enhanced the mitogenic effect of EGF on confluent monolayers (110 +/- 0.6% vs. EGF alone; P < 0.05). Northern blot analysis demonstrated that PAD cells express EGF receptor mRNA, and this was not significantly modified by the addition of RA. Growth arrested (serum starved) PAD cells expressed RAR-alpha mRNA which was upregulated eightfold at three hours following the addition of 10% FCS. Thus, our data show that RA is directly mitogenic for serum starved human renal adenocarcinoma cells and that it exerts complex modulation of cell growth in the presence of EGF and serum components.

Adenocarcinoma↗
PubMed1994

ICAM-1 directs migration and localization of interstitial leukocytes in experimental glomerulonephritis.

Recent studies of rat anti-GBM disease have demonstrated a functional role of the ICAM-1/LFA-1 interaction in the entry of leukocytes into the glomerulus and an association between interstitial ICAM-1 expression, leukocyte infiltration and tubulointerstitial damage. In the current study, we used immunogold ultrastructural techniques to identify ICAM-1/LFA-1 interactions in the initiation of interstitial leukocyte infiltration during the first 24 hours of rat accelerated anti-GBM disease. In normal rats, there was weak constitutive ICAM-1 expression in the interstitium: on the endothelial luminal surface of interstitial capillaries, venules and arterioles, on the entire surface of interstitial fibroblast-like cells and confined to the brush border of proximal tubules. As early as 1.5 hours after injection of anti-GBM serum, there was a marked increase in the intensity of ICAM-1 expression, most notably on capillary endothelium, fibroblast-like cells and brush borders of proximal tubules, particularly in the periglomerular/perihilar areas. Mononuclear leukocytes exhibiting strong surface LFA-1 (CD11a and CD18) expression were seen adherent to the endothelium of interstitial capillaries, with ICAM-1 and LFA-1 antigens present at sites of contact. In addition, mononuclear cells migrating into the interstitium showed areas of close apposition to interstitial fibroblast-like cells, and here ICAM-1 and LFA-1 expression were also prominent at the sites of contact. This is the first study to demonstrate sites of ICAM-1/LFA-1 interaction in mononuclear cell migration and localization in glomerulonephritis. The results suggest that up-regulation of periglomerular/peritubular capillary ICAM-1 expression is important for mononuclear cell entry into the interstitium, while interaction with fibroblast-like cells may facilitate movement and subsequent focal accumulation of mononuclear cells at sites within the interstitium.

Animals↗
PubMed1994

The ICAM-1/LFA-1 interaction in glomerular leukocytic accumulation in anti-GBM glomerulonephritis.

Recent studies of rat anti-glomerular basement membrane (anti-GBM) disease have demonstrated a functional role for ICAM-1 in the entry of leukocytes into the glomerulus, both in the early polymorphonuclear (PMNL) influx and the more delayed monocyte/macrophage infiltration. In the current study we used immunogold ultrastructural techniques to identify the exact sites of expression of ICAM-1 (CD54) in the glomerulus and the expression of CD11a and CD18 by infiltrating glomerular leukocytes in the first 24 hours of accelerated anti-GBM disease in rats. In normal rats there was constitutive ICAM-1 expression on the luminal surface of the glomerular endothelium and parietal epithelium of Bowman's capsule. In disease ICAM-1 expression was progressively increased over 24 hours on a thickened, reactive glomerular endothelium, being most prominent on endothelium adjacent to the mesangial stalks. Mesangial cells demonstrated surface ICAM-1 expression only in focal areas of superficial mesangiolysis. PMNL, the predominant glomerular inflammatory cell in the first 12 hours of accelerated anti-GBM GN, expressed abundant surface CD18 which was present at the sites of adhesion of the PMNL to the glomerular endothelium. In contrast PMNL expressed only very sparse surface CD11a, suggesting that another beta 2 integrin, Mac-1, which shares a common beta chain with LFA-1 may be the more important PMNL counter receptor for ICAM-1 in the glomerulus. Glomerular monocyte/macrophage infiltration became evident within glomerular capillary loops and the mesangium from 6 to 24 hours. These adherent and migrating leukocytes expressed abundant surface CD11a and moderate CD18 particularly at their sites of adhesion to glomerular endothelium.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Interstitial activated (IL-2R+) mononuclear cells and Ia antigens in experimental focal glomerulosclerosis.

Tubulointerstitial localization of major histocompatibility complex (MHC) class II (Ia) antigens and immune-activated mononuclear cells (IL-2R+) and its suppression by prednisolone (PSL) were studied in a progressive model of focal glomerulosclerosis (FGS) induced by aminonucleoside (AN) and protamine sulfate (PS) given as 4 four day courses in rats. Tissues were prepared for the quantification of leucocytes on days 24, 52 and 80. The numbers of total leucocytes (CD45+), Ia+ cells, monocytes/macrophages, T lymphocytes (CD5+) and IL-2R+ cells (CD25+) were enumerated in immunoperoxidase sections using monoclonal antibodies: OX1, OX6, ED1, OX19 and ART18, respectively. The effects of PSL at a dose of 3 mg/kg body weight, which was begun from day 30, 12 days after the second series of injections, and continued for 50 days, were studied on day 80. There was no significant increase of glomerular T cells or IL-2R+ cells throughout the study. By contrast, each cell group in the interstitium increased in number throughout the disease evolution. Specifically IL-2R+ cells, which were rarely seen before AN + PS injection, were expressed by 5% of total leucocytes on day 80. Ia antigens also increased time-dependently and were found in proximal tubular cells on day 80. PSL treatment suppressed IL-2R and Ia expression in proportion to the decrease of total leucocytes and T cells. These results imply that delayed type hypersensitivity related to the appearance of immune activated T cells (IL-2R+) and MHC class II antigens may play a role in the progression of interstitial lesions and consequent renal dysfunction in a nonimmune-initiated FGS model.

Animals↗
PubMed1994

Suppression of pulmonary injury in experimental 'Goodpasture's syndrome' by deoxyspergualin (DSP).

DSP is a potent immunosuppressive drug which can prevent allograft rejection and suppress acute rejection episodes. In this study, the ability of DSP to suppress pulmonary injury in experimental Goodpasture's syndrome was investigated. Passive accelerated anti-glomerular basement membrane (GBM) disease was induced in rats by priming with rabbit IgG, followed 5 days later by injection of rabbit anti-GBM serum (day 0). Groups of five animals were treated with DSP (5 mg/kg intraperitoneally per day) or saline (untreated) from day 0 until being killed on days 1, 7, 14 or 21. At day 1, both DSP-treated and untreated animals exhibited similar pulmonary haemorrhage, oedema, and prominent perivascular leucocyte infiltration. Untreated animals subsequently developed severe widespread pulmonary damage including granulomatous lesions and extensive fibrosis, which correlated with infiltration of macrophages and immune-activated (IL-2R+) mononuclear cells (P < 0.01). Tumour necrosis factor-alpha (TNF-alpha), a known mediator of acute lung damage, was produced by pulmonary mononuclear cells throughout the experimental course. In contrast, DSP treatment resolved pulmonary haemorrhage, prevented the appearance of granulomatous lesions, and resulted in a histologically normal lung structure by day 21. This improvement was associated with a marked suppression of macrophage infiltration (P < 0.001 versus untreated), accumulation of immune activated (IL-2R+) mononuclear cells (P < 0.01 versus untreated), and TNF-alpha production (P < 0.05 versus untreated). DSP treatment also suppressed the deposition of rat anti-rabbit IgG immunoglobulin and C3 along the alveolar basement membrane (P < 0.05 versus untreated). In conclusion, DSP suppressed pulmonary injury in accelerated anti-GBM disease by acting on the local cellular immune response and the systemic humoral immune response. Further studies are warranted to determine whether this could be a useful drug for the treatment of Goodpasture's syndrome in humans.

Animals↗
PubMed1994

The adequacy of fragmin as a single bolus dose with reused dialyzers.

Thirty-four hemodialysis patients were studied in a crossover fashion to compare the effectiveness of bolus-dose Fragmin (a low molecular weight heparin) with regular heparin usage in hemodialysis. For each anticoagulant, 3 dialyzes were studied for each patient; the first sessions involved a new dialyzer, and the subsequent sessions involved dialyzers reprocessed with peracetic acid. To assess the effectiveness of the anticoagulation regimens, the following were measured: the dialyzer fiber bundle volume and the instantaneous dialyzer clearances for urea (1 h into the second session). In addition, factor Xa levels were measured in 5 patients during the first and second sessions at 0 min, 30 min, and 4 h. Fiber bundle volumes were (in ml) 75.4 +/- 8.8, 73.0 +/- 8.9, and 73.5 +/- 7.6 on first, second, and third uses with Fragmin (p = ns); and 77.8 +/- 9.0, 73.4 +/- 8.1, and 73.8 +/- 8.1 with heparin (p < 0.001 second and third vs. first). Thus, there were no significant differences between Fragmin and heparin. Instantaneous dialyzer clearances were 165.8 +/- 12.6 ml/min with Fragmin and 163.8 +/- 9.8 with heparin (p = ns). Factor Xa levels were 0 predialysis, 0.81 +/- 0.17 U/ml at 30 min on first use, and 0.92 +/- 0.09 U/ml on second use (p = ns); they were 0.51 +/- 0.21 U/ml at 4 h on first use and 0.61 +/- 0.16 U/ml on second use (p = ns). Thus, bolus-dose Fragmin provided similar results to constant infusion heparin and is not deleteriously influenced by reprocessing dialyzers with peracetic acid.

Adult↗
PubMed1994

Suppression of experimental glomerulonephritis by the interleukin-1 receptor antagonist: inhibition of intercellular adhesion molecule-1 expression.

Interleukin-1 is a proinflammatory cytokine produced in glomerulonephritis. Blocking the action of interleukin-1 by the administration of the interleukin-1 receptor antagonist (IL-1ra) has been shown to prevent renal function impairment, reduce glomerular injury, inhibit leukocyte infiltration, and suppress tubulointerstitial damage in experimental antiglomerular basement membrane disease. A key mechanism in the entry of leukocytes into the kidney is the interaction between the interleukin-1 inducible intercellular adhesion molecule-1 (ICAM-1; CD54) and lymphocyte function-associated antigen-1 (CD11a/CD18). Therefore, this study investigated whether the inhibition of this mechanism was the means by which IL-1ra suppressed leukocyte infiltration in rat accelerated antiglomerular basement membrane glomerulonephritis. Disease was induced in two groups of six rats; animals were treated by constant sc infusion of recombinant human IL-1ra or saline from the initiation of disease until being euthanized 14 days later. In saline-treated animals, there was marked up-regulation of ICAM-1 in the glomerulus and interstitium, In which was associated with leukocyte infiltration. In particular, focal accumulation of CD11a+ and CD18+ cells was apparent in areas of tubulointerstitial damage exhibiting intense ICAM-1 expression. IL-1ra treatment partially reduced glomerular ICAM-1 expression and leukocyte infiltration. However, IL-1ra treatment resulted in a dramatic inhibition of interstitial ICAM-1 expression, interstitial leukocyte infiltration, and tubulointerstitial damage. In conclusion, this study has shown that interleukin-1 is a major inducer of ICAM-1 expression within the renal tubulo-interstitium--a process associated with focal leukocyte infiltration and tubulointerstitial damage.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

A sensitive method of non-radioactive in situ hybridization for mRNA localization within human renal biopsy specimens: use of digoxigenin labeled oligonucleotides.

A sensitive method of non-radioactive in situ hybridization using digoxigenin-labeled oligonucleotides is described for the detection of mRNA within human renal biopsy specimens. Although non-radioactive in situ hybridization typically has the drawback of low sensitivity, we increased the sensitivity of this method, providing a practical alternative to the use of radiolabelled probes. The four main points are: 1) assessment of the efficiency of labeling, 2) optimization of the probe concentration for hybridization, 3) requirement of deproteinization of tissues with HCl and proteinase K, and 4) the use of a four-layer immunoperoxidase staining system. This technique was found to clearly localize individual mRNA positive cells within cryostat tissue sections. A variety of controls including sense probes, excess unlabeled anti-sense probes, and RNase-treatment demonstrated the specificity of the technique. This improved method is a powerful technique for detecting mRNA within human renal tissue and will be most useful in the study of gene expression in the pathogenesis of renal diseases.

Actins↗
PubMed1994

Pulmonary expression of ICAM-1 and LFA-1 in experimental Goodpasture's syndrome.

The functional importance of ICAM-1 and its ligands, the beta 2-integrins, in leukocytic accumulation in pulmonary injury has been recently demonstrated in experimental models of lung disease. However, the exact location of these adhesion molecules remains unknown. In the current study we have used immunogold ultrastructural techniques to define the precise location of ICAM-1 in the lung and its interaction with beta 2-integrin expressing leukocytes in the early stages of experimental Goodpasture's (GP) syndrome in the rat. In normal animals there is strong constitutive ICAM-1 expression on the luminal surface of the alveolar epithelium that is confined to type I cells and completely absent from type II cells. Constitutive expression of ICAM-1 on the pulmonary capillary endothelium is comparatively weak. In GP syndrome there is an increase in ICAM-1 expression, which is still confined to the alveolar type I epithelial cells and capillary endothelium. This is associated with an early (1.5 hours) influx of CD18 expressing polymorphonuclear leukocytes, which are seen migrating into alveoli and the pulmonary interstitium. There is a later (6-12 hours) influx of CD11a/CD18 expressing macrophages which are present in the interstitium and in large numbers in the alveolar spaces, where they are very closely apposed to and adherent to the alveolar epithelium. This is the first study to demonstrate the precise ultrastructural location of ICAM-1 in the normal rat lung and in disease. In vivo administered antibody to ICAM-1 gains access to the extravascular sites within the lung, in particular the surface of alveolar type I epithelial cells, and this raises the possibility that beneficial effects of such antibodies may extend beyond their ability to inhibit interactions between leukocytes and endothelial cells.

Animals↗
PubMed1994

Prevalence of HPV DNA in cervical specimens in women with renal transplants: a comparison with dialysis-dependent patients and patients with renal impairment.

The aim of this study was to assess the prevalence of human papillomavirus (HPV) DNA in women who had received a renal transplant and to compare this with two control groups. Women who had a functioning renal transplant for greater than 6 months (n = 69) were compared with women on maintenance dialysis (n = 89) and women with impaired renal function (creatinine 0.15-0.39 mmol/l) (n = 22). Women were excluded if they had had a hysterectomy, were older than 65 years, or were not yet sexually active. A questionnaire and cervical scrape were obtained from each participant. The cervical scrape was analysed for HPV DNA using PCR and the L1 consensus primers. The participation rate of transplant patients, dialysis patients and those with impaired renal function ('normal' group) was 69, 68, and 78% respectively. The characteristics of the three groups of women at enrollment were similar. No cytological abnormalities were present in the 'normal' population but 11 of 89 patients on maintenance dialysis and nine of 69 transplant patients had cytological abnormalities of atypia or greater (P = 0.08 and P = 0.07, for 'normal' compared to dialysis and transplant groups respectively). One (4.5%) of the 'normal' women had evidence of HPV DNA, while 18 (20%) of patients on maintenance dialysis and 15 (22%) of transplant patients were positive (P = 0.07 and P = 0.05, for 'normal' compared to dialysis and transplant groups respectively). This study suggests that not only transplant recipients but also dialysis patients may have a higher prevalence of risk factors (cytological abnormalities and HPV DNA) for the development of cervical cancer.

Adult↗
PubMed1994

Macrophages in renal injury.

There is good evidence from experimental studies that glomerular macrophages are important in acute renal injury and an increasing acceptance that they also play a role in chronic glomerular injury by stimulating mesangial cell proliferation and glomerulosclerosis. However, it is now evident that the contribution of macrophages and T cells within the interstitium must be taken into account. Indeed, if it is proved that progressive renal injury occurs via interstitial DTH mechanisms, regardless of the nature of the initial glomerular insult, then such mechanisms may provide a suitable target for the development of novel therapeutic strategies.

Animals↗
PubMed1993

Suppression of experimental crescentic glomerulonephritis by the interleukin-1 receptor antagonist.

The role of interleukin-1 (IL-1) in the pathogenesis of experimental crescentic glomerulonephritis was investigated. Administration of the interleukin-1 receptor antagonist (IL-1ra) was used to block the action of IL-1 during disease development. Two groups of six rats were primed with rabbit IgG, followed five days later by injection of rabbit anti-GBM serum (day 0). Animals were treated with a constant infusion of recombinant human IL-1ra (plasma level approximately 100 to 200 ng/ml) or saline (untreated) from day -1 until being killed on day 14. Untreated animals exhibited severe proteinuria and development renal dysfunction shown by increased serum urea and serum creatinine and reduced creatinine clearance. In contrast, IL-1ra treated animals had significantly reduced proteinuria (IL-1ra vs. untreated, P < 0.05) and maintained normal renal function (IL-1ra vs. untreated, P < 0.05). Histologically, IL-1ra treatment markedly reduced glomerular hypercellularity, glomerular necrosis and crescent formation and almost completely abrogated tubular atrophy and fibrosis. IL-1ra treatment suppressed glomerular macrophage accumulation by 57% (P < 0.01), while macrophage accumulation in the interstitium was completely abrogated and immune activation of the interstitial T cell infiltrate was prevented. This study demonstrates that IL-1 plays a key role in the pathogenesis of anti-GBM glomerulonephritis, and blocking its effects may provide a novel therapeutic approach to the treatment of human progressive glomerulonephritis.

Animals↗
PubMed1993

Delineation of pulmonary alveolar macrophage subpopulations by flow cytometry in normal subjects and in patients with lung cancer.

We have previously described alterations in pulmonary alveolar macrophage (PAM) function in patients with lung cancer when compared with control subjects. This study examined PAM from five patients with lung cancer, seven normal volunteers and nine control patients, to assess whether any differences in surface phenotypic markers were present in lung cancer versus non-cancer subjects, and what changes might be induced with interferon-gamma (IFN-gamma) stimulation. After 3 days' culture with or without IFN-gamma no differences were seen in the percentages of cells staining positively in each group for HLA class I, class II and ICAM-1 (CD54) antigens. However, in 13 out of 14 control subjects, and only one out of the five cancer subjects, dual PAM populations were identified. The second PAM population (PAM-2) was larger and demonstrated a higher expression of class I and ICAM-1 antigens. Unlike the unfractionated PAM population, PAM-2 consistently responded to IFN-gamma stimulation with an increase in both class I (90 +/- 25%) and ICAM-1 (45 +/- 10%) antigens, while there was no change in class II antigen expression. In three subjects PAM-2 was found to induce a significantly greater mitogen response than the rest of the PAM population. If confirmed in a larger group of patients, the absence of PAM-2 in the majority of patients with lung cancer may underlie the functional PAM defects observed in these patients.

Adult↗
PubMed1993

Trafficking of inflammatory macrophages from the kidney to draining lymph nodes during experimental glomerulonephritis.

Macrophage accumulation within the glomerulus and renal interstitium is a prominent feature of most forms of glomerulonephritis, but the fate of these inflammatory cells is unknown. Macrophage trafficking to the draining kidney lymph nodes (KLN) was assessed in a detailed kinetic analysis of accelerated antiglomerular basement membrane (GBM) disease in the rat. Leucocytes draining to KLN via lymphatic vessels were identified within the marginal sinus by MoAb labelling of tissue sections. In anti-GBM disease, there was a significant increase in the weight of the KLN due to both lymphoproliferation within the nodes and increased lymphatic drainage from the inflamed kidney, as evidenced by prominent dilation of the marginal sinus and increased numbers of cells within the sinus. In non-inflamed lymph nodes, few ED1+ macrophages were present within the marginal sinus (3.0 +/- 0.6/100 nucleated cells). However, in anti-GBM disease, macrophages became the major cell type within the dilated marginal sinus of the KLN, as shown by labelling with ED1, ED2 and ED3 MoAbs, peaking at 74 +/- 2.6 ED1+ cells/100 nucleated cells at day 14. These changes were not simply due to systemic antigen administration, since in the axillary lymph node (ALN) there was no obvious dilation of the marginal sinus and macrophages accounted for a maximum of only 15 +/- 4.6 ED1+ cells/100 nucleated cells. In conclusion, this study provides indirect evidence that there is significant trafficking of the renal macrophage infiltrate to the KLN during experimental glomerulonephritis. This may be a mechanism whereby nephritogenic antigens, released as a consequence of the local inflammatory response, may be presented to T and B lymphocytes within lymph nodes, resulting in the amplification of the immune response in glomerulonephritis.

Animals↗