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Biomedical subjects

N W Boyce

Publications and source records attributed to N W Boyce.

At least 37 records · Page 2Linked to original sources
PubMed1988

Tubular antigen-associated renal disease in New Zealand white rabbits. II. Investigation of mediators of glomerular injury: localization and characterization of the glomerular capillary wall antigen.

Mediation of the glomerular lesion and proteinuria produced by sheep antirabbit F x 1A globulin (SAFG) in rabbits was examined by prior treatment with cobra venom factor and nitrogen mustard. SAFG binding and proteinuria at 24 h were independent of complement or leucocytes but dose dependent. SAFG reacted by immunoblot with a wide range of antigens in deoxycholate extracts of rabbit glomeruli and autologous F x 1A including eight prominent shared bands of 29-128 kd. Immunogold electron microscopy has revealed the in vivo glomerular binding of SAFG as discrete, nonlinear and predominantly within the laminae rarae, in association with epithelial and particularly endothelial components of the glomerular capillary wall. In vitro binding was prominent on the endothelium. Proteinuria in this model is mediated by antibody without requirement for complement or leucocytes. The putative antigen(s) is/are associated with components of the glomerular capillary wall which share epitopes with autologous tubular F x 1A. This model is an example of an in situ immune complex glomerular nephritis and is distinct from the classical anti-F x 1A model, passive Heymann's nephritis in the rat.

Animals↗
PubMed1988

A new experimental model of in-situ immune complex disease of the lung.

A model of acute immunological lung injury, initiated by the binding of passively administered antibody to an antigen (Concanavalin A (Con A] affixed to the pulmonary endothelium, is described. Pulmonary injury, monitored using the 125I-albumin lung permeability index (LPI) did not occur with antigen deposition alone (LPI 0.235 +/- 0.012). The binding of antibody to the 'planted' lung antigen resulted in injury only when antibody binding exceeded a threshold value of 7.4 +/- 1.4 micrograms antibody globulin per gram of lung. Alevolar-capillary permeability changes were maximal 4 to 8 h after antigen-antibody interaction (LPI at 2 h, 0.353 +/- 0.015: at 4 h, 0.387 +0.33; at 8 h, 0.373 +/- 0.025; at 24 h, 0.289 +/- 0.031; at 48 h, 0.239 +/- 0.022). Lung injury was significantly attenuated by neutrophil (PMN) depletion (LPI at 4 h, 0.325 +/- 0.014: P less than 0.01cf PMN-intact animals), and further reduced by complement depletion (LPI at 4 h, 0.275 +/- 0.023: P less than 0.05 cf PMN-intact and PMN-deplete animals). This model of immune lung injury demonstrates the potential for in situ immune reactions on the pulmonary endothelial surface to induce acute inflammatory injury. Further the model illustrates the cooperative effects of neutrophils and complement in the genesis of inflammation, with both these mediator systems contributing to immunological pulmonary injury.

Acute Disease↗
PubMed1988

Alveolar macrophage procoagulant activity is increased in acute hyperoxic lung injury.

Alveolar macrophage accumulation and interstitial fibrin deposition are prominent in adult respiratory distress syndrome and chronic interstitial lung diseases. The role of alveolar macrophages in the initiation of fibrin deposition and lung injury in these diseases is uncertain. Expression of procoagulant activity by these cells may provide evidence of macrophage activation and involvement in the initiation of lung fibrin deposition. An experimental model of hyperoxia-induced lung injury in rats was studied for assessment of the relationship of lung injury, fibrin deposition, and alveolar macrophage procoagulant activity. Lung injury was assessed histologically and functionally, and the accumulation of inflammatory cells was quantified by bronchoalveolar lavage. Pulmonary injury, manifested by increased capillary permeability, developed progressively during exposure to hyperoxia and was associated with significant augmentation of the procoagulant activity of alveolar macrophages early in the disease. This increase preceded the accumulation of polymorphonuclear leukocytes. Alveolar macrophage procoagulant activity had functional characteristics consistent with tissue factor. These studies provide evidence of early alveolar macrophage activation in acute hyperoxic lung injury in rats and suggest a role for procoagulant activity in the development of interstitial fibrin deposition.

Animals↗
PubMed1987

Intrarenal hemodynamic alterations induced by anti-GBM antibody.

An isolated perfused kidney system (IPK) was used to study the direct intrarenal hemodynamic effects of binding of anti-glomerular-basement membrane (anti-GBM) antibody in the absence of all other circulating humoral and cellular inflammatory mediators. Control IPK's (perfused with Krebs-Henseleit buffered 5% albumin solution containing non-immune globulin) had a renal vascular resistance (RVR) mean +/- SEM 3.10 +/- 0.47 mm Hg/ml/min and a GFR mean +/- SEM 0.63 +/- 0.8 ml/min/g. Anti-GBM antibody administration raised RVR (4.83 +/- 0.52 mm Hg/ml/min, P less than 0.01) and lowered GFR (0.34 +/- 0.04 ml/min/g, P less than 0.01). Perfusate renin activity was higher after antibody administration (684 +/- 87 ng AI/ml/hr compared with control 308 +/- 42 ngAI/ml/hr, P less than 0.01). Treatment with Sar1Ala8All (3 X 10(-6) M) or captopril (10 mg/ml) attenuated antibody-induced vasoconstriction (RVR mm Hg/ml/min, Sara1Ala8All = 3.78 +/- 0.13 captopril = 3.26 +/- 0.12, both P less than 0.05 compared with anti-GBM alone). Both inhibitors of the renin-angiotensin system (RAS) also aggrevated the decline in GFR seen after antibody administration (GFR ml/min/g, Sara1Ala8All = 0.24 +/- 0.05, Captopril = 0.18 +/- 0.03, both P less than 0.05 compared with anti-GBM alone). These IPK studies demonstrate that anti-GBM antibody itself may directly induce intrarenal hemodynamic alterations in the absence of complement activation, neutrophil infiltration, neural influences or circulating vasoactive substances. The results from perfusate renin sampling and blockade of the RAS provide evidence that anti-GBM antibody deposition activates the intrarenal RAS and thereby induces significant hemodynamic alterations.

Animals↗
PubMed1987

Quantitation of intraglomerular mononuclear phagocytes in experimental glomerulonephritis in the rat using specific monoclonal antibodies.

Intraglomerular mononuclear phagocytes were quantitated, in normal Sprague-Dawley rats and in animals with diffuse proliferative glomerulonephritis, using recently described specific monoclonal antibodies (ED1, ED2, ED3) and a 4-layer immunoperoxidase technique. Results obtained with the immunoperoxidase technique were compared with estimates of glomerular mononuclear cellularity based upon glomerular histochemistry and glomerular cell culture. Normal animals (n = 12) had no significant glomerular mononuclear phagocyte population by immunoperoxidase [0.01 macrophages per glomerular cross section (MO/gcs)], histochemistry (+0.2 +/- 0.1 staining intensity) or glomerular cell culture [0.10 +/- 0.02 MO/glomerulus (MO/glom)]. Evolution of diffuse proliferative glomerulonephritis was associated with a progressive rise in glomerular mononuclear phagocyte infiltration using all three techniques. Immunoperoxidase staining (ED1) at the time of maximal macrophage infiltration of glomeruli revealed 6.21 +/- 1.78 MO/gcs (n = 12) using the ED1 macrophage marker. This correlated with histochemical (+3.8 +/- 0.2 staining intensity) and glomerular cell culture (17.6 +/- 4.5 MO/glom) estimates of the glomerular mononuclear phagocyte population. In addition, significant numbers of intraglomerular monocytes possessed the ED2 and ED3 macrophage differentiation antigens (0.82 +/- 0.41 and 0.24 +/- 0.15 MO/gcs respectively). Thus these specific monoclonal antibodies provide a reliable and readily reproducible means for the quantitation of intraglomerular mononuclear phagocytes. In addition, they provide evidence for intraglomerular macrophage differentiation in experimental glomerulonephritis in the rat.

Animals↗
PubMed1987

Modulation of normobaric pulmonary oxygen toxicity by hydroxyl radical inhibition.

The effects of hydroxyl radical inhibition on an experimental model of normobaric pulmonary oxygen toxicity have been studied. The metal ion chelator, desferrioxamine (which inhibits hydroxyl-radical generation) or the hydroxyl-radical scavenger, dimethylthiourea (DMTU), were administered in an attempt to block hydroxyl-radical-mediated tissue injury. Lung injury was monitored in Sprague-Dawley rats by examining lung histology and bronchoalveolar lavage and by assessing pulmonary capillary permeability using the 125I-albumin lung permeability index and the lung weight:body weight ratio. Control animals had lung permeability indices 0.183 +/- 0.005 and lung weight to body weight ratio of 4.50 +/- 0.10 (all as mean +/- SEM). With increased duration of exposure to hyperoxia, there was a progressive increase in pulmonary inflammation, with thickening of alveolar membranes and atelectasis and a progressive increase in lung permeability indices (0.434 +/- 0.088 at 24 hrs; 0.954 +/- 0.165 at 48 hrs; and 1.55 +/- 0.214 at 60 hrs); and lung weight to body weight ratio (5.28 +/- 0.11 at 24 hrs; 6.54 +/- 0.23 at 48 hrs; and 8.91 +/- 0.51 at 60 hrs). Treatment with desferrioxamine provided significant protection from lung injury after 24 hrs of hyperoxia (eg., lung permeability indices 0.250 +/- 0.018; lung weight to body weight ratio 4.68 +/- 0.14, both p less than 0.025; cf. 24-hr hyperoxia controls) but no reduction in pulmonary injury was observed after 48 and 60 hrs of hyperoxia exposure.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

Evidence for direct renal injury as a consequence of glomerular complement activation.

An isolated perfused kidney (IPK) preparation was used to study the functional consequences of antibody-initiated glomerular complement activation in an environment devoid of circulating inflammatory cells. Control IPK, with antibody bound to the glomerular basement membrane (GBM) (mean +/- SEM, 165.0 +/- 5.7 micrograms globulin/g renal cortex), were perfused with a 5% albumin solution. Control urinary protein excretion was 0.306 +/- 0.112 mg/min, renal vascular resistance (RVR) was 4.72 +/- 0.69 mgHg/ml/min, and the glomerular filtration rate (GFR) was 0.41 +/- 0.01 ml/min/g. To produce glomerular complement activation, IPK with equal quantities of bound antibody (167.0 +/- 6.1 micrograms/g) were perfused with fresh plasma. Glomerular complement activation was associated with linear deposition of C3 on the GBM, a significant increase in protein excretion (3.317 +/- 1.077 mg/min; p less than 0.001) and RVR (10.15 +/- 1.85 mmHg/ml/min; p less than 0.001), and a decline in GFR (0.38 +/- 0.01 ml/min/g; p less than 0.05). Equivalent IPK perfused with decomplemented plasma demonstrated neither glomerular complement deposition nor augmented renal injury. By using both complement repletion and depletion techniques, this study demonstrates that antibody-initiated glomerular complement activation produces direct, neutrophil-independent renal injury. Thus, activated complement components may directly contribute to antibody-induced immune renal injury, in addition to their well established role in the recruitment of circulating inflammatory cells.

Animals↗
PubMed1986

Pulmonary manifestations of the clinical syndrome of acute glomerulonephritis and lung hemorrhage.

The pulmonary manifestations at the time of initial diagnosis were reviewed in 45 patients with the clinical syndrome of acute glomerulonephritis and lung hemorrhage. Initial pulmonary radiographic appearances encompassed a wide variety of abnormalities, and alveolar hemorrhage could not be reliably differentiated from other causes of pulmonary infiltration. The diseases underlying the syndrome included antiglomerular basement membrane (anti-GBM) disease (8/45), a systemic vasculitis (25/45), and idiopathic glomerulonephritis with idiopathic lung hemorrhage (12/45). A variety of acute pulmonary complications were seen, the most common being acute respiratory failure (13/45). Mortality directly due to pulmonary disease was uncommon (3/45 died from fulminant lung hemorrhage). Most deaths were from extrapulmonary manifestations of the underlying disease or infection. Follow-up studies in 22 patients 6 months after initial presentation indicated that although respiratory symptoms (3/22) or pulmonary radiologic abnormalities (5/22) were uncommon, the majority of patients had residual abnormalities on pulmonary function testing (16/22). Thus, the syndrome of alveolar hemorrhage with nephritis is associated with several distinct categories of underlying disease process. The initial chest radiograph is of limited value in differential diagnosis. Although a variety of acute and chronic respiratory complications may be anticipated and contribute significantly to morbidity, mortality is predominantly due to extrapulmonary progression of disease or infection complicating immunosuppressive therapy.

Adolescent↗
PubMed1986

Direct antiGBM antibody induced alterations in glomerular permselectivity.

The glomerular fixation of anti-glomerular-basement-membrane (antiGBM) antibody is associated with complement activation, neutrophil accumulation, and renal injury. This injury manifests both as an increase in the rate of urinary protein excretion and altered renal hemodynamic characteristics. We have utilized an isolated perfused kidney system (IPK) to assess the capacity of antiGBM antibody to alter glomerular permselectivity in the absence of both glomerular complement activation and neutrophil infiltration. Control perfusions with Krebs-Henseleit buffered 5% albumin solutions containing normal sheep globulin had a protein excretion rate of 0.223 +/- 0.044 mg/min (mean +/- SEM). Assessment of glomerular permselectivity using fractional dextran clearances demonstrated an intact negative charge barrier in control preparations. AntiGBM antibody bound in a dose related fashion to the kidney and was localized to the glomerular basement membrane on immunofluorescence. Antibody induced a significant increase in mean protein excretion (2.009 +/- 0.681 mg/min, P less than 0.01) in association with a loss of the glomerular filter's negative charge barrier. These IPK studies demonstrate that antiGBM antibody can itself produce proteinuria, in association with loss of the glomerular capillary negative charge barrier, in the absence of all circulating humoral and cellular inflammatory mediator systems.

Animals↗
PubMed1986

Lymphokine (MIF) production by glomerular T-lymphocytes in experimental glomerulonephritis.

Glomerular T-lymphocyte infiltration has recently been demonstrated to precede glomerular macrophage influx in a pre-immunized model of anti-glomerular basement-membrane antibody-induced glomerulonephritis (antiGBM-GN). In the current study, the functional role of these glomerular T-lymphocytes in directing macrophage localization was sought by measuring their production of macrophage migration inhibition factor (MIF). MIF activity in supernatants from cultured isolated glomeruli was measured in a conventional capillary tube bioassay. Glomerular T-lymphocytes (OX19 positive cells) were maximal (1.95 +/- 0.19 cells/glomerular cross section, c/gcs) 24 hours after injection of antiGBM antibody into sensitized animals. Seventy-two hours after antibody injection, T-lymphocyte numbers were reduced (1.02 +/- 0.14 c/gcs) while macrophage accumulation was maximal (at 24 hrs 4.2 +/- 1.3 macrophages/glomerulus (m/g), at 72 hrs 19.8 +/- 3.7 m/g). MIF activity was only detected in supernatants from T-lymphocyte infiltrated glomeruli (12 hrs 40.81 +/- 4.32% migration inhibition, 24 hrs 45.11 +/- 4.11% migration inhibition, 48 hrs 38.24 +/- 3.53% migration inhibition, 72 hrs 20.86 +/- 3.85% migration inhibition, all P less than 0.05). Control glomeruli from normal animals, pre-immunized animals given normal sheep globulin, pre-immunized animals given anti-GBM antibody and Cyclosporin A, and non-pre-immunized animals given antiGBM antibody did not contain glomerular T-lymphocytes, and their supernatants contained no MIF activity. This data indicates that the glomerular T-lymphocytes in pre-immunized antiGBM-GN are sensitized cells which release MIF and thus may direct glomerular macrophage localization in this model of antibody-induced glomerulonephritis.

Animals↗
PubMed1986

Hydroxyl radical mediation of immune renal injury by desferrioxamine.

The acute phase of glomerular injury in a model of antiglomerular basement membrane, antibody-induced glomerulonephritis (antiGBM-GN) in rabbits was shown to be neutrophil-dependent using nitrogen mustard depletion studies. Administration of desferrioxamine (DFX) prevented the development of proteinuria in this model of renal injury [24 hr protein excretion (mean +/- SEM): antiGBM-GN/DFX = 16.2 +/- 2.9 mg compared with antiGBM-GN control = 271.5 +/- 92.2 mg, P less than 0.01]. Antibody binding levels, glomerular filtration rates, circulating complement and neutrophil counts, glomerular C3 deposition, and neutrophil infiltration did not differ between DFX treated and antiGBM-GN groups. In vitro assay systems to assess oxygen radical production [superoxide anion (O2-) and hydroxyl radical (OH.)] by neutrophils activated via the interaction of antiGBM antibody, GBM and complement were established. In these assays, DFX inhibited OH. production by immunologically-stimulated neutrophils (ISN) [nM diphenol/hr/10(6) cells, mean +/- SEM, ISN/DFX = 8 +/- 2 compared with ISN = 191 +/- 22, P less than 0.01] while production of O2- was not affected [nM O2-/hr/10(6) cells, mean +/- SEM, ISN/DFX = 29.1 +/- 4.3 compared with ISN = 32.6 +/- 2.5, P greater than 0.05]. These studies demonstrate that the iron chelator desferrioxamine can prevent neutrophil-dependent immune renal injury by interfering with neutrophil function. Treatment with the hydroxyl radical scavenger dimethylthiourea also significantly attenuated renal injury in antiGBM-GN. Together, the in vivo and in vitro data strongly suggest that neutrophil-dependent immunological renal injury is mediated via hydroxyl radical production by activated neutrophils within glomeruli.

Acute Kidney Injury↗
PubMed1986

Clinicopathological associations in mesangial IgA nephropathy.

On hundred and fifteen renal biopsies performed in 112 patients with mesangial IgA nephropathy were reviewed and the histological disease patterns correlated with the clinical features at the time of initial biopsy. To determine the significance of macroscopic haematuria in this disease, specific comparisons were made between patients with a history of episodes of macroscopic haematuria and those with only microscopic haematuria. The mean age at initial biopsy was 38.3 years (90 males, mean 40.3 years; 22 females, mean 30.2 years). Histological examination showed 9 patients (8%) with class I disease (mesangial matrix expansion alone); 43 patients (38%) with class II disease (diffuse mesangial proliferation); 60 patients (54%) with class III disease (focal and segmental proliferation), including subsets of 20 patients (16%) with segmental sclerosis and/or synechiae and 23 patients (21%) with crescent formation. Class III disease and crescent formation correlated with an increased frequency of capillary loop IgA and glomerular fibrin deposition and with the presence of subendothelial and subepithelial deposits. The degree of renal impairment and the incidence of hypertension were increased in class III disease. Macroscopic haematuria patients were younger (mean 31.1 vs. 43.0 years; p less than 0.001), had less severe renal impairment (mean creatinine 116.2 vs. 213.3 mumol/l; p less than 0.001) and less class III disease (48 vs. 58%; p less than 0.05). The incidence of crescentic disease was equal in macroscopic (17%) and microscopic (23%) haematuria. Eventual progression to end-stage renal failure occurred in 12 patients (11%) and correlated with crescentic disease, renal impairment, hypertension and heavy proteinuria at the time of diagnosis.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1986

Idiopathic Goodpasture's syndrome. Fatal pulmonary haemorrhage and crescentic glomerulonephritis in the absence of immune-reactant deposition.

A 58-year-old woman was hospitalized with acute renal failure and unilateral pulmonary consolidation. Ten days later she developed massive pulmonary haemorrhage with diffuse pulmonary consolidation. Renal biopsy revealed 100% crescentic nephritis without immunofluorescence (IF) or electron microscopic evidence of immune reactant deposition. Circulating anti-glomerular basement membrane (antiGBM) antibody was not detectable by radioimmunoassay. Despite aggressive therapy pulmonary haemorrhage eventually proved fatal. IF of lung tissue revealed no immune-reactant deposition. This report represents a case of idiopathic Goodpasture's syndrome, both from an aetiological and an immunopathological viewpoint. It emphasizes that Goodpasture's syndrome (i.e. pulmonary haemorrhage and glomerulonephritis) occurs in a variety of situations which are not mediated by antiGBM antibody deposition and that alveolar haemorrhage should be considered in the differential diagnosis of all radiological pulmonary infiltrates, including unilateral opacities, when abnormalities of renal function coexist.

Adrenal Cortex Hormones↗
PubMed1986

Quantitation of the intrarenal uptake of immunoglobulin aggregates by macrophages in diffuse proliferative glomerulonephritis.

The intrarenal processing of circulating immune-complex-like-material is traditionally attributed to resident glomerular mesangial cells. To assess the contribution of infiltrating mononuclear cells to macromolecule processing by diseased glomeruli we have utilized an isolated perfused kidney system (IPK) to quantify the specific glomerular uptake of heat-aggregated immunoglobulin (AIgG) (as micrograms of aggregated IgG per 10(4) glomeruli (microgram 10(4)glom)). Mononuclear cell infiltrated glomeruli from animals with diffuse proliferative glomerulonephritis had a significantly augmented uptake of AIgG (48.9 +/- 3.8 micrograms/10(4)glom; normal 11.8 +/- 0.6 micrograms/10(4)glom; P less than 0.01). Specific blockade of mononuclear cell function by perfusion with anti-macrophage-serum (AMS) prevented increased AIgG uptake (12.8 +/- 1.2 micrograms/10(4)gloms; P less than 0.01), but had no effect on the AIgG uptake of normal kidneys (13.1 +/- 1.2 micrograms/10(4)glom). Thus, in diffuse proliferative glomerulonephritis the observed increase in the glomerular clearance of AIgG was due to phagocytosis by mononuclear cells. This study suggests that infiltrating, bone-marrow derived mononuclear cells may significantly contribute to the glomerular handling of circulating immune complexes by nephritic glomeruli.

Animals↗
PubMed1985

Glomerular permselectivity in the isolated perfused rat kidney.

Glomerular permselectivity characteristics were studied in the Sprague-Dawley rat in vivo and in the isolated rat kidney perfused with an erythrocyte-free Krebs-Henseleit buffered 5% albumin solution (IPK). IPK permselectivity in vitro, assessed by fractional clearances of neutral dextran (FCND) and dextran sulfate (FCDS) with molecular radii 18-43 A, was essentially similar to that of the Sprague-Dawley rat in vivo. The negative charge barrier of the IPK glomerular filter was intact [e.g., FCND of 36 A = 0.10 +/- 0.01 (SE) vs. FCDS of 36 A = 0.01 +/- 0.00 (P less than 0.01)]. Dextrans of an intermediate size (26-34 A) had lower fractional clearances in the IPK than in vivo [e.g., FCND of 30 A in IPK = 0.23 +/- .04 vs. FCND of 30 A in vivo 0.40 +/- 0.01 (P less than 0.01)]. This decreased clearance of dextrans of an intermediate molecular size is predicted by pore theory, since the IPK has an increased afferent glomerular plasma flow rate. As glomerular permselectivity characteristics in the IPK simulate in vivo characteristics, such preparations are suitable in vitro models in which to study factors that modulate permselectivity. The demonstration that the glomerular filter in the IPK has a normal negative charge barrier indicates that the increased protein excretion in IPK systems cannot be attributed to abnormalities of this component of the filtration barrier.

Animals↗
PubMed1985

Anti-glomerular basement membrane antibody-induced experimental glomerulonephritis: evidence for dose-dependent, direct antibody and complement-induced, cell-independent injury.

The immunopathogenesis of anti-glomerular basement membrane antibody-induced glomerulonephritis (anti-GBM-GN) involves the triad of antibody fixation to the glomerular basement membrane, local complement activation and polymorphonuclear leucocyte (PMN) infiltration. We sought to investigate the potential for contributions to renal injury from each component of this triad (i.e., antibody, complement, and PMN). This study compares the ability of antibody to induce injury in normal, PMN-depleted and dual (i.e., PMN + complement)-depleted rabbits by assessing the quantity of kidney-fixed antibody (KFA) necessary to induce proteinuria. (The KFA levels are expressed in micrograms of antibody bound per gram renal cortex.) Normal animals developed significant proteinuria at KFA 60 +/- 6 micrograms/g. PMN-depleted animals were injury free at KFA 60 +/- 6 micrograms/g, but developed heavy proteinuria at KFA 140 +/- 5 micrograms/g. The protection from injury by PMN depletion at lower KFA levels confirms the important contribution of PMN to injury in this model. Furthermore, the demonstration of a clearcut threshold for injury despite PMN-depletion indicates that glomerular antibody deposition and complement activation can cause direct PMN-independent injury. Dual depletion studies showed a significantly higher KFA threshold for injury in PMN + complement-depleted animals than in PMN-depleted, complement intact animals (195 +/- 10 micrograms/g, cf. 140 +/- 5 micrograms/g; p less than 0.01). The occurrence of injury despite dual mediator depletion demonstrates that antibody itself can produce direct, complement and PMN independent renal injury. Together the PMN depletion and dual depletion studies indicate that antibody-induced glomerular complement activation produces direct, PMN-independent renal injury that can be prevented by complement depletion. Thus each of the potential mediators studied is individually capable of producing renal injury in anti-GBM-GN. In addition to the well established injurious role of PMN, this study demonstrates that glomerular complement activation and anti-GBM antibody deposition may both produce neutrophil-independent components of renal injury. The relative contributions of the individual mediators to injury is dependent on the quantity of antibody deposited within the glomerulus.

Animals↗