Third component of human complement: C3.
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Avidin↗
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Results for “Complement C3a”
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The relationship between macrophages and C5b-9 complement complexes in human atherosclerosis.
The relationship between macrophages and the terminal C5b-9 complement complexes was investigated in human arteries affected with atherosclerosis by using monoclonal antibodies and indirect immunoperoxidase, immunogold silver staining, and double-labeling immunohistochemical techniques. Macrophages were found in all the atherosclerotic arteries as immunoreactive deposits with a nucleus, considered as intact cells, or without a nucleus, considered as cell remnants. The double-labeling technique shows C5b-9 deposits partially colocalized on the intact macrophages or on the cell debris of macrophage origin. These data suggest that C5b-9 complement complex may be formed on activated or dying macrophages with subsequent promotion of inflammatory events and progression of the atherosclerotic lesions.
Adult↗
A prospective study of the risk of an immediate adverse reaction to protamine sulfate during cardiopulmonary bypass surgery.
Protamine sulfate administration may cause life-threatening reactions. We prospectively examined the incidence of immediate adverse reaction after protamine in 243 patients who underwent cardiopulmonary bypass surgery. Twenty-six patients (10.7%) had reactions, and 1.6% had a precipitous drop in blood pressure immediately after protamine administration. Risk factors were previous exposure to protamine, diabetes, history of receiving protamine-containing insulin, and possibly vasectomy. However, neither a positive skin test nor a positive IgE ELISA for antiprotamine antibody predicted that a patient would have a reaction. C4a levels were increased in patients who had reactions as compared with age-, sex-, and cardiac disease-matched patients who did not have reactions, suggesting a role for complement in some reactions. Immediate adverse reactions to protamine are very common, and alternative therapies are urgently needed to eliminate the use of protamine.
Adult↗
Effects of the anaphylatoxins on circulation.
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Animals↗
Chemotactic activity of substances derived from antibody-loaded tumor cells on granulocytes.
Chemotactic activity of granulocytes attracted by tumor cells loaded either with anti-ganglioside monoclonal antibodies (mAb) or with antibody-glucose oxidase conjugates (mAb-GO) was investigated. The melanoma cell line SK-Mel-28 which expresses the ganglioside GD3 at high density as well as the neuroectodermal cell line SK-N-LO which expresses GD2 were used for the experiments. In the presence of 50% human AB-serum, antibody-loaded tumor cells induced chemotactic activity on granulocytes, probably due to the generation of C3a/C5a which could be detected in serum incubated with anti-GD3 loaded SK-Mel-28 cells. Both compounds could also be detected in vivo in the plasma of patients suffering from neuroblastoma during therapy with anti-GD2 antibodies. In another set of experiments mAb-GO conjugates generating high amounts of H2O2 in the presence of glucose were bound to these tumor cells. A significant lipid peroxidation could be observed in the simultaneous presence of iron and ascorbate. The lipid peroxidation products were measured as thiobarbituric acid-reactive substances (TBARS) and were also shown to induce chemotactic effects on granulocytes.
ABO Blood-Group System↗
Complement system protein C4 and susceptibility to hydralazine-induced systemic lupus erythematosus.
21 patients with systemic lupus erythematosus induced by long-term treatment with hydralazine were investigated to see whether susceptibility to this syndrome was associated with deficiency of the classical pathway complement protein, C4. 16 of 21 (76%) patients had one or more C4 null (ie, non-productive) alleles compared with 35 of 82 normal subjects (43%). This difference was significant. The HLA-DR4 antigen, known to be in linkage disequilibrium with the C4B null allele, was also significantly more frequent in the patients (14 of 21 patients compared with 31 of 81 normal subjects). Susceptibility to hydralazine-induced lupus, as in idiopathic systemic lupus erythematosus, may depend partly upon genetically determined C4 levels.
Alleles↗
Adipsin/acylation stimulating protein system in human adipocytes: regulation of triacylglycerol synthesis.
Through their capacity to store fatty acids as triacylglycerol molecules, adipocytes serve a vital physiologic role. This study presents further evidence that this process can be modulated in human adipocytes by the adipsin/acylation stimulating protein (ASP) pathway and suggests a novel function for the product of this system--ASP. The data demonstrate the following: (1) ASP stimulates triacylglycerol synthesis within adipocytes, and this occurs to a greater extent in differentiating than undifferentiated cells (242% +/- 32% vs 168% +/- 11%, p < 0.01, respectively, at an ASP concentration of 88 ng/mL; (2) ASP does not affect the Km for triacylglycerol synthesis but does substantially increase Vmax; (3) when ASP is generated in vitro through incubation of its precursor proteins under appropriate conditions, triacylglycerol synthesis increases to the same extent as when plasma-purified ASP is added to the medium; (4) human adipocytes contain mRNA for the specific serine protease adipsin and the two precursor proteins C3 and factor B required to interact for the production of ASP; and (5) the extent to which cultured differentiating adipocytes produce ASP is proportional to the degree to which they have accumulated triacylglycerol mass during differentiation (r2 = 0.7523, p < 0.0005). These findings provide the first evidence for the existence of the adipsin/ASP pathway in human adipocytes, and this may markedly enhance our understanding of the processes which regulate triacylglycerol clearance from plasma.
Acylation↗
Design, synthesis, and evaluation of A/C/D-ring analogs of the fungal metabolite K-76 as potential complement inhibitors.
The terpenoid 6,7-diformyl-3',4',4a',5',6',7',8',8a'-octahydro-4,6',7'-trihydrox y-2',5',5', 8a'-tetramethylspiro[1'(2'H)-naphthalene-2(3H)-benzofuran] (1a; K-76), a natural product of fungal origin, and its monocarboxylate sodium salt 1c (R = COONa; K-76COONa) inhibit the classical and alternative pathways of complement, and 1c was shown to inhibit the classical pathway at the C5 activation step. In an attempt to elucidate the essential pharmacophore of 1a,c, the natural product was used as a "topographical model" for the design of partial analogs retaining the desired complement inhibiting potency. Therefore, A/C/D-ring analogs have been synthesized, as shown in Scheme 1 using 3-methoxyphenol (3) and limonene chloride (5) as starting materials, which contain functional groups similar to those found on the natural product. The use of (4R)-(+)- and (4S)(-)-limonene chloride (5a,b, respectively) provided two series of compounds differing in the stereochemistry of the C-4 chiral center (limonene moiety numbering). The in vitro assay results of the inhibition of anaphylatoxin production and classical complement-mediated hemolysis revealed that 7-carboxy-2-(R,S)-methyl-2-(1'-methylcyclohexen-(4'R)-yl)-4-met hoxybenzofuran (13a) and 7-carboxy-2-(R,S)-methyl-2-(1'-methylcyclohexen-(4'S)-yl)-4-met hoxybenzofuran (13b) were active in the same range of concentrations as the natural product.
Animals↗
Activation of complement by DMSO and ethanol and its inhibition by soluble complement receptor type 1.
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Complement Activation↗
Generation of the membrane attack complex during haemodialysis: impact of classical and alternative pathway components.
1. The generation of the plasma SC5b-9 complex (the soluble form of the membrane attack complex) during haemodialysis was studied in 29 patients together with markers of the classical (C4d fragment) and alternative (Bb fragment) pathways and the common iC3b fragment. 2. In the patients dialysed with Hemophan and Cuprophan membranes, a rapid increase in the plasma levels of SC5b-9 complex, Bb fragment and iC3b fragment occurred within 15 min of the initiation of the haemodialysis procedure. The SC5b-9 complex and the Bb fragment concentrations remained at a plateau until 120 min thereafter. The iC3b fragment level showed a continual decline. 3. The C4d fragment concentrations remained unchanged, indicating that generation of the membrane attack complex is most likely due only to activation of the alternative pathway. 4. The generation of the membrane attack complex occurred throughout the full haemodialysis period. In patients treated with Polysulfon membranes no statistically significant variation in these components was noted. 5. The study shows that the membrane attack complex may be generated during the full period of the haemodialysis session and is a stable index of biocompatibility. 6. Moreover, it seems be involved directly in haemodialysis-associated phenomena.
Complement Activation↗
Complement split products and the pathogenesis of SLE.
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Anaphylatoxins↗
Complement and anaphylatoxin responses to cross-clamping of the aorta. Studies during general anaesthesia with or without extradural blockade.
Complement activation and anaphylatoxin formation were studied in 28 patients undergoing aortic reconstructive surgery under general anaesthesia. In 12 of the patients an extradural catheter was placed in the L1-2 space and 2% mepivacaine was injected until blockade reached the T4 level. The remaining 16 patients were operated upon under general anaesthesia alone. Complement activation was not obvious until aortic cross-clamping. The release of anaphylatoxin was less pronounced during cross-clamping in the extradural group.
Aged↗
C5a and thromboxane generation associated with pulmonary vaso- and broncho-constriction during protamine reversal of heparin.
The authors conducted a study in humans to determine the mediators associated with acute pulmonary vaso- and broncho-constriction occurring episodically with protamine reversal of heparin anticoagulation. Of 48 adult patients investigated prospectively after termination of cardiopulmonary bypass, two presented a sudden increase of airway pressure, acute pulmonary hypertension, and systemic hypotension 1-3 min after right atrial protamine injection. In these two subjects, plasma levels of C5a increased from 0.7 and 2.2 to 9.8 and 9.9 ng/ml, respectively, and thromboxane B2 increased from 0.26 and 0.34 to 7.5 and 16.2 ng/ml 1 minute after drug injection. A third subject not identified prospectively had an identical reaction and mediator profile (C5a, 10.2 ng/ml; TxB2, 18.6 ng/ml at 1 min). The plasma levels of these mediators were unchanged in the remaining patients (C5a, 0.7 +/- 1.1 [x +/- S.D.] to 0.6 +/- 0.9 ng/ml; TxB2, 0.16 +/- 0.12 to 0.15 +/- 0.07 ng/ml). Plasma histamine was not involved in this type of reaction, but increased from 0.7-10.4 ng/ml in a fourth patient who became hypotensive without acute pulmonary hypertension, bronchoconstriction, or elevation of C5a or TxB2. The authors' data indicate that the generation of high plasma levels of C5a anaphylatoxins and thromboxane is associated with pulmonary vaso- and broncho-constriction induced by protamine reversal of heparin in humans.
Adult↗
In vitro activation of human complement by polyacrilonitrile dialyzer membrane assayed by complement binding to bystander red cells.
Quantitation of complement activation by polyacrilonitrile (PAN) dialyzer membrane is complicated by the high adsorptive capacity of the membrane for fluid phase anaphylotoxins. Assays for these anaphylotoxins, therefore, underestimate the degree of complement activation produced by this membrane. Alternative methods of measuring in vitro complement activation by the PAN and Cuprophan membranes were explored by incubating normal human erythrocytes with the membranes in the presence of serum. This led to deposition of C3d on these "innocent bystander" red cells, and provided an independent parameter for measuring complement activation. The PAN membrane caused significantly more C3d deposition on red cells, and thus more complement activation than Cuprophan. The possible significance of complement activation by PAN membrane, in consideration of its property of binding the resultant anaphylotoxins, is discussed.
Acrylic Resins↗
Psoriasis and leukocyte chemotaxis.
Transepidermal migration of leukocytes, with resultant formation of microscopic or macroscopic sterile subcorneal pustules is a phenomenon characteristically noted in psoriasis and related sterile pustular dermatoses. It is natural to assume the presence of potent neutrophil chemotactic substances in the subcorneal portion of the lesional epidermis, because this location is the target of the in vivo leukocyte chemotaxis. In fact, crude psoriasis scale extracts show remarkably high neutrophil chemotactic and activating properties as compared with those of other non-psoriatic inflammatory dermatoses. We isolated a psoriatic leukotactic factor (PLF) having a molecular mass of around 12 kD, distinct from those common to other inflammatory changes involving the skin or those released by bacteria. Further analysis of PLF identified C5 cleavage fragments, together with other chemotactic peptides, such as those derived from monocytes. Likewise, potent low-molecular-mass chemotactic factors, including cell membrane lipid derived chemotactic factor, e.g. leukotriene B4, are also increased in psoriatic lesions, as in other nonpsoriatic inflammatory dermatoses. However, their activity to stimulate the generation of oxygen radicals in neutrophils was found to be much weaker than that of PLF. The peripheral blood leukocytes from active psoriatic patients show enhanced function in chemotaxis, phagocytosis, active oxygen production, and enzyme release; patients' sera contain substances such as anaphylatoxins that activate leukocyte function. Further research is required for clearer understanding of the series of events resulting in the leukocyte chemotaxis, as well as for the elucidation of the background immunoregulatory mechanisms.
Cell Movement↗
Is contact activation of the coagulation system involved in the genesis of the first-use syndrome?
A number of mechanisms have been thought to be involved in the pathogenesis of the first-use syndrome. These include IgE antibody-mediated response to ethylene oxide-related antigens, membrane activation of the alternative complement pathway, activation of tissue mast cells and basophils by materials released from the dialyzer into the circulation, and transfer of bacterial products through high flux dialyzer. However, the possible role of the activation of blood coagulation system and platelets during dialysis has not been considered. The present communication reviews the theoretical basis for a possible connection between dialysis-induced activation of platelets and coagulation system with the first-use syndrome. Although the available data concerning the activation of intrinsic coagulation pathway during dialysis are conflicting, there is no controversy as to the occurrence of platelet activation. It is suggested that biochemical events triggered by activation of these systems may in part contribute to the genesis of first-use syndrome.
Anaphylaxis↗
Human complement activation by purified Capnocytophaga exopolysaccharide. Measurement by radioimmunoassay.
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Adult↗
Measurement of the chemotactic complement fragment C5a in rheumatoid synovial fluids by radioimmunoassay: role of C5a in the acute inflammatory phase.
Evidence suggests that complement is activated in rheumatoid joints. A sensitive radioimmunoassay for the activation fragment of C5, C5a, which is a potent chemoattractant for neutrophils, was therefore developed. A mean C5a concentration in 22 rheumatoid joint fluids of about 2.5 x 10(-9) mol/l was found. This concentration of C5a is sufficient to induce two of the characteristic features of the acute inflammatory phases of rheumatoid arthritis: neutrophil accumulation and microvascular plasma protein leakage. In animal models it has been shown that C5a is a potent inducer of inflammatory oedema by a neutrophil dependent mechanism. A striking feature of the acute inflammatory phases of rheumatoid arthritis is the appearance of high numbers of neutrophils in the synovial fluid. It is suggested that C5a might have a role in mediating neutrophil accumulation and, as a consequence, may be important in acute joint swelling and pain.
Adult↗