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PubMed1984

Effects of human anaphylatoxins on guinea pig atria.

Purified human C3a and C5a produce positive inotropic effects on spontaneously contracting atria isolated from guinea pigs. The increased amplitude of contraction induced by C5a has a threshold at 1 X 10(-9)M. This effect is concentration dependent, increasing by 180% at 1.7 X 10(-7)M C5a. The threshold concentration for a C3a-induced effect is four times greater than that for C5a. The C3a-induced effect is also concentration dependent, maximizing at 1 X 10(-7)M. Above that concentration, the increased response to C3a reaches a plateau value at approximately a 70% greater amplitude than that of untreated tissue. Unlike effects induced by anaphylatoxins in other tissues, these positive inotropic responses are not tachyphylactic. The same atrium will respond repeatedly to either C3a or C5a for a period of up to 4 h. Studies with histamine, leukotriene and prostaglandin inhibitors revealed that the anaphylatoxin-induced responses are not solely histamine mediated. Cimetidine partially inhibited the response of isolated guinea pig atria to C5a (e.g. 25%) and failed to affect the response of this tissue preparation induced by C3a. FPL 55712 inhibited the response to both anaphylatoxins by approximately 40%. The atrial response to C3a was inhibited by more than 70% by indomethacin, whereas the response to C5a was unaffected. This is the first report characterizing the specific action of purified C3a and C5a on isolated cardiac tissue. It was concluded that C3a acts primarily via prostaglandins and leukotrienes while C5a affects contractile intensity via vasoamines and leukotrienes.

Alprostadil↗
PubMed1991

Activation of rabbit C3: studies of the generation of cleavage products in vitro and of their metabolism in vivo.

The cleavage of purified, functionally active rabbit C3 by cobra venom factor and trypsin was analysed by reducing and non-reducing sodium dodecyl sulphate electrophoresis and autoradiography. The specific aim of the study was to compare these reactions to those that occur with human C3. Analysis showed that the pattern of breakdown was very similar to that for the human protein: while the beta-chain remained intact, there was step-wise degradation of the alpha-chain to form C3a, C3b, iC3b and C3c, all of which could be identified by gel analysis. The metabolic behaviour of three of these cleavage products, C3a, C3b and iC3b, was then examined in vivo using dual isotope techniques. Rabbits were studied simultaneously with 131I-C3 and 125I-labelled C3 breakdown products. Analysis of plasma and urine radioactivity for the subsequent 72 h showed that all three breakdown proteins had rapid rates of catabolism in vivo compared to the native molecule. Specifically, 93 and 98% of C3b and iC3b, respectively, were eliminated from the plasma compartment within 10 h of injection. C3a was completely eliminated within 10 h. By comparison, native C3 showed a half-life of 29 +/- 3 h (mean +/- SD) and a fractional catabolic rate of 4.30 +/- 0.75%/h. The data support the use of this species in studies of complement behaviour in models of human immune disease and further clarify the basis for changes in plasma C3 concentration that accompany active immune complex- and antibody-mediated activity, in vivo.

Animals↗
PubMed2006

C5 modulates airway hyperreactivity and pulmonary eosinophilia during enhanced respiratory syncytial virus disease by decreasing C3a receptor expression.

Enhanced respiratory syncytial virus disease, a serious pulmonary disorder that affected recipients of an inactivated vaccine against respiratory syncytial virus in the 1960s, has delayed the development of vaccines against the virus. The enhanced disease was characterized by immune complex-mediated airway hyperreactivity and a severe pneumonia associated with pulmonary eosinophilia. In this paper, we show that complement factors contribute to enhanced-disease phenotypes. Mice with a targeted disruption of complement component C5 affected by the enhanced disease displayed enhanced airway reactivity, lung eosinophilia, and mucus production compared to wild-type mice and C5-deficient mice reconstituted with C5. C3aR expression in bronchial epithelial and smooth muscle cells in the lungs of C5-deficient mice was enhanced compared to that in wild-type and reconstituted rodents. Treatment of C5-deficient mice with a C3aR antagonist significantly attenuated airway reactivity, eosinophilia, and mucus production. These results indicate that C5 plays a crucial role in modulating the enhanced-disease phenotype, by affecting expression of C3aR in the lungs. These findings reveal a novel autoregulatory mechanism for the complement cascade that affects the innate and adaptive immune responses.

Animals↗
PubMed1999

Hemodynamic effects of methylprednisolone in patients undergoing cardiac operation and early extubation.

BACKGROUND: Whether or not methylprednisolone is beneficial during cardiac operation remains controversial. This study examines the effects of the drug on complement activation and hemodynamics in patients undergoing cardiac operation and early extubation. METHODS: Patients undergoing cardiac operation were randomized to receive either intravenous methylprednisolone (group MP) or intravenous placebo (group NS). Complement 3a (C3a) levels and hemodynamic parameters were obtained perioperatively. Extubation was accomplished at the earliest clinically appropriate time. RESULTS: Both groups exhibited equivalent increases in C3a levels after exposure to bypass. Group MP exhibited increased cardiac index, decreased systemic vascular resistance, and increased shunt flow when compared to group NS. More group MP patients required hemodynamic support and group MP patients had prolonged extubation times. CONCLUSIONS: Methylprednisolone was unable to attenuate complement activation and led to hemodynamic alterations (primarily vasodilation) that may hinder early extubation in patients after cardiac operations.

Adult↗
PubMed1988

Development of a simple radioimmunoassay for human C3a.

A radioimmunoassay was devised for the human complement cleavage product, C3a, using charcoal separation and selective precipitation of interfering substances. When compared with the commercially available immunoassay now marketed, the assay reported here was somewhat simpler to perform; furthermore, it overcame delivery and availability problems in Europe. The assay showed a mean recovery of 87% of known amounts of C3a or C3adesarginine and had a sensitivity of 32 ng C3a per milliliter of plasma; coefficients of variance were comparable to other radioimmunoassays in common use. Using this assay in a first clinical application, we were able to document a small but statistically significant rise in [C3a] during cardiopulmonary bypass.

Anaphylatoxins↗
PubMed1981

Anaphylactic actions of platelet-activating factor.

Platelet-activating factor (1-O-alkyl-2-acetyl-sn-glycero-3-phosphorylcholine) is a potent inducer of systemic anaphylactoid reactions in animals. It was found to be similarly potent in contracting smooth muscle of guinea pig ileum and lung and in enhancing vascular permeability when injected subcutaneously into these animals. This factor, therefore, possesses in vitro and in vivo bioactions that resemble those of C3a and C5a anaphylatoxins. However, platelet-activating factor induces a slowly developing, sustained contractile wave in ileum that is not inhibited by an antihistaminic compound, pyrilamine, whereas C3a and C5a stimulate rapid transient contraction that is abrogated by the antihistamine. Furthermore, platelet-activating factor desensitized the ileum to restimulation by itself but not by C3a or C5a; conversely, C3a and C5a desensitized the ileum to themselves but not to platelet-activating factor. Thus, platelet-activating factor possesses a distinctive set of anaphylactic actions. It stimulates a slow wave of muscle contraction and can act independently of histamine release and receptors for the C3a and C5a anaphylatoxins.

Anaphylatoxins↗
PubMed1997

Detection and quantification of the control proteins of the alternative pathway of complement in 3T3-L1 adipocytes.

The complement peptide C3a desarg is identical to acylation-stimulating protein (ASP), a human plasma protein that potently stimulates adipocyte triacylglycerol synthesis and glucose transport. Both human and murine adipocytes express mRNA and/or protein for the complement components C3 and factors B and D (adipsin) required to generate ASP. However, the regulatory mechanisms controlling this process are unknown. We have established a semiquantitative reverse transcriptase polymerase chain reaction (RT-PCR) technique to demonstrate the presence in mouse 3T3-L1 adipocytes of mRNA for all components of the alternative pathway, including the control proteins factors I and H, CR1 and properdin. On differentiation, mRNA for C3 (fivefold) and factor D (> 50-fold) increased, whereas stimulation with tumour necrosis factor (TNF)-alpha and interleukin (IL) 1 beta led to eightfold increases in factor B mRNA. Metabolic labelling followed by immunoprecipitation showed that factor B protein is normally present in small quantities, and is greatly increased by cytokine stimulation. The larger quantities of C3 and H proteins present were little affected, whereas levels of C3a increased on cytokine stimulation. These results suggest that the rate-limiting step in the cytokine-induced production of ASP in adipocytes is factor B synthesis.

3T3 Cells↗
PubMed1987

Anaphylatoxin-induced neutrophil chemotaxis and aggregation. Limited aggregation and specific desensitization induced by human C3a and synthetic C3a octapeptides.

Human neutrophil aggregation was induced by highly purified human C3a and chemically synthetic COOH-terminal peptides of C3a (C3a-8R; Ala-Ala-Ala-Leu-Gly-Leu-Ala-Arg) in a dose-dependent manner and was 40% of human C5a-induced aggregation at each optimal concentration. In contrast to C5a and formyl-Met-Leu-Phe (f-MLP), C3a and C3a-8R showed little chemotactic activity. Specific desensitization of neutrophil aggregation was observed with C3a, C3a-8R, C5a and f-MLP, but not with C3a-des-Arg-7R, indicating that the human neutrophil has C3a-specific binding sites which are different from C5a and f-MLP receptors. An additive effect on aggregation was observed at suboptimal concentrations of C5a (1 X 10(-8) M) and C3a (1 X 10(-6) M) or C3a-8R (1 X 10(-5) M). These studies suggest that a subpopulation of human neutrophils have specific binding sites for C3a and C3a may work cooperatively with C5a during the process of neutrophil activation by increasing aggregation and lysosomal enzyme release.

Anaphylatoxins↗
PubMed1987

C3a(C3adesArg) induces production and release of interleukin 1 by cultured human monocytes.

Purified human C3a(C3adesArg) induced dose-dependent generation of intracellular IL 1 activity and release of IL 1 in cultures of human mononuclear adherent cells in serum-free conditions. Concentrations of C3a(C3adesArg) of 10(-8) M and 6 hr of culture were sufficient to induce production of cell-associated IL 1, as detected in monocyte lysates. Ten- to 100-fold higher concentrations of C3a(C3adesArg) and 24 hr of culture were required for induction of IL 1 release. Release of IL 1 induced by suboptimal amounts of C3a(C3adesArg) was greatly enhanced by the addition of indomethacin to the culture medium. Contamination with C5a of the C3a(C3adesArg) preparation did not account for C3a(C3adesArg)-induced IL 1 production. Induction of IL 1 activity by C3a(C3adesArg) was not due to contaminating LPS, as indicated by the following observations: the amount of contaminating LPS in C3a(C3adesArg) was below that which could induce IL 1 release from human monocytes in serum-free conditions; induction of IL 1 by C3a(C3adesArg) was not suppressed by polymyxin B; kinetics of IL 1 production and release in the presence of C3a(C3adesArg) differed from those observed in the presence of LPS; and sialated gangliosides, which inhibit IL 1 release induced by LPS, had no effect on the induction of IL 1 by C3a(C3adesArg). The C3a(C3adesArg) preparation used in this study mostly contained the desArg derivative, suggesting that, in contrast with the requirement for an intact C-terminal arginyl residue for the spasmogenic activity of C3a, both C3a and its C3adesArg derivative may interact with receptors on human monocytes. By inducing IL 1 production and release, C3a(C3adesArg) may contribute to the generation of the inflammatory process and the regulation of the immune response.

Cells, Cultured↗
PubMed1984

Analysis of the binding of fluorescent C5a and C3a to human peripheral blood leukocytes.

Fluorescein-labeled human C5a and C3a were prepared and utilized to analyze the binding of C5a and C3a to human neutrophils and mononuclear cells. The fluorescein derivatives of C5a (Fl-C5a) and C3a (Fl-C3a) contained approximately one fluorescein molecule per molecule of protein. Fl-C5a retained biologic activity as determined by neutrophil O2- production, enzyme release, receptor binding, and reaction with rabbit anti-C5a antibody. Fl-C3a was biologically active as measured by contraction of guinea pig ileal strips, and maintained 87% of its antigenic character when reacted with rabbit anti-human C3a. The binding of Fl-C5a and Fl-C3a to human neutrophils and mononuclear cells was assessed with the use of flow cytometry. Fl-C5a bound to greater than 90% of neutrophils, with an average ED50 ranging from 2.8 to 6.8 nM, depending on the method of analysis. Fl-C5a binding to neutrophils was specific and was not inhibited by the presence of formyl-methionyl-leucyl-phenylalanine (f-MLP), C3a, or casein. Fl-C5a binding was totally blocked by an excess of C5a. C5a des arg partially inhibited the binding of Fl-C5a to neutrophils, but was 1000-fold less effective than C5a. Similar experiments with mononuclear cells showed that Fl-C5a was bound by monocytes but not by lymphocytes. Fl-C5a binding to monocytes was blocked totally by C5a but not by C3a or f-MLP. Comparative binding studies with neutrophils, monocytes, and lymphocytes showed that Fl-C5a was bound by an average of 93% +/- 4 of neutrophils, 68% +/- 9 of monocytes, and 6% +/- 3 of lymphocytes. Fl-C3a did not show significant binding to neutrophils, monocytes, or lymphocytes. These studies demonstrate that fluorescein derivatives of C5a and C3a can be prepared with retention of biologic activity, and provide a means to evaluate the binding of C5a to individual cells.

Adult↗
PubMed1999

Chimeric receptors of the human C3a receptor and C5a receptor (CD88).

Chimeras were generated between the human anaphylatoxin C3a and C5a receptors (C3aR and C5aR, respectively) to define the structural requirements for ligand binding and discrimination. Chimeric receptors were generated by systematically exchanging between the two receptors four receptor modules (the N terminus, transmembrane regions 1 to 4, the second extracellular loop, and transmembrane region 5 to the C terminus). The mutants were transiently expressed in HEK-293 cells (with or without Galpha-16) and analyzed for cell surface expression, binding of C3a and C5a, and functional responsiveness (calcium mobilization) toward C3a, C5a, and a C3a as well as a C5a analogue peptide. The data indicate that in both anaphylatoxin receptors the transmembrane regions and the second extracellular loop act as a functional unit that is disrupted by any reciprocal exchange. N-terminal substitution confirmed the two-binding site model for the human C5aR, in which the receptor N terminus is required for high affinity binding of the native ligand but not a C5a analogue peptide. In contrast, the human C3a receptor did not require the original N terminus for high affinity binding of and activation by C3a, a result that was confirmed by N-terminal deletion mutants. This indicates a completely different binding mode of the anaphylatoxins to their corresponding receptors. The C5a analogue peptide, but not C5a, was an agonist of the C3aR. Replacement of the C3aR N terminus by the C5aR sequence, however, lead to the generation of a true hybrid C3a/C5a receptor, which bound and functionally responded to both ligands, C3a and C5a.

Anaphylatoxins↗
PubMed1991

Effect of a short maximal physical exercise on coagulation, fibrinolysis, and complement system.

In 11 healthy young subjects, the plasma concentrations of the thrombin-antithrombin III complex, fibrinopeptide A, tissue-plasminogen activator, complement fragments C3a and C4a, and histamine were measured before and after a graded maximal bicycle exercise test. The analyses were carried out 30 min before and immediately before exercise, immediately after exercise, and 30 and 60 min later. All post-exercise values were corrected for plasma volume changes, which were calculated from hematocrit and hemoglobin values. Immediately post-exercise, thrombin-antithrombin III, tissue-plasminogen activator, complement fragments C3a and C4a, and histamine were all significantly elevated (p less than 0.01), compared with the pre-exercise values; 30 and 60 min later the values normalized and significant differences from the pre-exercise values could no longer be measured. Fibrinopeptide A did not change significantly after exercise. The present results provide evidence for a simultaneous activation of coagulation, fibrinolysis, and complement system as well as for a release of histamine after a short maximal exercise.

Adult↗
PubMed2006

Are quality differences responsible for different adverse reactions reported for SD-plasma from USA and Europe?

Thromboembolic adverse reactions reported after transfusion of SD-plasma in the United States (US) prompted us to perform a comparative study with SD-plasma from the US and the European (EU) market. In SD-plasma from US, residual tri-N-butyl phosphate was found, and citrate concentrations were lower than in EU-plasma. Except for substantial losses of FV, FVIII and antiplasmin found for all SD-plasmas, clotting factor activities were mainly retained. However, for SD-plasma from US, markedly elevated concentrations of lipoprotein (a) [Lp(a)], fibrin monomer and a particularly high degree of complement activation (C3a des-Arg) were observed. Furthermore, pronounced differences were found for protein S. Although SD-plasma pools from US contained nearly normal concentrations of free and bound protein S antigen, protein S activities were almost completely absent. In contrast to this, SD-plasma from EU showed a moderate loss of both protein S activity and free antigen. Antitrypsin inhibitor activities were much more diminished in SD-plasma from US than from EU. In view of a possible thrombogenicity of SD-plasma from US, the loss of protein S and elevated Lp(a) concentrations could be of significance. The very high levels of C3a des-Arg in US plasma could possibly have an additional effect, through priming platelet activation after transfusion.

Blood Coagulation Factors↗
PubMed1985

Salivary gland lymphocytes in primary Sjogren's syndrome lack lymphocyte subsets defined by Leu-7 and Leu-11 antigens.

Primary Sjogren's Syndrome (SS) is an autoimmune disease characterized by dry eyes and dry mouth due to lymphocytic infiltration of lacrimal and salivary glands. Biopsies of their salivary glands provided an opportunity to characterize the phenotypic and functional properties of inflammatory site lymphocytes. We found that the salivary gland lymphocytes (SGL) of SS patients differed from the peripheral blood lymphocytes of the same patients because: a) SGL lacked lymphocytes reactive with anti-Leu-7 and anti-Leu-11 monoclonal antibodies; b) SGL lacked natural killer (NK) activity; and c) SGL lacked the ability to suppress polyclonal B cell responses in the presence of complement fragment C3a, a function that requires the presence of Leu-7+ cells. These studies also showed that the SGL of SS patients differed from tonsillar lymph node (LN) lymphocytes of immunologically normal individuals because tonsillar LN contained Leu-7+ T cells, and tonsillar LN could suppress polyclonal B cell responses in the presence of the complement fragment C3a. The absence of this regulatory subset in the salivary glands of SS patients may contribute to pathogenesis, because these cells may be important in the suppression of polyclonal antibody synthesis and in the elimination of neoplastic or viral infected cells.

Adolescent↗
PubMed1998

Inflammatory signals induce neurotrophin expression in human microglial cells.

Inflammatory processes involving reactive microglia, e.g., those associated with beta-amyloid containing neuritic and core plaques in Alzheimer's disease, appear to contribute to neuronal degeneration in the CNS. The fact that increased nerve growth factor (NGF) protein levels were found throughout brains of Alzheimer's disease patients led us to investigate neurotrophin synthesis in a human microglial cell line showing typical properties of human microglial cells, including expression of neurotrophins such as NGF, as well as the NGF receptor trkA and the low-affinity neurotrophin receptor p75. We found that the cytokines interleukin-1beta and tumor necrosis factor-alpha synergistically stimulate microglial NGF transcription and protein release. Moreover, exposure of microglial cells to complement factor C3a induces NGF expression. To assess the role of the transcription factor nuclear factor-kappaB (NF-kappaB) in inflammatory mediator-induced microglial NGF expression, the effect of the NF-kappaB inhibitor pyrrolidine dithiocarbamate (PDTC) was analyzed. In the presence of PDTC, a dose-dependent inhibition of cytokine-activated NGF expression occurred. In contrast, the C3a-dependent stimulation of NGF synthesis was not influenced by PDTC. In addition, microglial neurotoxicity-mediating beta-amyloid peptides A beta(1-40) and A beta(1-42) failed to alter NGF synthesis, whereas A beta(25-35) specifically induced NF-kappaB-dependent microglial NGF expression. In conclusion, inflammatory signals (cytokines and complement factors), as well as A beta(25-35), are potent stimulators of human microglial NGF synthesis involving NF-kappaB-dependent and -independent mechanisms. Microglial secretion of neurotrophins appears to be involved in early processes of neuronal regeneration.

Amyloid beta-Peptides↗
PubMed2000

Discrimination of sepsis and systemic inflammatory response syndrome by determination of circulating plasma concentrations of procalcitonin, protein complement 3a, and interleukin-6.

OBJECTIVE: To evaluate whether plasma concentrations of procalcitonin (PCT), interleukin-6 (IL-6), protein complement 3a (C3a), leukocyte elastase (elastase), and the C-reactive protein (CRP) determined directly after the clinical onset of sepsis or systemic inflammatory response syndrome (SIRS) discriminate between patients suffering from sepsis or SIRS and predict the outcome of these patients. DESIGN: Prospective study. SETTING: Medical intensive care unit at a university hospital. PATIENTS: Twenty-two patients with sepsis and 11 patients with SIRS. MEASUREMENTS AND MAIN RESULTS: The plasma concentrations of PCT, C3a, and IL-6 obtained < or =8 hrs after clinical onset of sepsis or SIRS but not those of elastase or CRP were significantly higher in septic patients (PCT: median, 16.8 ng/mL, range, 0.9-351.2 ng/mL, p = .003; C3a: median, 807 ng/mL, range, 422-4788 ng/mL, p < .001; IL-6: median, 382 pg/mL, range, 5-1004 pg/mL, p = .009, all Mann-Whitney rank sum test) compared with patients suffering from SIRS (PCT: median, 3.0 ng/mL, range, 0.7-29.5 ng/mL; C3a: median, 409 ng/mL, range, 279566 ng/mL; IL-6: median, 98 pg/mL, range, 23-586 pg/mL). The power of PCT, C3a, and IL-6 to discriminate between septic and SIRS patients was determined in a receiver operating characteristic analysis. C3a was the best variable to differentiate between both populations with a maximal sensitivity of 86% and a specificity of 80%. An even better discrimination (i.e., a maximal sensitivity of 91% and a specificity of 80%) was achieved when PCT and C3a were combined in a "sepsis score." C3a concentrations also helped to predict the outcome of patients. Based on the sepsis score, a logistic regression model was developed that allows a convenient and reliable determination of the probability of an individual patient to suffer from sepsis or SIRS. CONCLUSIONS: Our data show that the determination of PCT, IL-6, and C3a is more reliable to differentiate between septic and SIRS patients than the variables CRP and elastase, routinely used at the intensive care unit. The determination of PCT and C3a plasma concentrations appears to be helpful for an early assessment of septic and SIRS patients in intensive care.

Adult↗
PubMed1987

[The effect of benzydamine on various functions of human granulocytes and their interaction with endothelial cells].

The influence of the non-steroidal antiinflammatory drug benzydamine (Tantum) was studied on several functions of human polymorphonuclear leukocytes, namely their adhesion to endothelial cells, the leukocyte auto-aggregation and their locomotion into cellulose nitrate filters or on glass surfaces. The granulocytes were stimulated either by the synthetic oligopeptide N-formyl-methionyl-leucyl-phenylalanine (FMLP) or the physiologically important complement anaphylatoxins C3a and C5a-desArg. The experiments showed that benzydamine reduces effectively the attachment of granulocytes to endothelium of isolated guinea pig aortic strips (IC50 3-4 X 10(-6) mol/l). This effect seems to be exclusively due to the inhibition of granulocyte adhesiveness and cannot be washed out. Benzydamine also diminishes leukocyte aggregation induced by either the complement peptides C3a, C5a-desArg or FMLP, and in addition causes deaggregation of already formed leukocyte aggregates. However, benzydamine is inhibitory only at 1-3 X 10(-4) mol/l. Likewise, C5a-desArg-induced leukotaxis and phagocyte polarization on glass surfaces as well as spontaneous migration of unstimulated granulocytes in Boyden chambers are decreased only at 10(-4) mol/l. By contrast, benzydamine usually augments chemotaxis in Boyden chambers induced by concentration gradients of the stimuli. This effect might be explained by the prevention of the known auto-oxidative inhibition of phagocytes exerted by benzydamine. Regarding the therapeutic significance, inhibition of the leukocyte-endothelial interaction appears to be of considerable pharmacologic relevance to explain the antiphlogistic properties of benzydamine in vivo.

Animals↗