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PubMed1991

[The relationship between complement C3 receptors (CR1, CR3) on polymorphonuclear leukocytes and complement fragments during hemodialysis].

The expression of complement receptor type 1 (CR1) and type 3 (CR3) on polymorphonuclear leukocytes (PMNs) and generation of complement fragments, C3a, C5a, C4d, iC3b and Bb, were studied in patients during hemodialysis using cuprammonium rayon (Cu) membranes. Furthermore, the relation between the expression of CR1 and CR3 on PMNs from healthy donors and complement fragments was investigated. The expression of CR1 and CR3 on PMNs increased during hemodialysis. Plasma C3a, C5a and iC3b levels increased in the first 15 minutes and then decreased at 120 minutes of dialysis. But plasma Bb level remained high until the end of hemodialysis. Purified Bb had no effect on the expression of CR1 and CR3 on PMNs, but C5a augmented those expression in vitro. Nafamostat mesilate, an artificial proteinase inhibitor, inhibited augmentation of complement receptors on PMNs in concentration dependent fashion. C5a generated through the activation of complement was thought to take an important role in the increased expression of CR1 and CR3 on PMNs.

Aged↗
PubMed1983

Human platelet activation by C3a and C3a des-arg.

C3a liberated from C3 by treatment with C3 convertase (or by trypsin) induced aggregation of gel-filtered human platelets and stimulated serotonin release. At concentrations of 10(-10) M to 8 X 10(-12) M, C3a induced aggregation when added alone to platelets. However, at lower concentrations (2 X 10(-12) M) C3a did not aggregate platelets directly but exhibited highly significant synergism (two-way analysis of variance P less than 0.0001) with ADP in mediating platelet aggregation and release of serotonin. Removal of the C-terminus arginine from C3a abolished anaphylotoxin activity but did not affect the platelet-stimulating activity of the peptide. C3a and C3a des-arg were equally reactive in mediating platelet aggregation and release of serotonin. Further C3a and C3a des-arg exhibited synergism with ADP of equal significance in both aggregation and the release reaction. The concentrations of C3a required for the platelet-stimulating activity involve relatively small number of molecules per platelet (4,000-10,000 for the synergistic reaction with ADP). These data suggest the possibility of a C3a (C3a des-arg) receptor on human platelets. This premise is strengthened by the demonstration ultrastructurally of C3a on the platelet membrane subsequent to C3a stimulation.

Adenosine Diphosphate↗
PubMed1986

Complement activation during systemic lupus erythematosus. C3a and C5a anaphylatoxins circulate during exacerbations of disease.

To determine whether activated complement components appear in the circulation of patients with systemic lupus erythematosus (SLE), we measured C5a and C3a by radioimmunoassay. Mean C5a concentration in the plasma of acutely ill SLE patients was 46.0 ng/ml, compared with 17.1 ng/ml in normal controls (P less than 0.01). Mean C3a concentration in patients with severe disease was 526 ng/ml, compared with 134 ng/ml in controls (P less than 0.01). In patients with moderately active SLE, the mean C3a concentration, but not the mean C5a concentration, was also elevated. In addition, C3a was elevated in 15 or 21 patients with active SLE, whereas low levels of C3 or C4 were noted in only 7 of these 21 patients. We conclude that the measurement of complement-derived anaphylatoxins may be useful in the management of patients with SLE. In addition, we suggest that these circulating mediators may contribute to the pathogenesis of vascular injury in patients with the disease.

Complement Activation↗
PubMed1990

Anaphylatoxins C3a and C5a adsorption on acrylonitrile membrane of hollow-fiber and plate dialyzer--an in vivo study.

We studied the adsorption of anaphylatoxins C3a and C5a on acrylonitrile (AN69) hollow-fiber (AN69HF) and plate (AN69P) dialyzers in 8 patients during 4-hour hemodialyses (HD). Blood passed first through a cuprophan dialyzer and then through AN69 dialyzers that were not in contact with dialysis fluid. Plasma C3a and C5a were measured in samples taken from the afferent and efferent blood lines of the acrylonitrile dialyzers at 15, 60 and 240 min. Plasma C3a concentrations decreased significantly in blood that had passed through AN69 dialyzers. This decrease, indicating membrane adsorption, was maximal (by 65% in AN69HF and by 59% in AN69P) at 15 min and minimal (by 53% in AN69HF and by 18% in AN69P) at 240 min. The decrease in plasma C5a concentrations was smaller and significant throughout HD only with AN69HF. The amount of C3a adsorbed was at least 45,000 micrograms in AN69HF and 18,000 micrograms in AN69P. These findings demonstrate that acrylonitrile dialyzers adsorb more C3a and C5a than they produce. This membrane adsorption may explain why the increase of plasma C3a and C5a is inhibited during HD.

Acrylonitrile↗
PubMed1991

FUT-175 as a potent inhibitor of C5/C3 convertase activity for production of C5a and C3a.

We examined the inhibitory effect of FUT-175 on the C3/C5 convertase activity of the cobra venom factor-derived enzyme CVF,Bb by measuring C5b6-mediated reactive lysis of unsensitized guinea pig erythrocytes and by measuring directly the released fragments C3-des-Arg and C5a-des-Arg. In this study, we showed that the concentration of 4.5 X 10(-6) M of FUT-175 caused 50% inhibition of C5 convertase activity of CVF,Bb in reactive hemolysis assays, and that 4.0 X 10(-6) M FUT-175 caused 50% inhibition of the production of C3a and C5a generated by the C3/C5 convertase activity of CVF,Bb.

Animals↗
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↗
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↗
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↗
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↗
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↗
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↗
PubMed1982

C3a-induced lysosomal enzyme secretion from human neutrophils: lack of inhibition by f met-leu-phe antagonists and inhibition by arachidonic acid antagonists.

C3a-induced lysosomal enzyme secretion from human peripheral neutrophils in a noncytolytic, dose-dependent (10-100 microgram/ml) process. Release of both primary and secondary granule constituents occurred when neutrophils were exposed to C3a plus cytochalasin B, however, C3 alone induced limited release of lysozyme. A competitive antagonist of the formyl-peptide receptor on neutrophils, t boc (phe-leu) 2-phe, did not block the release induced by C3a. Arachidonic acid antagonists, nordihydroguaiaretic acid and quercetin caused dose-dependent inhibition of release induced by C3a plus cytochalasin B, however, lysozyme release induced by C3a in the absence of cytochalasin B was minimally affected. Indomethacin at high concentration (greater than 10(-5) M) had similar inhibitory effects.

Anaphylatoxins↗
PubMed1983

Anaphylatoxin formation during hemodialysis: comparison of new and re-used dialyzers.

Hemodialysis of 11 endstage renal failure patients with new cuprophan hollow fiber dialyzers produced significant leukopenia as well as increased plasma levels of both C3a and C5a antigens during the initial phases of the procedure. Formalin-fixed new dialyzers produced quantitatively similar phenomena in eight of these same patients. By contrast, hemodialysis with re-used dialyzers, that is dialyzers exposed to blood prior to formalin sterilization, produced only a 20 to 30% decline in peripheral blood leukocyte counts. Correspondingly, C3a antigen formation within re-used dialyzers was only 20% of that observed in new dialyzers. Re-used dialyzers also differed significantly from either new or formalin-fixed new dialyzers in that C3b antigen could be readily detected within them even after extensive washing. These observations suggest that C3b deposition on the cellulosic membrane surface during first use markedly diminishes the complement activating potential of cuprophan dialyzers when they are subsequently re-used.

Adult↗
PubMed1984

Immunoregulatory effects of C3 and its major cleavage fragments.

The immunoregulatory effects of highly purified C3 and its major cleavage fragments on in vitro responses of human peripheral blood mononuclear cells (PBMC) were examined. Polyclonal immunoglobulin production induced by PWM and T-cell proliferation stimulated by tetanus toxoid in human PBMC were inhibited by human C3b. This effect occurred in a dose range of 10(-6) to 10(-8) M and was observed in cultures containing human serum but not under serum-free conditions. This noncytotoxic suppression did not appear to be mediated by prostaglandin release nor by interference with antigen uptake and presentation by monocytes. In contrast, the addition of C3a resulted in a mild enhancement of immunoglobulin production and T-cell proliferation. This effect, however, was observed only under serum-free conditions and, thus, may not have physiologic importance. The native C3, from which the above fragments were generated, had no effect on these lymphocyte responses. These results suggest that regulation of immune responses may be one consequence of C3 cleavage during complement activation in vivo.

Antibody Formation↗