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PubMed1996

Effects of inhibition of complement activation using recombinant soluble complement receptor 1 on neutrophil CD11b/CD18 and L-selectin expression and release of interleukin-8 and elastase in simulated cardiopulmonary bypass.

The inflammatory response to cardiopulmonary bypass includes activation of complement and induction of several neutrophil activation pathways. A recombinant soluble form of complement receptor 1 was used as a specific inhibitor of complement activation in simulated cardiopulmonary bypass circuits. Substantial complement activation was observed in these circuits with progressive accumulation of both plasma C3a and terminal complement complex. Soluble complement receptor 1 resulted in a significant reduction in C3a levels (p < 0.01) but did not inhibit terminal complement complex generation. A marked rise in neutrophil CD11b/CD18 expression, simultaneous loss of L-selectin expression, and a progressive accumulation of plasma elastase-alpha 1-antitrypsin occurred and were not affected by soluble complement receptor. However, generation of interleukin-8 in the circuits was inhibited (p < 0.05) by pretreatment with soluble complement receptor. These data suggest that changes in neutrophil activation seen during cardiopulmonary bypass may not be induced directly by anaphylatoxin generation.

CD11 Antigens↗
PubMed1997

Complement activation by cross-linked truncated and chimeric full-length beta-amyloid.

The activation of complement by beta-amyloid (A beta) has been implicated in the local inflammatory response in Alzheimer's disease. To assess the structural parameters required for this activation, beta-sheet-containing fibrils of A beta1-28 were induced by low pH and then chemically cross-linked to constrain the beta-sheet conformation. Chimeric A beta peptides with a substituted C-terminal sequence derived from two different transmembrane proteins were also assessed for the ability to form fibrils rich in beta-sheet structure and to activate complement. Both the cross-linked A beta1-28 and the chimeric A beta peptides were strong activators of the classical complement pathway. These results suggest that the C-terminal residues (29-42) of A beta facilitate fibril assembly required for complement activation but do not contain the interaction sites required for complement activation, further supporting the hypothesis that C1q binds to the N-terminal hydrophilic domain of A beta, and that a fibrillar beta-sheet-rich conformation is required for effective binding and activation of C1.

Amino Acid Sequence↗
PubMed1997

Characterization of neuronal cell death induced by complement activation.

The complement system plays an important role in human immune defense mechanism. Its activation via either the classical or the alternative pathway can lead to the formation of membrane attack complex (MAC) and subsequently kills target cells. Activation of the classical pathway can be initiated with binding of C1q which is first factor of complement cascade to the Fc (fragment crystalline) region of immunoglobulin. This triggers a cascade of proteolytic events resulting in the activation of C5 convertase which cleaves C5 into C5b and C5a. The C5b then binds C6, C7, C8 to form a C5b-8 complex. Binding of C9 molecules to C5b-8 forms C5b-9, the MAC, which pore size increases as the number of C9 in the complex increases. If this membrane lesion persists and results in uncontrolled ion fluxes, the cells swell and eventually lyse. To restrict the activity of the complement system, endogenous complement inhibitors are available to regulate complement-mediated cytolysis. This enables the complement system to distinguish "self" from "foreign" and protect the host from inadvertent complement attack. Activation of the classical complement cascade has been reported in Alzheimer's disease and other neurodegenerative disorders. Recently, we demonstrated that complement activation causes neuronal cell death in vitro, and this neurodegenerative process is regulated by homologous restriction. In this article, we describe the use of two cell lines as in vitro models to evaluate cell injury/cell death induced by complement activation.

Animals↗
PubMed1991

Neutrophil polarization and immunoelectrophoresis assays in the study of complement activation by biomaterials.

The neutrophil polarization assay, a technique used to measure chemotaxis, was adapted to examine complement activation. Complement activation in serum which had been incubated with metallic and polymeric biomaterials was examined using the neutrophil polarization assay and immunoelectrophoresis assay. In agreement with previous publications, nylon activated the complement cascade, but PTFE did not. The neutrophil polarization assay was found to be the most sensitive technique for examining complement activation by endotoxin but the immunoelectrophoresis assay is the technique most sensitive for detecting complement activation by cobalt powder. In both assays, complement activation was not detected in serum incubated with chromium powder. However, serum incubated with silver and nickel powder stimulated neutrophils to polarize indicating that these powders may activate complement.

Biocompatible Materials↗
PubMed1994

Complement activation by the hydroxyl radical during intestinal reperfusion.

This study examines the hypothesis that hydroxyl radical (OH.) generation during intestinal reperfusion activates the complement system forming the potent chemotaxin C5a. Anesthetized Sprague-Dawley rats underwent 120 min of intestinal ischemia and 60 min of reperfusion (IIR). Complement (C) activation was assessed by measuring total plasma C activity and C5a-related chemotaxis and leukoaggregation. Dimethylthiourea and the iron chelator deferoxamine were utilized to assess the role of the OH. in the activation of C in this model. Sham-operated animals served as controls. Total plasma C activity of animals sustaining IIR was 64% of controls (p < .05). Plasma of animals sustaining IIR induced greater chemotaxis and leukoaggregation than plasma from sham-operated groups (p < .05). Treatment of IIR plasma with anti-C5a antibody ameliorated the enhanced leukoaggregation characteristic of IIR plasma. Pretreatment with dimethylthiorea and deferoxamine prevented reperfusion-induced activation of complement and inhibited the chemotactic activity of plasma from IIR animals. These data are consistent with the hypothesis that IIR activates complement and that the OH. generated during reperfusion may be one mechanism by which C is activated in this injury model.

Animals↗
PubMed1994

Effects of complement activation products on the synthesis of decay accelerating factor and membrane cofactor protein by human mesangial cells.

We previously demonstrated that activation of terminal complement components (C8 and/or C9) increases the synthesis and expression of decay accelerating factor (DAF) on human glomerular cells. DAF is a cell membrane-associated complement regulatory protein that inhibits complement activation on cell surfaces. In the present studies we evaluated, first, the mechanisms by which complement activation stimulates DAF synthesis, and second the effect of complement activation on the synthesis. and expression of membrane cofactor protein (MCP), another complement regulatory protein, by human mesangial cells (HMC) in culture. Complement activation by immune complexes resulted in increased DAF mRNA levels by at least two mechanisms: deposition of activated C3 on HMC and generation of soluble complement activation products, specifically C5a. The increase in DAF mRNA levels induced by activated C3 or C5a was short lived (less than 4 hr). In contrast, the up-regulation of DAF mRNA levels induced by activation of the complete complement cascade persisted for at least eight hours. The effect of complement activation on DAF mRNA levels was not affected by cycloheximide, a protein synthesis inhibitor. However, cycloheximide alone resulted in a significant up-regulation of DAF mRNA levels on HMC. In contrast to those findings complement activation did not cause an up-regulation of MCP mRNA, nor an increase in the synthesis of this protein. However, by FACS, complement produced a small but significant increase of MCP protein levels on HMC. In conclusion, both MCP and DAF are present on HMC. Several activated complement components are capable of increasing DAF mRNA levels, but DAF protein levels increase only after activation of the whole complement cascade.(ABSTRACT TRUNCATED AT 250 WORDS)

Antigens, CD↗
PubMed1999

Complement activation by oxidatively modified low-density lipoproteins.

BACKGROUND: Oxidatively modified low-density lipoproteins (LDLs) have been implicated in the pathogenesis of atherosclerosis and are found in human vascular lesions. There is increasing evidence that complement activation may also play a role in atherogenesis. Activated complement proteins have been demonstrated to be present in early atherosclerotic lesions, and lipids isolated from lesions have been shown to activate complement, hence their designation as lesion complement activator (LCA). The question now arose whether oxidized LDLs would also activate complement. MATERIAL AND METHODS: The complement-activating capacity of a lesion complement activator preparation and of minimally as well as heavily oxidized LDL was investigated by measuring SC5b-9 formation in normal human serum. In addition, C3 conversion was followed using two-dimensional immunoelectrophoresis. RESULTS: Minimally and heavily oxidized LDL generated small but significant amounts of SC5b-9 (7.9 microgram mL-1, SD 3.5, and 10.8 microgram mL-1, SD 1.2, respectively; n = 6) compared with native LDL (3.3 microgram mL-1, SD 1.4; P < 0.05), whereas LCA generated substantially larger amounts of the terminal complex (32.0 microgram mL-1, SD 3.2). Both oxidized LDL preparations caused only minor C3 conversion. CONCLUSIONS: These findings show that oxidation does not confer relevant complement-activating properties on LDL, suggesting that the lesion complement activator is not directly related to oxidized LDL. Oxidized LDL is probably of minor importance for complement activation in atherosclerotic lesions.

Arteriosclerosis↗
PubMed1988

Lack of complement activation by human IgA immune complexes.

Complement activation may play an important role in renal injury associated with glomerular deposition of IgA immune complexes. The ability of naturally occurring human IgA immune complexes (IgA-IC) and covalently cross-linked human IgA oligomers (X-IgA) to activate complement were examined in vitro and in vivo. Large-sized IgA-IC were isolated from a patient's serum by affinity purification (Jacalin-Sepharose) and gel chromatography. Stable X-IgA were prepared by chemical cross-linking with a heterobifunctional reagent, N-succinimdyl 3-(2-pyridyl-dithio) propionate (SPDP). Treatment of fresh normal human serum with large amounts of either IgA-IC or X-IgA failed to activate C3. The C3 consumption was measured immunochemically by the decrease of the B antigen on the native C3 and by the generation of iC3b. Addition of these complexes to serum did not result in cleavage of factor B. Administration of human IgA-IC or X-IgA to mice, killed after 6 h, resulted in glomerular deposition of IgA. Despite the presence of intense glomerular IgA deposits no C3 was detected. Collectively, these findings suggest that neither soluble nor renal localized human IgA complexes activate complement.

Animals↗
PubMed1989

Accentuated complement activation in patient plasma during the adult respiratory distress syndrome: a potential mechanism for pulmonary inflammation.

The adult respiratory distress syndrome (ARDS) represents an acute inflammatory lung disorder, characterized by both refractory hypoxemia and a mortality rate approaching 95%. Researchers have proposed that activation of the complement (C) system may play a role in the development of the pulmonary inflammation associated with ARDS. The purpose of this investigation was to determine whether complement activation occurs to a greater extent in patients with ARDS than in patients without ARDS, thereby providing a potential mechanism for the acute inflammation seen in ARDS. In this study, we assessed plasma complement activation by measuring complement activation by-products: C1rC1s-C1 inhibitor complex and C3b-P complex, generated subsequent to activation of the classical and alternative pathways, respectively, and also the terminal complement complex, formed after activation of either the classical or alternative complement pathway. Multivariate discriminant analysis revealed that these three complement activation complexes could distinguish patients with ARDS from those without ARDS (p less than 0.04). Furthermore, these three complexes provided a more sensitive discriminator of ARDS than did plasma levels of C3a desarginine (p greater than 0.30), C5a desarginine (p greater than 0.41) and total hemolytic complement activity (CH50) (p greater than 0.72). We conclude that a temporal association exists between the complement activation and the development of ARDS. Therefore, we suggest that complement activation by-products be included in the armamentarium for ARDS.

Adult↗
PubMed1987

The IgA-binding lectin jacalin induces complement activation by inhibition of C-1-inactivator function.

Jacalin, a D-galactose-specific lectin from jackfruit, interacts with human IgA and one or two other serum proteins. Incubation of jacalin with fresh human serum was shown to result in activation of the complement system. Therefore the mechanism of complement activation by jacalin was studied. Jacalin was extracted from jackfruit seeds (crude preparation) and purified to homogeneity by affinity chromatography on IgA-Sepharose to yield a pure preparation of jacalin. Both crude and pure jacalin were able to activate complement, accompanied by conversion of C3. Consumption of C1, C4 and C-1-inactivator (C-1-In) indicated involvement of the classical pathway. Aggregated IgG (AIgG) caused partial (38%) and jacalin induced complete consumption of C1-In functional activity. It was found upon Ouchterlony analysis that jacalin forms a precipitation line with purified C-1-In. In addition binding of 125I-C-1-In to jacalin-Sepharose was observed, and this binding was inhibitable by either secretory IgA or D-galactose. Next to binding of jacalin to C-1-In, jacalin was also shown to inhibit the functional activity of C-1-In. These results indicate that jacalin induces complement activation by inhibition of C-1-In function and thereby facilitates the activation of precursor C1 in either the absence or presence of low amounts of C1 activators.

Complement C1 Inactivator Proteins↗
PubMed1979

Complement activation by parasites. A review.

Activation of complement by parasites (living parasites or purified parasite antigens) is involved in several mechanisms of the host parasite relationship. In most of the experiments performed in vitro, complement activation was found to be lethal for the parasites, but sometimes it could be essential for the development of parasitemia. Both classical and alternative complement pathways may be activated by parasites; the classical pathway nearly always requires the involvement of antibodies whereas the alternative pathway is activated directly by products released by the parasites or present in their teguments. Activation of complement, especially via the alternative pathway may also be a prerequisite for cellular adherence to parasites which can then cause their death.

Animals↗
PubMed2000

Inhibition of heparin/protamine complex-induced complement activation by Compstatin in baboons.

Complement activation products are major components of the inflammatory response induced by cardiac surgery and cardiopulmonary bypass which contribute to postoperative organ dysfunction, fluid accumulation, and morbidity. Activation of the complement system occurs during extracorporeal circulation, during reperfusion of ischemic tissue, and after the formation of heparin-protamine complexes. In this study we examine the efficacy of Compstatin, a recently discovered peptide inhibitor of complement, in preventing heparin/protamine-induced complement activation in baboons. The study was performed in baboons because Compstatin binds to baboon C3 and is resistant to proteolytic cleavage in baboon blood (similar to humans); Compstatin inhibits only the activation of primates' complement system. After testing various doses and administration regimens, Compstatin produced complete inhibition at a total dose of 21 mg/kg when given as a combination of bolus injection and infusion. Compstatin completely inhibited in vivo heparin/protamine-induced complement activation without adverse effects on heart rate or systemic arterial, central venous, and pulmonary arterial pressures. This study indicates that Compstatin is a safe and effective complement inhibitor that has the potential to prevent complement activation during and after clinical cardiac surgery. Furthermore, Compstatin can serve as the prototype for designing an orally administrated drug.

Animals↗
PubMed1981

Rocket immunoelectrophoresis of C4 and C4d. A simple sensitive method for detecting complement activation in plasma.

Activation of complement component C4 has recently been measured by the quantitation of C4 and C4d (a cleavage fragment of C4) by electroimmunodiffusion in gels containing specific precipitating antibodies for C4 and C4d (Rocket immunoelectrophoresis, RIE). Quantitative measurements of the complement component C4 and its fragment C4d were determined in rocket immunoelectrophoresis (RIE) and compared with measurements of total hemolytic complement activity (CH50) or concentrations of C4 as determined by single radial immunodiffusion (RID). This newly developed RIE assay shows activation of the classical complement pathway and involves electroimmunodiffusion in gels containing specific precipitating antibodies for C4 and its cleavage fragment, C4d. In 37 plasma samples, excellent correlation was demonstrated between the C4 in RIE and CH50 (r = .70) and C4 by RID (r = .87). In vivo activation of C4 was determined by measuring the ratio of C4d to C4; 21 of the plasma samples assayed had ratios greater than 1.1 indicating activation of C4. In 13 of the plasma samples there were correspondingly low CH50 values, whereas 8 had normal CH50 levels. Therefore, activation can be detected in those instances when other measurements (CH50 and C4 quantitation) are normal. Thus the RIE assay for plasma C4 activation appears to be the most sensitive method available for assessing in vivo activation of the classical pathway of complement.

Animals↗
PubMedDate not supplied

Complement activation by cigarette smoke condensate and tobacco infusion.

The capacity of tobacco infusion and cigarette smoke condensate to activate the complement pathway was investigated in vitro by hemolytic and immunological assays. Complement activity was studied using samples of normal human serum incubated at 37 degrees C with different dilutions of tobacco infusion and cigarette smoke condensate. In all mixtures containing tobacco infusion or cigarette smoke condensate at a concentration of 0.1: 1, total hemolytic complement showed an average progressive decrease of 90% and 50%, respectively, after 60 min of incubation. This decrease was associated with a decrease of both classical and alternative pathway activities. In addition, cleavage fragments of C3, C4, and factor B were identified with immunochemical analyses. This study suggests that tobacco infusion and cigarette smoke condensate are activators of complement either through the classical or alternative pathway.

Blood↗
PubMedDate not supplied

The effects of activated complement on myocardial performance in vitro.

Activated complement has been implicated in the dysfunction of several organ systems, but can it directly affect the myocardium? This possibility was studied using human right atrial trabeculae contracting isometrically "in vitro" in four solutions: Tyrode's (T), autologous arterial blood (B), plasma (P) and denaturated plasma (DP). Complement was activated by the addition of Zymosan while vehicle alone was used as control. Complement activation occurred in the blood and plasma solutions, as assessed by a significant drop in CH50 (p less than 0.05), while there was no detectable complement activity in either T or DP. Myocardial functional integrity was assessed by the change in contractile parameters with time. Subsequent resting forces, relative developed forces (DF), and rates of decay of DF were similar between muscles contracting in the four solutions. We conclude that activated complement has no direct effect on myocardial performance.

Blood↗
PubMed1979

Complement activation in acne vulgaris: consumption of complement by comedones.

Comedones, the contents of acne lesions, were shown to consume scomplement hemolytic activity in normal serum. This consumption was stimulated by the addition of serum from patients with inflammatory acne. Absorption of acne serum with Propionibacterium acnes cells removed all stimulating activity. Immunoelectrophoretic analysis of serum incubated with comedones revealed the conversion of C3 and factor B in normal serum. The addition of acne serum resulted in cleavage of C4. In serum treated with ethylene glycol-bis(beta-aminoethyl ether)-N,N'-tetraacetic acid, only C3 and factor B were converted. This indicates that comedones may activate complement by either the classical or the alternative pathway. It is suggested that P. acnes cells in comedonal material are responsible for the complement activation.

Acne Vulgaris↗
PubMedDate not supplied

Dialysis leukopenia and hypoxemia in a patient without measurable complement activity.

We have studied complement activity, total leukocyte counts, PO2 and acid-base balance during a single hemodialysis with cuprophan membranes in a patient with hereditary angioedema and C3NeF-positive chronic membranoproliferative glomerulonephritis. Before, during and after the dialytic procedure plasma complement activity (total hemolytic complement, classical and alternative pathway activities) was not detectable and no C3-conversion occurred, while profound leukopenia (from 8,500 to 1,800 leukocytes/microliter) and hypoxemia (from 101.8 to 86 mmHg PO2) were found within 20 min from the initiation of hemodialysis. Similar results were obtained by studying the same parameters during two additional hemodialytic procedures. In vitro experiments showed that the patient's C3 could not be converted, either by cuprophan or zymosan, a specific and potent complement activator, even under optimal experimental conditions. Our data demonstrate that complement activation is not the only possible mechanism responsible for early leukopenia (as well as hypoxemia) during dialysis with cuprophan membranes.

Acid-Base Equilibrium↗
PubMed1992

Regulation of complement activity by vaccinia virus complement-control protein.

A major protein secreted by vaccinia virus-infected cells has structural similarity to the super-family of complement-control proteins. This vaccinia complement-control protein (VCP) was studied to determine how it regulates complement activation. VCP was bound by C4b and C3b and served as a cofactor with factor I in cleaving these two molecules. VCP inhibited the formation and accelerated the decay of the classical C3 convertase. It also accelerated decay of the alternative pathway convertase, although higher concentrations were apparently needed. In vitro, therefore, VCP interfered with the classical and alternative complement pathways at several steps. In vivo, this interference may increase the virulence of vaccinia virus by enabling it to escape attack by the host's complement system.

Complement Activation↗