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PubMed1979

Complement activation by aluminium and zirconium compounds.

The activation of complement by a number of metal compounds, previously found to induce chronic inflammation, was investigated. Results obtained were compared with complement activation by inulin and zymosan. It was shown that complement activation by these metal compounds did not necessarily involve either the classical or the alternative pathways. Some of these compounds were unable to activate complement in the absence of detectable plasminogen. The results obtained indicate a relationship between the ability of these compounds to induce chronic inflammation in the guinea-pig and to activate complement.

Aluminum↗
PubMed1986

Compartmental distribution of complement activation products in artificial kidneys.

The compartmental distribution of the human anaphylatoxins C3a and C5a has been defined during simulated hemodialysis performed with various types of hemodialyzers. New cuprophan hollow fiber dialyzers were found to activate human complement very readily in vitro, while re-used cuprophan dialyzers displayed only modest complement activating potential. The C3a and C5a antigens, formed as a result of complement activation in these dialyzers, accumulated predominantly in the blood path and were not adsorbed extensively on the membrane surface or transported into the dialysate compartment. Cellulose acetate membranes also produced complement activation in vitro, but to a lesser degree than new cuprophan hollow fibers. However, these membranes exhibited a significant capacity to bind the anaphylatoxins to their surface. Polyacrylonitrile membranes appeared to be unique in that they not only failed to activate complement significantly, but they rapidly adsorbed large quantities of C3a and C5a. These findings demonstrate that hemodialysis membranes may differ with regard to their complement activating potential as well as their ability to remove circulating anaphylatoxins from the blood path. Clinical measurements of anaphylatoxin production during hemodialysis reflect these dynamic events.

Complement Activation↗
PubMed1986

Complement activation by 19S IgM rheumatoid factor: relationship to disease activity in rheumatoid arthritis.

19S IgM rheumatoid factor (RF) in rheumatoid arthritis (RA) are polyclonal autoantibodies directed against the Fc piece of IgG. Rheumatoid patients with RF tend to have aggressive synovitis, nodules, and extraarticular manifestations. Although RF titer does not correlate with disease activity, RF activates complement (C) by the classical pathway. Thus, we postulated that selective stimulation of cell clones producing efficient C activating RF molecules might be associated with disease flares, independent of changes in serum RF concentration. To address the question, 42 patients with RA were evaluated prospectively. Serum RF concentration was measured by radioimmunoassay (RIA) and C activating activity by hemolytic assay. We then calculated the mean hemolysis (MH) of sensitized sheep erythrocytes (SRC) produced/ml of RF serum (MH/ml) and MH/microgram of RF as an expression of RF C activating properties (CAP). The following observations were made: RF CAP varied among the patients studied; RF CAP varied over time in individual patients; RF CAP differences varied in both groups independently from RF concentration; RF CAP correlated with both systemic and articular disease activity; and total RF concentration correlated with articular findings and nodules but less well with systemic disease activity.

Adult↗
PubMed1990

Isolation and characterization of a complement-activating lipid extracted from human atherosclerotic lesions.

The major characteristics of human atherosclerotic lesions are similar to those of a chronic inflammatory reaction, namely fibrosis, mesenchymal cell proliferation, the presence of resident macrophages, and cell necrosis. Atherosclerosis exhibits in addition the feature of lipid (mainly cholesterol) accumulation. The results of the present report demonstrate that a specific cholesterol-containing lipid particle present in human atherosclerotic lesions activates the complement system to completion. Thus, lipid could represent a stimulatory factor for the inflammatory reaction, whose underlying mechanistic basis may be, at least in part, complement activation. The complement-activating lipid was purified from saline extracts of aortic atherosclerotic lesions by sucrose density gradient centrifugation followed by molecular sieve chromatography on Sepharose 2B. It contained little protein other than albumin, was 100-500 nm in size, exhibited an unesterified to total cholesterol ratio of 0.58 and an unesterified cholesterol to phospholipid ratio of 1.2. The lipid, termed lesion lipid complement (LCA), activated the alternative pathway of complement in a dose-dependent manner. Lesion-extracted low density lipoprotein (LDL) obtained during the purification procedure failed to activate complement. Specific generation of C3a desArg and C5b-9 by LCA indicated C3/C5 convertase formation with activation proceeding to completion. Biochemical and electron microscopic evaluations revealed that much of the C5b-9 present in atherosclerotic lesions is membraneous, rather than fluid phase SC5b-9. The observations reported herein establish a link between lipid insudation and inflammation in atherosclerotic lesions via the mechanism of complement activation.

Aorta↗
PubMed1988

Selective lung leukosequestration after complement activation.

This study tests whether activated complement leads to a selective entrapment of polymorphonuclear leukocytes (PMN's) in the lungs. Awake sheep were infused for 5 min with zymosan-activated plasma (ZAP, 2.5 mg/ml) at a rate of 5 ml/min into the superior vena cava (IV, n = 4) or intra-arterially into the aortic arch or femoral artery (IA, n = 8). At the end of IV infusion, leukocyte counts fell from 8,862 to 1,631/mm3 (P less than 0.01). PMN counts across the lungs decreased by 74%. There were increases in plasma thromboxane (Tx) B2 from 114 to 2,733 pg/ml (P less than 0.01), mean pulmonary arterial pressure from 12 to 42 mmHg (P less than 0.01), and physiological shunt from 13 to 25% (P less than 0.05). Within 1 h lymph TxB2 levels had risen from 301 to 4,916 pg/ml (P less than 0.01), lung lymph flow (QL) rose from 3.7 to 11.1 ml/30 min (P less than 0.05), lymph-to-plasma protein ratio (L/P) remained unchanged at 0.63, and lymph protein clearance increased from 2.3 to 7.5 ml/30 min (P less than 0.05). Leukosequestration, quantitated by capillary PMN counting and by assaying the granulocyte marker myeloperoxidase, occurred relative to sham animals (P less than 0.05) in the lung and spleen but not in other organs. Intra-arterial ZAP infusion led to changes that were similar in magnitude and timing to the IV group.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Inflammation in the lungs of rats after deposition of dust collected from the air of wool mills: the role of epithelial injury and complement activation.

In a previous study assessing respiratory symptoms in individuals employed in wool textile mills in the north of England relations between symptoms of chronic bronchitis, breathlessness and wheeze, and rhinitis and current exposure to airborne mass concentration of dust were shown. As preliminary steps in defining the potential hazard associated with dust from the air of wool mills the ability of inspirable dust, collected from the air of wool textile mills, to cause inflammation when injected into the lungs of rats was determined. Dusts were collected from the beginning of wool processing (opening) in one factory and from the middle (combing) and late (backwinding) stages of the process in two other factories. Ability of the dusts to cause inflammation was assessed by instillation into the lungs of rats followed by bronchoalveolar lavage. All the dusts caused some inflammation which peaked on day 1 and did not persist beyond one week. A distinctive aggregation response of mononuclear cells in the lavage, however, had a different time course, peaking at day 7. An attempt was made to determine how the wool mill dusts caused inflammation and experiments showed that the dusts themselves had no inherent chemotactic activity but that they did have a pronounced ability to generate chemotaxins in serum and so could activate complement in lung fluid. In addition, dust collected from ledges in the mills had the ability to injure epithelial cells in vitro which could also contribute to inflammation. A role for endotoxin in the inflammatory activity of the dusts was not discounted and a leachate of the dust had the ability to cause inflammation when injected into the lungs of rats. Wool mill dust is likely to be a complex mixture of materials and these experiments represent a preliminary approach to understanding the biological activity of the whole unfractionated dust and further studies are in progress to define more accurately the toxic material(s) in the dust.

Animals↗
PubMed1986

Oxygen free radical generation during cardiopulmonary bypass: correlation with complement activation.

To determine the relationships among complement activation, pulmonary leukosequestration, and oxygen free radical generation, we prospectively studied 15 patients undergoing cardiopulmonary bypass for myocardial revascularization. Plasma levels of C3a, C4a, and hydrogen peroxide (a marker of oxygen free radical generation) were measured before, during, and after extracorporeal circulation. The results confirm that cardiopulmonary bypass activates complement via the alternate (C3a) pathway. This first phase of complement activation was accompanied by an increase in plasma H2O2 (from 80 +/- 8 to 155 +/- 13 microM/ml; p less than .001) and by pulmonary sequestration of polymorphonuclear leukocytes. Protamine administration after cardiopulmonary bypass further activated complement via the classical (C4a) pathway but was not accompanied by a change in plasma hydrogen peroxide. We hypothesize that both complement activation and excess oxygen free radical generation contribute to the pathophysiology of extracorporeal circulation.

Blood Cells↗
PubMed1980

Complement activating property of the protein-rich endotoxin (OEP) of Pseudomonas aeruginosa. II. Complement activating property of the lipopolysaccharide portion and the inhibition by polymyxin B.

In order to elucidate the active principle and the mechanism of complement activation of protein-rich endotoxin (OEP) of P. aeruginosa, the complement consumption of the LPS from OEP was studied either in guinea pig serum (GPS) or in factor D-depleted GPS (D-dpl-GPS) in the presence or absence of polymyxin B. Polymyxin B is an inhibitor of the classical pathway (CP) activation due to the lipid A of LPS. The LPS from OEP had about 5 times higher the activity than OEP in GPS. This value corresponds to the LPS content (about 20%) in OEP. It was not likely that the protein portion (about 80%) of the OEP participates to activate complement. In GPS, the ability of the LPS from OEP was only partially inhibited by polymyxin B. In D-dpl-GPS in which the alternative pathway (AP) may be abrogated, the consumption by the LPS from OEP markedly decreased, and was furthermore diminished in the presence of polymyxin B. These results suggest that the LPS from OEP is the active principle of OEP and activates both the CP and the AP. It was noteworthy that two fold or less polymyxin B in weights did not inhibit the ability of E. coli 0111:B4 LPS to activate only the AP, but rather enhanced it.

Animals↗
PubMed1990

Evacuation of microscopic air bubbles from Dacron reduces complement activation and platelet aggregation.

Complement activation by biomaterials may play an important role in vascular graft failure since the physiologically active polypeptides, C3a and C5a, have several relevant properties. C3a promotes platelet aggregation and release, and C5a activates neutrophils, which may stimulate platelet aggregation by liberation of platelet activating factor or by a direct neutrophil platelet interaction. Microscopic air bubbles (nuclei) are found in the surface roughness or pores of most biomaterials, and their number and size are related to the surface tension of the material. Therefore two interfaces can be postulated to exist when Dacron is exposed to blood: (1) a blood/biomaterial, and (2) a blood/air interface. These air nuclei in the surface and the biomaterial itself are capable of activating complement. The purpose of these experiments was to eliminate these surface nuclei from Dacron by a process termed denucleation and subsequently to determine the effect of this intervention on complement activation and platelet aggregation in vitro. Dacron was denucleated by pretreatment that involved serial rinsing with ethanol and degassed buffer that results in replacement of the air nuclei by buffer. Both control and denucleated pieces of Dacron (2, 4, and 6 cm2) were then incubated in human plasma. Each plasma sample was assayed for complement activation products (C3a, C5a, and C4a) by means of radioimmunoassays, and the degree of autologous platelet aggregation that resulted from the addition of a portion of each incubated plasma sample to an autologous platelet suspension was measured. There was a significant reduction in C3a and C5a in the plasma samples incubated with denucleated Dacron as compared to control Dacron (p less than 0.001, analysis of variance [ANOVA]).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1977

Complement activation by interaction of polyanions and polycations. III. Complement activation by interaction of multiple polyanious and polycations is the presence of C-reactive protein.

Interactions between heparin and protamine previously were found to result in activation of the complement (C) system. In the present investigation, this interaction was shown to result in the binding of purified C1, and this was markedly enhanced in the presence of C-reactive protein (CRP). CRP also enhanced C consumption during heparin-protamine interactions in whole serum, and in the presence of CRP depletion of C components C1-3 was observed. Similar C1 binding and C consumption in the presence of CRP were seen upon the interaction of multiple additional polyanions including DNA, ENA, hyaluronic acid, chondroitin sulfate, and dextran sulfate with the polycations protamine sulfate and poly-L-lysine. These effects were observed with CRP concentrations well within the range found in normal human sera and considerably less than those found in most acute phase sera. We suggest, therefore, C activation by polyanion-polycation interactions in the presence of CRP may be important to certain reactions of host defense and inflammation.

Anions↗
PubMed1988

Complement activation by vascular prostheses and its role in progression of arteriosclerotic lesions.

This study, using C3a, C4a, and C5a assay and crossed immunoelectrophoresis in vitro and in vivo, was designed to determine whether vascular prostheses activate the complement system. The degree of complement activation and the pathway of activation were also studied. The complement levels (C3, C4, CH50) in different arterial diseases were measured, and the relationship of complement levels to serum lipids in patients with arteriosclerosis obliterans (ASO) was also investigated, in order to clarify a relationship between the complement system and arteriosclerosis or other arterial diseases. Bovine graft, dacron, and PTFE activated the complement system in vitro. In order of the degree of complement activation, bovine graft ranked first, followed by dacron and PTFE. The patient group with acute arterial occlusion showed high C3 and C4 levels. The healthy elderly group showed higher C3 and C4 levels than the healthy persons in their twenties. In ASO patients, C3 levels correlated with serum lipid levels. Judged from the relation of complement activation by vascular prostheses to the progression of arteriosclerotic changes, vascular prostheses should be assessed with regard to complement activation.

Arterial Occlusive Diseases↗
PubMed1991

Complement activation during prolonged extracorporeal membrane oxygenation.

Short-term cardiopulmonary bypass activates the complement system, possibly resulting in pulmonary dysfunction from granulocyte aggregation and pulmonary endothelial damage. These effects may be inhibited by steroids. Prolonged extracorporeal membrane oxygenation (ECMO) is used for newborn respiratory failure, but the effects of ECMO on complement activation are unknown. Twenty-one newborn infants with respiratory failure treated with ECMO were randomly assigned to group I (control, no steroids) or group II (30 mg/kg intravenous methylprednisolone before ECMO). Depletion assays of C3 and C5 were performed in each group at intervals before and during ECMO (declining values indicate complement activation). The groups were compared for complement levels, survival, time on ECMO and on the ventilator, and total hospitalization time. Steroids significantly shortened the time on ECMO and time on the ventilator after ECMO but did not affect survival or total hospitalization time. Steroids also enhanced activation of C3 and C5. Complement activation occurs during ECMO. Steroid administration paradoxically causes earlier complement activation but shortens ECMO and ventilator times. Complement activation during ECMO is of questionable significance. The benefits of steroids during ECMO may be mediated through other mechanisms.

Birth Weight↗
PubMed1984

Complement activating cryoglobulins in the nephritis of systemic lupus erythematosus.

Complement activation in vitro by cryoglobulins isolated from the sera of 28 patients with systemic lupus erythematosus (SLE) was examined by incubating the cryoglobulin with normal human serum and performing crossed-immunoelectrophoresis of the mixture to detect C3 conversion. Eighteen of the 28 SLE cryoglobulins activated complement; eight by the classical pathway, four by the alternative pathway exclusively, and six by both pathways. In contrast only two out of 20 cryoglobulins isolated from the sera of normal subjects activated complement and both did so by the classical pathway. Twenty-three of the 28 SLE sera activated complement and complement activating cryoglobulins were isolated from 15 of these 23 sera. The parent sera of cryoglobulins activating complement had lower C4 and C3 concentrations than sera whose cryoglobulins did not split complement but these differences were not significant. The ability of SLE cryoglobulins to activate complement in vitro suggests that these immune complexes activate complement in vivo and thus may contribute to tissue damage in this disease. The activation of both classical and alternative complement pathways is in keeping with other evidence that both pathways are involved in SLE.

Adult↗
PubMed1984

The chemotactic activity of normal and complement-activated serum as measured by the leading-front method using a Boyden chamber.

The chemotactic activity in serum, defined as the attractant effect of serum on the migration of neutrophil granulocytes (PMN) has been investigated for the purpose of characterizing the major chemotactic factors in serum as measured by the leading-front technique, using a modified Boyden chamber. The chemotactic activity was measured in fresh and heated normal and activated serum and in serum fractions thereof separated by gel filtration. By gel filtration on Sephacryl S-200 a partly heat-labile C3-C5-associated chemotactic factor with molecular weight between 70,000 and 150,000 was isolated from fresh normal serum. The heat-labile chemotactic activity was destroyed by pronounced complement activation. Gel filtration of complement-activated serum on a Sephacryl S-200 column showed the existence of one C5-associated chemotactic factor with approximately 70,000 molecular weight and one unidentified factor with approximately 150,000 molecular weight, whereas no low molecular weight chemotactic activity was demonstrated. On the other hand, gel filtration of activated serum on a Sephadex G-75 column demonstrated one C5-associated chemotactic factor of approximately 70,000 molecular weight and one 10,000-50,000 molecular weight factor active only in the presence of 2% normal serum. This investigation suggests that the chemotactic activity in fresh normal serum is mediated by a partly heat-labile C3-C5-associated complex. In activated serum three chemotactic factors were demonstrated, one unidentified factor with 150,000 mol wt and two C5-dependent factors with 70,000 and 10,000-50,000 mol wt, the latter probably corresponding to C5a desarg. Accordingly, this study also suggests that C5a is not the only chemotactic factor generated in serum.

Blood Physiological Phenomena↗
PubMed1981

Factors affecting complement activation by Staphylococcus aureus cell walls, their components, and mutants altered in teichoic acid.

In a previous study, Staphylococcus aureus purified cell walls (PCW), consisting of peptidoglycan (PG) plus covalently linked teichoic acid (TA), were found to be more active in complement consumption than isolated PG. Isolated TA has now been shown to be capable of activating complement. Mild sonication markedly increased the ability of PG to activate complement but had essentially no effect on the activities of PCW and TA. Optimal sonication of PG did not yield activities equal to those of PCW in dose-response and kinetic studies, which may imply that TA plays some role in complement consumption. Sonication did not lead to solubilization of PCW or PG but may have enhanced the activity of PG in complement consumption by better dispersing PG particles, thereby exposing more surface area. Lysostaphin solubilization of PCW and PG markedly decreased their activities in complement consumption. The PCW of an S. aureus TA-deficient mutant, which were mostly PG, caused similar amounts of complement consumption as the parent strain PCW. Of the treatments of PCW commonly used to isolate PG, formamide and periodate extractions in particular led to PG preparations with lower activities in complement consumption than the PCW from which they were prepared, although these activities were stimulated by sonication. When whole organisms were studied by using a TA-deficient mutant, a mutant with an additional cell surface polymer, and the TA-containing parent strains and complement consumption by these strains was compared, no difference was found in either the rate or the degree of complement activation. This led to experiments demonstrating that both material released extracellularly from staphylococci and the cytoplasmic fraction of S. aureus were active in complement consumption. The results of these experiments indicate that both physical and chemical factors must be considered in studies of complement activation by isolated bacterial cell wall components. Under certain conditions, staphylococcal TA may enhance complement activation, but studies with whole organisms clearly show that this cell wall constituent does not play an essential role in this process. In addition, studies of complement consumption with intact organisms have demonstrated that there may be contributions both from cell surface components and from material released by the cells.

Cell Wall↗
PubMed1984

Complement activation and hypersensitivity reactions to dialysis membranes.

Certain patients receiving hemodialysis experience recurrent chest pain, dyspnea, and hypotension during exposure to new cuprophane-membrane dialyzers (the "first-use syndrome"). Because activation of complement may be involved in these events, we examined in vivo complement activation with new cuprophane membranes and in vitro activation by zymosan in 6 such patients, and compared them with 10 patients who did not have symptoms during dialysis. All patients with the first-use syndrome had maximal complement activation 10 minutes after initiation of dialysis, with C3a des-arginine (desArg), the stable metabolite of C3 activation, equal to 8533 +/- 157 ng per milliliter (mean +/- S.E.M.). In asymptomatic patients the maximal C3a desArg value occurred at 15 minutes and was only 2907 +/- 372 ng per milliliter (P less than or equal to 0.0001). At a concentration of 3.8 x 10(-5) g of zymosan per milliliter, patients with the first-use syndrome had a C3a desArg level of 29.6 +/- 1.4 micrograms per milliliter, whereas it was only 16.6 +/- 2.3 micrograms per milliliter in asymptomatic patients (P less than or equal to 0.0001). Two other patients, who experienced cardiopulmonary collapse during the first two minutes of dialysis, had a C3a desArg level of 18,900 and 7800 ng per milliliter, respectively. We conclude that the occurrence of adverse symptoms associated with new cuprophane-membrane dialyzers correlates with complement activation.

Adult↗
PubMed1989

Biocompatibility of urinary catheters. Effect on complement activation.

The ability of 2 brands of urinary catheters to activate the complement system in vitro as a marker of biocompatibility was investigated. Pieces of a silicone/latex catheter and an all-silicone catheter were incubated in human serum. Complement activation was tested in 2 enzyme immunoassays, one evaluating C3 activation and the other the terminal complement complex (TCC) formation. The silicone/latex catheter caused considerably more complement activation in both assays than did the all-silicone one. The findings are in agreement with previous results of tissue toxicity tests. The methods presented may prove valuable for the practical purpose of testing the biocompatibility of urinary catheters.

Biocompatible Materials↗