Extensive crescent formation with antifibrinolytic therapy in a case of diffuse endocapillary glomerulonephritis.
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Acute Disease↗
Biomedical subjects
V Cattell
Publications and source records attributed to V Cattell.
Prostaglandin E1 suppresses macrophage infiltration and ameliorates injury in an experimental model of macrophage-dependent glomerulonephritis.
Prostaglandin E1 (PGE1) suppresses macrophage infiltration and ameliorates injury in an experimental model of macrophage dependent glomerulonephritis. Macrophages are mediators of glomerular injury in models of proliferative glomerulonephritis. We have recently shown that macrophages in glomerulonephritis have low prostaglandin E2 (PGE) generation, and other evidence implicates eicosanoids as regulators of macrophage activation. Here we have studied in rats the effect of 15(s)-15-methyl PGE1 (M-PGE1) on accelerated nephrotoxic nephritis, a model of acute macrophage-dependent glomerular injury. M-PGE1 ameliorated proteinuria (day 4; 61 +/- 13 mg/24 h, n = 9; vehicle treated, 164 +/- 17 mg/24 h, n = 11; P less than 0.002) and glomerular hypercellularity; quantification of infiltrating macrophages by isolating glomerular cells showed reduction in the numbers of macrophages (44 +/- 9/glomerulus; vehicle treated, 119 +/- 15/glomerulus; P less than 0.02) with inhibition of Ia antigen expression on infiltrating macrophages (8 +/- 5%; vehicle treated 25 +/- 4% P less than 0.05). Glomerular binding of nephrotoxic globulin and levels of autologous antibodies were not affected by M-PGE1. Thus the mechanism of suppression involves inhibition of macrophage accumulation and activation. M-PGE1 administered to normal rats did not affect numbers of resident leucocytes (12.6 +/- 1.5/glomerulus; vehicle treated, 13.2 +/- 1.3/glomerulus) or alter Ia antigen expression (4.1 +/- 0.2 Ia + cells/glomerulus; vehicle treated, 3.9 +/- 0.6/glomerulus). This study suggests a therapeutic role for PGE1 in this type of glomerulonephritis, and has implications for the pathophysiology of macrophage-mediated inflammation.
Alprostadil↗
Functional characteristics of macrophages in glomerulonephritis in the rat. O2- generation, MHC class II expression, and eicosanoid synthesis.
Macrophage infiltration is important in the pathogenesis of acute proliferative glomerulonephritis (gn). The state of activation of macrophages during gn may be central to their role in injury. To study this, a method for extracting macrophages from nephritic glomeruli in active in situ gn was developed. MHC Class II (Ia) antigen expression, superoxide (O2-) generation, and eicosanoid synthesis were compared with thioglycollate elicited peritoneal macrophages (TEM). At the height of inflammation there were 407 +/- 83 macrophages/glomerulus. Compared with TEM, Ia expression, and in vitro production of O2- were enhanced. Synthesis of prostaglandin E2 was greatly reduced (day 6 gn, 62 +/- 10 ng/mg; TEM 663 +/- 128 ng/mg cell protein). Thromboxane synthesis was relatively conserved (day 6 gn, 109 +/- 28 ng/mg; TEM 201 +/- 53 ng/mg). Leukotriene B4 (LTB4) was undetectable (day 6 gn, less than 13 ng/mg; TEM 119 +/- 56 ng/mg). This large influx of activated macrophages in glomeruli may be fundamental to pathogenesis of glomerular inflammation.
Animals↗
The origin of Ia antigen-expressing cells in the rat kidney.
The lineage of Ia antigen expressing (Ia+) cells that have been detected in the parenchyma and interstitium of the rat kidney has not been defined. The authors have studied the origins of Ia+ cells in chimeric rats using monoclonal antibodies to define cells of bone marrow and parenchymal origin. PVGc RTI rats (recipients) received intravenously 2 X 10(6) bone marrow cells from F1 hybrid PVG RTIc/RTIu rats (donors) 1 day after 1000 rads whole body irradiation. Ia chimerism was monitored in blood and isolated glomeruli by immunofluorescence and in frozen sections by immunoperoxidase, using monoclonal antibodies MRC OX3 (anti-Ia RTIu), MRC OX4 (anti-RTIc and u), and MRC OXI (anti-rat leukocyte common antigen). In normal F1 hybrid kidneys, glomerular cell counts were as follows: OXI+, 7.19 +/- 0.23/gl; OX4+, 3.03 +/- 0.14; OX3+, 2.34 +/- 0.1 (76% detectable expression of RTIu). OXI+, OX4+, and OX3+ cells were codistributed in cells in the interstitium between renal tubules. Proximal tubules were weakly OX4+, OX3+. In chimeric rats 5 days after irradiation, blood leukocytes, and renal OX1+ and OX4+ cells were depleted; OX3+ cells were not detected; by 4 weeks blood leukocytes were restored to normal numbers, and 85% of Ia+ cells were OX3+. By 6 weeks OXI+ and OX4+ cells were restored in glomeruli and interstitium, with increasing expression of OX3+ cells; at 10 weeks 75% of glomerular Ia+ cells were OX3+ (equivalent to detectable level of OX3+ cells in normal F1 hybrids) and OX1+, OX4+, and OX3+ cells appeared in equivalent numbers in the interstitium. Groups of proximal tubules were OX4+ and OX3-. These results in established bone marrow chimeras show that in the normal rat kidney bone marrow derived leukocytes expressing Ia antigen are present in the glomerulus and interstitium. Ia antigen is also expressed on some proximal tubular cells. There is no evidence for endothelial Ia positivity.
Animals↗
Leukotriene B4 production in normal rat glomeruli.
The production of the lipoxygenase metabolite of arachidonic acid, leukotriene B4 (LTB4) by normal rat glomeruli has been studied. Isolated glomeruli from saline-perfused rat kidneys were incubated in Kreb's buffer for 15 min at 37 degrees C. The concentrations of LTB4 and other eicosanoids in cell-free supernatants were determined by direct radioimmunoassays (RIA). Mean basal syntheses of eicosanoids were: thromboxane B2 (TXB2) 0.77 +/- 0.13, prostaglandin (PG) E2 0.40 +/- 0.05, 6-keto-PGF1 alpha 0.38 +/- 0.06 ng/mg glomerular protein (mean +/- SEM n = 8). In these assays immunoreactive LTB4 synthesis was 0.12 +/- 0.02 ng/mg. In samples incubated with BW755C, 50 micrograms/ml, an inhibitor of arachidonate metabolism via both the cyclo-oxygenase and lipoxygenase pathways, there was more than 80% inhibition of the synthesis of TXB2, PGE2 and 6-keto-PGF1 alpha. However, immunoreactive LTB4 was only reduced by 44%, suggesting the presence of other materials which cross-react in the RIA. The presence of authentic LTB4 in the supernatants was confirmed after extraction and high-pressure liquid chromatography (HPLC). This material represented 25% of the original material detected by RIA. Although the physiological role of LTB4 in the normal state is unknown, its chemotactic activity may be of great significance during glomerular inflammation.
Animals↗
Isolation and characterization of inflammatory leukocytes from glomeruli in an in situ model of glomerulonephritis in the rat.
Inflammatory cell populations in glomerulonephritis (GN) are not well characterized. A method is reported for isolating leukocytes from glomeruli. GN was induced in rats by perfusing left kidneys (LKs) with cationized human IgG followed by intravenous rat anti-human IgG serum. Acute GN developed in LKs with proteinuria, deposition of human and rat IgG and C3, leukocyte infiltration, and capillary wall electron-dense deposits. Glomeruli (GL) isolated at 24 hours were digested with collagenase, trypsin, and DNase, and the resulting cells were as follows (mean +/- SEM): LK, 354 +/- 25/GL; RK, 214 +/- 32/GL. Cells were labeled with monoclonal antibody MRCOX1 (anti-rat leukocyte common [LC] antigen) followed by FITC F(ab')2 rabbit anti-mouse Ig: LK, 170 +/- 11 leukocytes/GL;RK, 8 +/- 2 leukocytes/GL (P less than 0.001). Isolated cells were sorted by flow cytometry to 98% pure LC+ cells with greater than 80% viability (Giemsa staining: 86% mononuclear cells, 14% neutrophils); the ultrastructure was that of maturing macrophages and neutrophils. This method quantitates leukocyte infiltration and provides leukocytes from nephritic glomeruli suitable for in vitro studies.
Animals↗
Canine chronic renal disease: prevalence and types of glomerulonephritis in the dog.
In a prospective survey, one hundred and eleven dogs with canine chronic renal disease, presenting to 24 veterinary practices in East Anglia and the West Midlands (geographical area 8,600 square miles) were identified. More than 20 different breeds were represented. In 76 cases, clinical details, blood and urine biochemistry, serology and kidney tissue for light and electron microscopy, and immunohistochemistry were obtained. Forty (52%) had glomerular (GN) and 36 (48%) non-glomerular (NGN) disease. Types of GN identified were (W.H.O. classification, number of cases in brackets): focal glomerulonephritis (gn) (5), diffuse mesangial proliferative gn (8), diffuse endocapillary proliferative gn (2), mesangiocapillary gn type I (8), diffuse crescentic gn (1), diffuse sclerosing gn (7), amyloid (6), unclassifiable gn (3). Eight dogs with GN and 13 with NGN had extra-renal lesions. In only one GN case (bacterial endocarditis) was the etiology clear. Proteinuria, but not age, breed, sex, serum creatinine or hematuria, discriminated between GN and NGN groups. This prospective survey identifies GN, with morphological types as found in humans, as a common cause of canine chronic renal disease.
Amyloidosis↗
Effect of a thromboxane synthetase inhibitor on eicosanoid synthesis and glomerular injury during acute unilateral glomerulonephritis in the rat.
Eicosanoid synthesis was studied in a model of in situ glomerulonephritis (gn) in the rat. Unilateral gn was induced by perfusion of left kidneys with 200 micrograms cationized human IgG followed by intravenous (i.v.) autologous anti-human IgG antiserum. Rats developed proteinuria in the first 24 hours and hypercellular gn with leukocyte infiltration in the left kidney. Synthesis of thromboxane B2 (TXB2), prostaglandin E2 (PGE2) and 6-ketoprostaglandin F 1 alpha(6-keto-PGF 1 alpha) was measured at 6, 12, 18 and 24 hours in isolated glomeruli by radioimmunoassay. In nephritic glomeruli there was a nine-fold rise in TXB2 at six hours (5.35 ng/mg glomerular protein) when compared to control (0.6 ng/mg). TXB2 was still elevated at 24 hours (2.7 +/- 1 ng/mg; control 0.7 +/- 0.2 ng/mg). There were no consistent changes in PGE2 or 6-keto-PGF 1 alpha. No changes were found in right kidneys of nephritic or control rats. Treatment of nephritic rats with a selective thromboxane synthetase inhibitor, dazmegrel (20 mg/kg 8 hourly intraperitoneally), suppressed glomerular TXB2 at 24 hours. TXB2 was also inhibited in right (non-nephritic) kidneys and serum. Dazmegrel did not inhibit proteinuria or glomerular hypercellularity. We conclude there is a major increase in glomerular TXB2 in this model which does not play an essential role in the development of proteinuria or cellular infiltration.
6-Ketoprostaglandin F1 alpha↗
In vivo induction of Ia antigen in resident leukocytes in the normal rat renal glomerulus.
The normal rat glomerulus contains a mesangial population of mononuclear leukocytes, 35 to 70% of which express class II major histocompatibility complex antigen (equivalent to mouse Ia) Schreiner GF, Unanue ER: Lab Invest 51:515, 1984. Inducing factors for cellular expression of class II antigens in normal leukocytes are unknown. In this population, glomerular leukocyte origin and Ia expression have been studied in kidneys from bone marrow-irradiated Lewis rats transplanted into normal syngeneic recipients. Leukocytes (LC+) and Ia positive (Ia+) cells were enumerated in isolated glomeruli by immunofluorescence using monoclonal antibodies to rat common leukocyte antigen (MRC OX1) and rat Ia antigen (MRC OX3, and OX4). Irradiation to donors caused extreme depletion of glomerular LC+ cells. Twenty-four hours after renal transplantation into normal recipients the glomerular LC+ population was restored to 65% of normal, and by 3 days was complete. In contrast Ia+ cells which were also depleted by irradiation, remained low 24 hours post-transplantation and only reached normal levels after 4 days. Thus, Ia antigen expression is induced in a population of leukocytes derived from circulating mononuclear leukocytes after a residence time of 3 to 4 days in the glomerulus. While the glomerular factors responsible are unknown, these experiments provide the first evidence for in vivo basal Ia induction in a normal resident mononuclear leukocyte population.
Animals↗
Methods of identification of macrophages in tissues.
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Acid Phosphatase↗
Blood leucocyte infiltration after intravenous injection of ferritin in the rat.
Monocytes infiltrate glomeruli during mesangial deposition of ferritin, and during experimental glomerulonephritis. To determine whether this is solely a local phenomenon, leucocyte infiltration in other organs has been studied following intravenous ferritin injection. Lewis rats received an i.v. injection of 150 mg ferritin/100 g body weight. At 24 h there was a peripheral blood leucocytosis (ferritin-treated rats 26.32 +/- 13.7, control rats 8.54 +/- 2.41 X 10(6) cells/ml) due to increase in polymorphs and monocytes. Bone marrow cell counts fell (ferritin-treated rats 49 +/- 7, control 80 +/- 11 X 10(6)/100 g body weight). Cell counts on cell suspensions of perfused, enzyme-digested lung, liver and spleen, and lung lavage showed major significant increases in total cell counts: lung 250 +/- 36 (89 +/- 16), lung lavage 2.6 +/- 0.8 (1.4 +/- 0.5), liver 140 +/- 37 (60 +/- 11), spleen 306 +/- 38 (200 +/- 27) X 10(6)/100 g body weight (control values in parentheses). Cytospin preparations of these suspensions, stained for non-specific esterase showed that the increase in cell numbers was due to increases in non-specific esterase-positive cells (monocytes) and polymorphs. These results demonstrate a generalized leucocyte mobilization, sequestration, and tissue infiltration after i.v. ferritin. The renal glomerulus therefore is not the only site of leucocyte accumulation. These findings may have relevance for studies on inflammation mediated by leucocytes in models of experimental immune complex glomerulonephritis.
Animals↗
Mitomycin-induced hemolytic uremic kidney. An experimental model in the rat.
Hemolytic uremic syndrome (HUS) reported in some patients treated for cancer with mitomycin is of unknown pathogenesis, and evidence implicating mitomycin is inconclusive. To determine whether mitomycin can induce direct renal damage, left kidneys in Lewis rats were perfused with mitomycin (60-4000 micrograms). Control rats received perfusions of saline only. Renal tissue was examined from 1 hour up to 1 month later. In 29 of 31 rats left renal disease developed: in 9 (mitomycin, 1000-4000 micrograms), severe cortical infarction; in 20 (mitomycin, 60-500 micrograms), lesions indistinguishable from human HUS. Glomerular endothelial damage was the earliest detectable abnormality, followed by platelet accumulation and later capillary wall splitting typical of microangiopathy. Some kidneys had interlobular artery necrosis and thrombosis. Right kidneys were normal. In no rats in the control group (10) did HUS develop. Thus, mitomycin directly produced renal lesions indistinguishable from human HUS, which suggested a mechanism for injury seen in mitomycin-treated patients and provided a new model of HUS.
Animals↗
The role of platelets in mesangial localization: carbon uptake in thrombocytopenic rats.
The role of platelets in mesangial localization has been studied in Lewis rats following a single intravenous injection of colloidal carbon 32 mg/100 g body weight. Following carbon injection there was an abrupt thrombocytopenia (peripheral platelet count at 10 min 165 +/- 107 X 10(3)/mm3). Temporary sequestration of platelets in lung, liver and spleen was demonstrated using quinacrine-labelled platelets. Carbon was quantitated in blood, lung, liver and spleen by digestion and spectrophotometry and in glomerular mesangium by particle counting of histological sections under oil-immersion microscopy. In thrombocytopenic rats (busulphan 17.5 mg/kg weight) blood carbon levels (up to 1 h after injection) were higher than normal controls (P less than 0.01) and mesangial carbon content at 24 h was significantly increased (P less than 0.01). No significant alteration in mononuclear phagocytic function was detected at 24 h. In platelet-restored thrombocytopenic rats, (busulphan-treated, infused with homologous platelets) blood and mesangial carbon levels were decreased towards normal values. These findings show that (1) platelets are involved in the initial removal of carbon from the blood (2) mesangial localization is related to blood levels and (3) platelet numbers affect both these parameters. The finding of increased mesangial deposition in thrombocytopenic rats may have significance for immune complex glomerulonephritis where platelet numbers may be low due to persistent platelet activation.
Animals↗
Ferritin deposition in the glomerular deposits of focal glomerular sclerosis in the rat.
The glomerular lesions of focal sclerosis clinically associated with a steroid-resistant nephrotic syndrome, are of unknown origin. IgM and C3 deposits and electron dense material found in areas of sclerosis are not convincing evidence of an immune pathogenesis. These deposits have been studied in a rat model of focal sclerosis induced by uninephrectomy and repeated aminonucleoside administration. Sclerotic lesions closely resembling human disease developed in the remaining kidney. There was a severe progressive proteinuria. Seventy-eight days after initial aminonucleoside injection 65 per cent of glomeruli were sclerotic with IgM, IgG, C3 and fibrinogen deposits, and electron dense deposits by electron microscopy. To study macromolecule in this model of focal sclerosis, ferritin uptake 4 and 24 h after intravenous ferritin given at 77 days was compared in focal sclerosis rats with control rats without sclerosis (uninephrectomy plus saline-only injections). In focal sclerosis rats sclerotic areas contained massive accumulations of ferritin. In unaffected segments of sclerotic glomeruli, and normal glomeruli of focal sclerosis rats, ferritin concentration was no different from controls. Abnormal ferritin trapping in areas of sclerosis suggests that the presence of IgM and C3 may be due to a similar mechanism, and is not indicative of an immune pathogenesis for focal sclerosis.
Animals↗
Monocyte infiltration in human glomerulonephritis: alpha-1-antitrypsin as a marker for mononuclear phagocytes in renal biopsies.
Alpha-1-antitrypsin detected by immunoperoxidase has been used as a marker for infiltrating monocytes on formalin-fixed, paraffin-embedded sections of 75 renal biopsies. Patients were classified on the basis of glomerular hypercellularity on light microscopy. Monocytes increased with increasing glomerular hypercellularity, most being in diffuse proliferative GN (DPGN) and severe mesangiocapillary GN (MCGN-S). Monocytes were reduced by 48-95% in repeat biopsies of DPGN, mesangial proliferative GN and focal GN, but not in MCGN. In electron micrographs (70 biopsies) monocytes were identified but less frequently than by alpha-1-antitrypsin. Highest numbers were found with subepithelial or subendothelial deposits and lowest numbers in biopsies without deposits. The results show monocytes are detectable in human proliferative GN, numbers increasing with increasing glomerular hypercellularity, and subendothelial and subepithelial deposits.
Biopsy, Needle↗
Uptake and clearance of ferritin by the glomerular mesangium. I. Phagocytosis by mesangial cells and blood monocytes.
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Animals↗
The origin of proliferating cells in the glomerulus and Bowman's capsule in nephrotoxic serum nephritis: effects of unilateral renal irradiation.
The origin of proliferating cells in glomeruli and Bowman's capsules during nephrotoxic nephritis (NTN) in rabbits was studied, using unilateral renal irradiation to suppress glomerular cell division. Left (LI) kidneys received 2400-12,000 rad on Days 1-5 after i.v. nephrotoxic serum (NTS) 1 or 1.5 ml/kg body wt. Renal histology, cell labelling 1 h after a pulse of tritiated thymidine (H3T) (0.5 mCi/kg), and mitotic rate were compared in right non-irradiated (RO) kidneys and LI kidneys. Differences in H3T uptake were not significantly suppressed (P less than 0.05) by 4800 rad whereas mitoses in glomeruli and Bowman's capsule were not. Glomerular hypercellularity and crescents were equivalent in LI given 4800 rad and in RO kidneys, but fibrin deposition was increased 2-fold in LI kidneys. In control rabbits (no NTS) LI kidneys showed no histological changes. The results suggest that most dividing cells detected in glomeruli and Bowman's space in NTN are monocytes, and that these cells form a large component of crescents.
Animals↗
Quinacrine mustard: a fluorescent platelet label. In vitro studies and in vivo localisation in Habu venom glomerulonephritis in rats.
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Animals↗