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PubMed1987

Assessment of complement activation during extracorporeal circulation by measurement of complement split C3d.

The present report summarizes our previous experience with the effect of various dialyzer membranes on leukocyte count, plasma C3d and C5a/C5ades-Arg, and total hemolytic complement. A relationship between the formation of C5a/C5ades-Arg within the dialyzer and hemodialysis leukopenia was demonstrated by comparing different membranes. Arterial plasma C3d was found to be a useful cumulative marker of complement activation during hemodialysis. C3d was shown to be generated in the artificial kidney with kinetics resembling the formation of C5a/C5ades-Arg. Total hemolytic complement transitorily decreased with all membranes, but did not reflect dialyzer biocompatibility. It is suggested that determination of complement-split C3d outdates previous more elaborate estimates of complement activation during hemodialysis.

Complement Activation↗
PubMed1987

Analysis of membrane processes for blood purification.

Physical phenomena play an important role in membrane processes for blood purification. They largely determine the separation performance of these devices and they interact with chemical and biological phenomena to determine their biocompatibility, or lack thereof, in the clinical setting. In the first part of this paper, analyses of physical phenomena which determine the separation and purification characteristics are reviewed for several processes, including hemodialysis, hemofiltration, combined hemodialysis and ultrafiltration, and membrane plasmapheresis with cross-flow microfiltration. Special attention is given to transport of high-molecular weight solutes in hemodialysis, for use in subsequent analyses, and to the factors which determine filtrate flux in membrane plasmapheresis, because recent findings in this area provide an understanding of filtration processes in general. The second part concerns the problem of biocompatibility, especially as manifested in renal prostheses. After reviewing some of the pathways to bioincompatibility, exploratory analyses are presented using relatively simple models. The objective of these analyses is to provide an initial quantitative framework for examining the likelihood of monocyte secretion of interleukin-1 being stimulated by various routes. Issues examined, for which illustrative calculations are presented, include (1) transport of endotoxin fragments across regenerated cellulose and other membranes, (2) anaphylatoxin C5a concentrations in conventional hemodialysis and (3) the effects of equilibrium and reaction phenomena, ultrafiltration, diffusive membrane permeation and membrane adsorption on the disposition of C5a which is generated at the membrane surface.

Animals↗
PubMed1988

Good biocompatibility of the polyamide hemofilter.

Chronic hemofiltration (HF) is now a well-established method, especially for elderly uremic patients and those suffering from cardiovascular problems. This is due to the fact that chronic HF offers superior treatment comfort with less hypotensive episodes, vomiting, muscle cramps and febrile reactions. Apart from the different blood purification techniques involved in chronic HF compared to hemodialysis (i.e. convection versus diffusion), it might well be that the better treatment comfort is attributable to a certain extent to the polyamide HF membrane used in our HF treatments. We studied different biocompatibility parameters and received the following data: (a) leukocytes and thrombocytes remained unchanged during a treatment session; (b) elastase increased slightly but there was no difference between the polyamide and polycarbonate membrane, and (c) arterial and venous concentrations of C5a and C3d remained almost unchanged. The superior treatment comfort and better vascular stability of HF over hemodialysis might also be due to the improved biocompatibility of the applied hemofilter as the polyamide membrane induces no changes in different biocompatibility parameters such as leukocytes, thrombocytes, C5a or C3d.

Biocompatible Materials↗
PubMed1988

Generation and removal of anaphylatoxins during hemofiltration with five different membranes.

The generation of anaphylatoxins (C3a and C5a) during hemofiltration with polysulfone (F60), acrylonitrile (AN69 HF), polyamid (FH77), polyacrylonitrile (PAN200) and cellulose-acetate (Duo-Flux) membranes were investigated. The 'net' production of C3a in the blood compartment during the treatment was 3,028 micrograms (Duo-Flux), 1,845 micrograms (FH77), 270 micrograms (F60), -2,388 micrograms (AN69 HF) and -5,189 micrograms (PAN200), the latter two negative values reflecting a high adsorption of C3a to the membrane material. Corresponding values for C5a were 185 micrograms (AN69 HF), 108 micrograms (F60), 83 micrograms (PAN200), 6 micrograms (FH77) and -133 micrograms (Duo-Flux). The sieving coefficient remained stable for C5a throughout the treatment, while it fell significantly for C3a with the F60 membrane (0.44-0.25) and increased significantly for the FH77 membrane (0.14-0.33). The cellulose-acetate membrane device produced the most pronounced drop in white blood cell counts and the acrylonitrile membrane the least. The Duo-Flux device was significantly less biocompatible than the other membranes investigated, while little differences were found between AN69 HF, F60, FH77 and PAN200. When hemodialysis is compared with hemofiltration employing the same membranes, the latter appears to be a more biocompatible treatment modality partly due to convective removal of activated complement from the blood compartment into the filtrate.

Anaphylatoxins↗
PubMed1986

Serum profiles of the regulatory complement proteins during the progression of renal damage in human glomerulonephritis.

Persistent activation of the complement system after escape from control by the regulatory proteins results in an excessive release of split products with inflammatory properties. Serum levels of the regulatory proteins of the complement system (Cl-INH, H, I and AT III) were assayed by the radial immunodiffusion technique in 521 serum samples from 124 patients with idiopathic chronic glomerulonephritis divided into two groups: 81 cases with normal renal function (NRF), and 43 cases with deteriorated renal function (DRF). Significant high mean levels of Cl-INH, H, I and AT III were found in patients with NRF, when they were compared with DRF patient groups. Positive correlations between the regulatory proteins and the corresponding complement components were found in patients with NRF, whereas they were reduced considerably in patients with DRF. Serial measurement of the control proteins showed a decay of the levels of Cl-INH, H and I in patients with progressive impairment of renal function. The presence of high levels of regulatory proteins suggest that a control mechanism may occur in patients with NRF; measurement of these proteins could, therefore, be of prognostic value, as the presence of high levels are indicative of a block of the complement system.

Antithrombin III↗
PubMed1989

Comparative study of C5a plasma levels with different hemodialysis membranes using an enzyme-linked immunosorbent assay.

Using a specific and sensitive ELISA for C5a, the present study shows that predialysis levels of C5a in end-stage renal disease patients are not elevated and that all membranes studied (Cuprophan, Hemophan, Gambrane and hydrophilic polysulfone) cause significant increases of C5a plasma levels albeit to different degrees. Higher increases of C5a were accompanied by larger decreases of circulating granulocytes and monocytes. Dialyzers with a newly introduced modified regenerated cellulose membrane, Hemophan, showed lower C5a plasma levels during hemodialysis than Cuprophan. With Hemophan C5a plasma levels were comparable to those with polysulfone membranes.

Adult↗
PubMed1975

Effects of anesthesia, surgery and inflammation upon host defense mechanisms. I. Effects upon the complement system.

Complement protein levels and C7 hemolytic activity were measured in four individuals following anesthesia and surgery, and in a group of 20 patients with inflammatory diseases. Seven of the eight complement components studied characteristically were elevated, most dramatically C1s and C3PA. Elevation of C1s often was greater than elevation of C1q, displaying an independent variation of C1s and C1q in both postoperative and inflammatory disease patient groupds. The major increases of C components were seen subsequent to the peak C-reactive protein response, as was the occurrence of the 'reactor state', a propensity to formation of C56 which surprisingly was associated with increased levels of C7. Levels of properdin frequently were reduced postoperatively. It is concluded that multiple complement components, with the notable exception of properdin, respond as acute phase reactants which are elevated and changed in proportion postoperatively and during inflammatory disease.

Anesthesia, General↗
PubMed1980

Mediators of immune complex-induced aggregation of polymorphonuclear neutrophils. I. C5a anaphylatoxin, neutrophil cationic proteins and their cleavage fragments.

This study reports the results of in vitro investigations on the aggregation of polymorphonuclear neutrophils (PMN) induced by the C5a anaphylatoxin complement component as well as the cationic proteins (CP), which are released by challenging PMN with immune complexes (IC). The carboxy-peptidase-derived des-Arg fragments of CP and C5a; CPi and C5ai, inactive in terms of anaphylactic and chemotactic activity, nevertheless showed a more potent ability to aggregate PMN than CP and C5a. The process of PMN aggregation required metabolic energy and divalent cations, Ca++ and Mg++. The microtubular system and the subplasmalemmal microfilaments appeared to be of critical importance. Electron microscopic studies on aggregates of PMN obtained on stimulation with CP, C5a, CPi and C5ai showed parallel tracts of variable length of cell membranes at the points where cells were in contact with each other.

Anaphylatoxins↗
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↗
PubMed1982

Morphological changes in human polymorphonuclear leukocytes induced by C3a in the presence and absence of cytochalasin B.

Treatment of human peripheral polymorphonuclear leukocytes(PMNs) with C3a leads to profound changes in cell morphology, along with the limited secretion of lysozyme. Simultaneous addition of C3a and cytochalasin B enhances the release of lysosomal enzymes and renders the cell morphology similar to that seen when either C5a or n-formyl peptides are added to PMNs in the presence of cytochalasin B. The morphological response of PMNs treated with C3a is considerably more heterogeneous than that induced by either C5a or n-formyl-methionyl-leucyl-phenylalanine, indicating that some, but not all, PMNs have receptors for C3a.

Cell Membrane↗
PubMed1985

New developments in immunopathology with special reference to complement and immune complexes.

The last few years have seen rapid advances in our understanding of immune phenomena, and these are now being translated into a new understanding of immunopathology. This paper reviews a number of areas where important new knowledge has been gained in the area of complement and immune complexes as a cause of disease. An understanding of the role of the metabolism of complement proteins has led to an understanding of how these proteins interact with receptors to cause phagocytosis. New understanding of the lysis-producing steps has led to new diagnostic tests for complement-induced damage as well as new knowledge of how complement functions to kill microorganisms. New methods for purifying anaphylatoxins have made these proteins available for study in man. A model of serum sickness in man has allowed for the more detailed understanding of how immune complexes cause disease and has led to the appreciation of new clinical signs of immune-complex-mediated disease in man.

Antigen-Antibody Complex↗
PubMed1985

Indomethacin enhances in vitro histamine release induced by anti-IgE and Ca-ionophore but inhibits C5a-induced release reactions from basophils of atopics and normals.

Preincubation of peripheral leukocytes from atopics and normals significantly enhanced histamine release induced by anti-IgE and calcium ionophore. On the other hand, there was a significant inhibition (ca. 40%) of C5a-induced histamine release by indomethacin both in atopics and controls. In the group of patients with atopic eczema, anti-IgE-induced histamine release was significantly higher than in controls both without and with indomethacin.

Adolescent↗
PubMed1985

Adhesion of guinea pig polymorphonuclear leukocytes to autologous aortic strips: influence of chemotactic factors and of pharmacological agents which affect arachidonic acid metabolism.

In superfusion experiments, the complement peptide C5a-desArg and the leukotriene B4 (LTB4) enhanced adhesion of guinea pig polymorphonuclear leukocytes to autologous aortic strips (threshold at about 10(-8) M, maximal effects at 10(-7) M). C5a-desArg acted primarily by stimulation of the leukocytes: pretreatment of them with the peptide abolished their response by deactivation, whereas pretreatment of the endothelium did not affect adhesion. However, the endothelium obviously cooperated in the response: enhanced adhesion was obtained only when the leukocytes were exposed to C5a-desArg while in contact with the endothelium. The cooperation is most probably due to release of arachidonic acid from endothelium and formation of lipoxygenase products (LTB4?) therefrom by the stimulated leukocytes. Incubation of leukocytes with nordihydroguaiaretic acid or with relatively high concentrations of indomethacin--both known to inhibit lipoxygenases-- lowered the effect of C5a-desArg, but not that of LTB4 nor the spontaneous adhesion. On the other hand, the stable prostacyclin analogue ZK 36 374 decreased C5a-desArg-induced adhesion, while pretreatment of the aortic strips with indomethacin increased it. These results suggest that endogenous prostacyclin may also play a role in this system by reducing adhesion.

Animals↗
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↗
PubMed1988

Human C5a induces a substantial histamine release in human basophils but not in tissue mast cells.

The histamine-releasing effect of human C5a was compared with that of concanavalin A in blood basophils and isolated adenoidal mast cells from the same donors. In basophils, C5a (10 ng/ml) induced a significant histamine release (7.5 +/- 2.1%, corrected value). In isolated adenoidal mast cells C5a had only a marginal effect (2% histamine release), although the cells responded markedly to concanavalin A stimulation (about 13% release). The results support the view that the heterogeneity of mast cells and basophils is also reflected in the expression of anaphylatoxin receptors on their surface.

Adenoids↗
PubMed1988

C5a-induced bronchoconstriction: absence of a role of circulating white blood cells and platelets.

C5a causes an intense bronchoconstriction when injected intravenously into the guinea pig. The present study was designed to determine if circulating white blood cells or platelets were important target cells for the induction of bronchoconstriction on intravenous injection of C5a. To accomplish this, we examined the effect of C5a on numbers of circulating cells as well as the effect of depletion of various circulating cell populations on C5a-induced bronchoconstriction. Intravenous injection of C5a caused a precipitous drop in circulating granulocytes which preceded the maximum bronchoconstrictor response. The levels of circulating platelets and mononuclear cells were unchanged by intravenous injection of C5a. Depletion of either white blood cells or platelets did not significantly alter either the maximum bronchoconstrictor response to C5a or the time course of the response. Thus, these studies suggest that C5a-induced bronchoconstriction in the guinea pig is not dependent on an interaction of C5a with circulating white blood cells or platelets.

Airway Resistance↗
PubMed1988

The significance of complement activation in the pathogenesis of hypersensitivity pneumonitis: sequential changes of complement components and chemotactic activities in bronchoalveolar lavage fluids.

Hypersensitivity pneumonitis (HP) is believed to be induced by immunological mechanisms, the details of which remain to be clarified. While a role for cellular immunity is accepted in the pathogenesis of HP, several clinical observations also suggest a role for immune-complex-mediated lung injury. We have previously demonstrated the presence of chemotactic factors for polymorphonuclear cells (PMNs) in bronchoalveolar lavage (BAL) fluids of acutely ill patients with the summer type of HP found in Japan. The present study correlated chemotactic factors for PMNs with the level of C5a des Arg in BAL fluids obtained from patients with summer type HP. Furthermore, this study demonstrated that PMNs were increased in BAL fluids obtained after 2 days of avoidance of exposure to the presumptive causative agent. The percentage of PMNs in the BAL increased in proportion to the activity of the chemotactic factors. Finally, leukotriene B4 was not detected in concentrated BAL or supernatant fluids of cultured macrophages. These results suggest that complement activation in the respiratory tract may occur as the early event in the pathogenesis of HP.

Alveolitis, Extrinsic Allergic↗