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PubMed1986

Compartmental distribution of complement activation products in artificial kidneys.

The compartmental distribution of the human anaphylatoxins C3a and C5a has been defined during simulated hemodialysis performed with various types of hemodialyzers. New cuprophan hollow fiber dialyzers were found to activate human complement very readily in vitro, while re-used cuprophan dialyzers displayed only modest complement activating potential. The C3a and C5a antigens, formed as a result of complement activation in these dialyzers, accumulated predominantly in the blood path and were not adsorbed extensively on the membrane surface or transported into the dialysate compartment. Cellulose acetate membranes also produced complement activation in vitro, but to a lesser degree than new cuprophan hollow fibers. However, these membranes exhibited a significant capacity to bind the anaphylatoxins to their surface. Polyacrylonitrile membranes appeared to be unique in that they not only failed to activate complement significantly, but they rapidly adsorbed large quantities of C3a and C5a. These findings demonstrate that hemodialysis membranes may differ with regard to their complement activating potential as well as their ability to remove circulating anaphylatoxins from the blood path. Clinical measurements of anaphylatoxin production during hemodialysis reflect these dynamic events.

Complement Activation↗
PubMed1990

[Determination of C3a and C5a in hemapheresis procedures].

Study of the interface between blood and artificial surfaces reveals numerous undesirable reactions. For example, the formation of biologically active peptides, C3a and C5a (anaphylatoxins), is a result of complement activation via the alternative pathway. It cannot be denied that the reinjection of large quantities of these molecules could be at the origin of serious side effects. We report herein the anaphylatoxin levels found with 9 hemapheresis procedures (4 plasma filtration membranes, 3 systems for platelet collection, 2 plasma treatment techniques (dextran sulfate cellulose column and cascade filtration)). All the filtration procedures generated very high levels of anaphylatoxins, especially C3a. In contrast, the centrifugation systems produced lower levels. However, considerable amounts of C3a were found with the Cobe Spectra and V50 Haemonetics blood cell separators. The anaphylatoxins generated by the primary filter were partially retained by the dextran sulfate column. These high toxin levels enable an assessment of the degree of hemo-incompatibility of these systems. However, it remains difficult to evaluate whether these anaphylatoxins are dangerous or not.

Blood Component Removal↗
PubMed1977

Characterization of a leukotactic factor derived from psoriatic scale.

A study was made on the in vitro characteristics and in vivo biological activities of a leukotactic factor derived from psoriatic scale (PLF). Sephadex G-75 chromatography showed that PLF eluted in the region of the 12,500 dalton protein marker. It resisted heating, lyophilization, acidity (pH 3) and alkalinity (pH 11), but was destroyed by trypsin digestion. The substance attracted polymorphonuclear leukocytes (PMNs) in vitro; this ability was inhibited by antiserum to C3a and was partially reduced by antiserum to C5. Although PLF showed strong chemotactic activity for PMNs, its activity for mononuclear cells was only mild. Intradermal injection of PLF into man or guinea-pig produced an erythematous response with dense tissue neutrophilia, the time course of which was similar to that of the Arthus response. PLF also provoked increased vascular permeability in guinea-pig skin. Moreover, repeated intradermal injection of PLF to the same site in guinea-pigs led to moderate acanthosis of the overlying epidermis. These observations strongly suggest that transepidermal migration of leukocytes in psoriatic lesions is provoked by PLF, whose activity appears to reflect that of complement cleavage products, particularly C3a, presumably produced by complement activation in the subcorneal region of the epidermis. Furthermore, it is postulated that PLF may be a factor which plays a crucial role in the production of typical psoriasiform tissue changes.

Animals↗
PubMed1996

Alkylation of cellulosic membranes results in reduced complement activation.

4-Vinyl pyridine was grafted to the surface of the cellulosic membrane Cuprophan, and subsequently alkylated with both C10 and C16 aliphatic chains. Complement activation of heparinized human blood, corrected for anaphylatoxin adhesion, was measured by radioimmunoassay. The surface treatments both yielded substantial reductions in C5a activity, with a lessor reduction in C3a and C4a activity. Alkylation with 10 and 16 carbon chains resulted both in enhancements of albumin adsorption and stability. These enhancements as well as the reductions in complement activation were statistically indistinguishable between the two treatments. The reduction in complement activation was influenced more by adsorption of endogenous albumin and possibly by the vinyl pyridine graft, than the removal of surface active hydroxyl groups from Cuprophan.

Adsorption↗
PubMed1996

Activation of circulating polymorphonuclear leukocytes in preterm infants with severe idiopathic respiratory distress syndrome.

We have studied activation of circulating polymorphonuclear leukocytes (PMN) in plasma of preterm infants with severe idiopathic respiratory distress syndrome (IRDS group, n = 15) and without IRDS (reference group, n = 15) during the first 5 postnatal days. We have observed lower median PMN counts in the IRDS group than in the reference group from d 2 (1.4 x 10(9)/L versus 4.8 x 10(9)/L in the reference group, p < 0.001) to d 4 to 6 (1.6 x 10(9)/L versus 4.0 x 10(9)/L, p < 0.01). Lower PMN counts in the IRDS infants were accompanied by lower median plasma elastase-alpha1-proteinase inhibitor (PI) concentrations (53.6 ng/mL versus 128.0 ng/mL in the reference group on d 2, p < 0.05). Simultaneously, median elastase-alpha1-PI/PMN ratios of these infants were significantly higher (40.8 ng/10(6) PMN versus 21.8 ng/10(6) PMN on d 2, p < 0.05), indicating activation of circulating PMN. Activation of circulating PMN in the IRDS group is associated with platelet-activating factor (PAF) release and complement activation from within 6 to 12 h of birth but not with release of tumor necrosis factor-alpha. PAF release was represented by significantly reduced inhibiting capacity (58% of normal human plasma, p < 0.01) and complement activation by higher median plasma C3a des-Arg concentrations (1680 ng/mL versus 325 ng/mL in the reference group, p < 0.001). We conclude that circulating PMN are activated in preterm infants with severe IRDS, which might be caused by systemic PAF release and complement activation. This activation process may play a role in the pathogenesis of the IRDS by influx of activated PMN into the lungs.

Complement C3a↗
PubMedDate not supplied

A protamine filter for extracorporeal heparin removal. Development, testing, blood compatibility evaluation, and future direction.

The authors previously developed a filter device containing immobilized protamine (termed "protamine filter") that could be used to remove heparin during extracorporeal perfusion. In vivo studies involving dogs showed that the protamine filter removed more than 50% of heparin from the animals' blood circuit in less than 20 min. In addition, the use of the protamine filter did not elicit statistically significant protamine induced hemodynamic and thrombocytopenic responses. Biocompatibility of the protamine filter was also evaluated, with the focus on its effect on the coagulation cascade, the complement system, and the blood antithrombin III levels. Results showed that heparin adsorbed to the protamine coated surface retained 20% of its original activated partial thromboplastin time activity, rendering the coated surface antithrombotic. Activation of the coagulation system by the protamine coated membrane and the untreated cellulose membrane, as measured by the elevation of prothrombin fragment F1 + 2 levels, was statistically identical. The CH50 hemolytic assay showed that the protamine coated membrane produced a reduction of 1.2 +/- 0.8% of the total complement levels, as compared to 9.4 +/- 1.6% by the untreated membrane. In addition, the change in C3a des Arginine levels after 30 min of circulation was 1.5 +/- 0.2 mg/ml by the protamine filter, as compared to 2.1 +/- 0.1 mg/ml by the untreated membrane. Unlike native heparin that would bind with antithrombin, heparin adsorbed on the protamine coated surface was devoid of such activity, and produced no depletion of circulating antithrombin. Because of the limited capacity of the protamine filter, the future system is envisioned to consist of two filters; while one filter is removing heparin the other will be regenerated. With a recently developed heparin sensor, it should be possible to design a sensor directed, biofeedback, two filter heparin removal system.

Adsorption↗
PubMed1988

Complement kinetics during continuous arteriovenous hemofiltration: studies with a new polysulfone hemofilter.

Biocompatibility of the Renaflo polysulfone hemofilter was assessed during treatments with continuous arteriovenous hemofiltration. Pre- versus postfilter levels of C3a, C4a, C5a and leukocyte counts were measured prior to and 15, 60 and 90 min after placement of the Renaflo. Results revealed a small, and previously unrecognized, increase in postfilter C3a (1,224 +/- 56 vs. 1,535 +/- 150 ng/ml, mean +/- SEM, n = 15; p less than 0.01). A comparable increase was also found during treatment with an Amicon polysulfone filter. There were no other significant changes in any parameter studied and no patient exhibited symptoms related to complement activation. We conclude that the Renaflo filter is safe for use during continuous arteriovenous hemofiltration. Although clinically insignificant, there is a detectable activation of C3 by polysulfone membranes.

Aged↗
PubMed1987

Polyacrylonitrile complement activation attenuated by simultaneous ultrafiltration and adsorption.

The highly permeable synthetic polyacrylonitrile (PAN) membrane (Filtral; Hospal, Basle) is regarded as biocompatible for its slight complement activation and leucocyte sequestration. The low C3a and C5a concentrations during PAN dialysis may be due to a lack of complement activation potential of this polymer, but also to elimination of activated complement components by the dialyser through adsorption and/or ultrafiltration (mol wt of C3a and C4a 9000 daltons; of C5a 11,000 daltons). Comparing arteriovenous differences throughout the study, higher concentrations of C3a (+23%; n.s.) and C5a (+80%; P less than 0.05) were measured in the efferent blood lines, suggesting a slight complement activation by the alternate pathway. A significantly lower C4a concentration in the efferent blood lines (-30%, P less than 0.05) indicates an elimination within the dialyser. Significantly higher arteriovenous concentration differences at the beginning of dialysis and increasing sieving coefficients suggest elimination by adsorption, mainly in the first 20 min of haemodialysis. The continuous decrease of C3a and C4a plasma concentrations in the afferent blood line suggests transport across the membrane and removal by the dialysate. Accordingly, measurable amounts of these complement components were detected in ultrafiltrate.

Acrylic Resins↗
PubMed2006

Complement activation by photooxidation products of A2E, a lipofuscin constituent of the retinal pigment epithelium.

Recent studies have implicated local inflammation and activation of complement amongst the processes involved in the pathogenesis of age-related macular degeneration (AMD). Several lines of investigation also indicate that bis-retinoid pigments, such as A2E, that accumulate as lipofuscin in retinal pigment epithelial (RPE) cells, contribute to the disease process. In an investigation of a potential trigger for complement activation in AMD, we explored the notion that the complex mixture of products resulting from photooxidation of A2E might include a range of fragments that could be recognized by the complement system as "foreign" and that could serve to activate the complement system, leading to low-grade inflammation. To this end, we established an in vitro assay by using human serum as a source of complement, and we measured products of C3 activation by enzyme immunoassay. Accordingly, we found that the C3 split products inactivated C3b (iC3b) and C3a were elevated in serum, overlying ARPE-19 cells that had accumulated A2E and were irradiated to induce A2E photooxidation. Precoating of microtiter plates with two species of oxidized A2E, peroxy-A2E, and furano-A2E, followed by incubation with serum, also activated complement. We suggest that products of the photooxidation of bis-retinoid lipofuscin pigments in RPE cells could serve as a trigger for the complement system, a trigger than would predispose the macula to disease and that, over time, could contribute to chronic inflammation. These findings link four factors that have been posited as being associated with AMD: inflammation, oxidative damage, drusen, and RPE lipofuscin.

Cell Line↗
PubMed1991

Improved biocompatibility of silicone rubber by removal of surface entrapped air nuclei.

Biomaterials activate the complement system which is important since C3a promotes platelet aggregation and release, and C5a activates neutrophils that may augment coagulation. Tiny air nuclei (microbubbles) are found in the surface roughness of biomaterials on exposure to a liquid, therefore two interfaces exist: (a) a blood/biomaterial, and (b) a blood/air interface. Experiments were carried out that documented that air bubbles activate complement and augment in vitro platelet aggregation in human plasma. The air nuclei were removed from the surface of silicone rubber by a technique termed denucleation to determine if complement activation and platelet aggregation could be reduced. We observed a significant reduction in C3a and C5a in the plasma samples incubated with denucleated silicone rubber as compared to the control samples (p less than 0.001, ANOVA). The plasma incubated with the denucleated silicone caused reduced platelet aggregation as compared to the plasma incubated with the control silicone when added to a platelet suspension (p less than 0.001, ANOVA). Surface chemical analysis by x-ray photo-electron spectroscopy (XPS) showed no change in the silicone rubber surface after the denucleation procedure.

Air↗
PubMed1998

Monocyte tissue factor expression and ongoing complement generation in ventricular assist device patients.

BACKGROUND: Ongoing complement activation in patients with a ventricular assist device may contribute to observed hemostatic abnormalities and cellular aggregation by mediating leukocyte and platelet activation, formation of leukocyte-platelet conjugates, and the tissue factor pathway of coagulation. METHODS: Blood from 30 patients was collected before ventricular assist device implantation and during the implantation period. Plasma levels of thrombin-antithrombin III complexes, C3a, and SC5b-9 were measured by commercial enzyme-linked immunosorbent assay. Flow cytometry was used to measure circulating monocyte tissue factor expression and circulating monocyteplatelet and granulocyte-platelet conjugates. RESULTS: Thrombin-antithrombin III complex level and monocyte tissue factor expression peaked in the early postoperative period, with maxima occurring on postoperative days 5 and 3, respectively. Levels of C3a and SC5b-9 remained dramatically elevated over normal values for the duration of the study (6 and 5 times upper normal, respectively). Levels of monocyte-platelet conjugates were normal before implantation, decreased during the first 4 postoperative days, and then increased and remained elevated. Levels of granulocyte-platelet conjugates were elevated over the normal range before implantation and remained elevated from postoperative days 3 to 21. A positive correlation was found between levels of SC5b-9 and granulocyte-platelet conjugates (Spearman R=0.66; p < 0.001), and between levels of C3a and thrombin-antithrombin III complex (Spearman R=0.13; p=0.021). CONCLUSIONS: The data suggest a model in which complement mediates formation of leukocyte-platelet aggregates and may indirectly contribute to thrombin generation through monocyte tissue factor expression.

Adult↗
PubMed2003

F(ab)'2-mediated neutralization of C3a and C5a anaphylatoxins: a novel effector function of immunoglobulins.

High-dose intravenous immunoglobulin (IVIG) prevents immune damage by scavenging complement fragments C3b and C4b. We tested the hypothesis that exogenous immunoglobulin molecules also bind anaphylatoxins C3a and C5a, thereby neutralizing their pro-inflammatory effects. Single-cell calcium measurements in HMC-1 human mast cells showed that a rise in intracellular calcium caused by C3a and C5a was inhibited in a concentration-dependent manner by IVIG, F(ab)2-IVIG and irrelevant human monoclonal antibody. C3a- and C5a-induced thromboxane (TXB2) generation and histamine release from HMC-1 cells and whole-blood basophils were also suppressed by exogenous immunoglobulins. In a mouse model of asthma, immunoglobulin treatment reduced cellular migration to the lung. Lethal C5a-mediated circulatory collapse in pigs was prevented by pretreatment with F(ab)2-IVIG. Molecular modeling, surface plasmon resonance (SPR) and western blot analyses suggested a physical association between anaphylatoxins and the constant region of F(ab)2. This binding could interfere with the role of C3a and C5a in inflammation.

Animals↗
PubMed1994

Polymeric biomaterials: influence of phosphorylcholine polar groups on protein adsorption and complement activation.

The introduction to polymeric biomaterials of phosphorylcholine polar groups represents an approach towards the development of materials with improved blood compatibility. In this respect, two biomaterials, one a copolymer of butyl methacrylate and 2-methacryloyloxyethylphosphorylcholine (MPC), (poly(BMA-co-MPC) and the other, MPC-grafted Cuprophan, were examined with respect to their influence on protein adsorption and complement activation. Protein adsorption was studied by measurement of the adsorption of radiolabelled single proteins (albumin and fibrinogen), while complement activation was measured using radioimmunoassay for C3a des Arg. The investigation demonstrated that the polymers containing phosphorylcholine polar groups can achieve a marked reduction in protein adsorption and complement activation and supports the utilization of phosphorylcholine polar groups as a means of improving the compatibility of biomaterials for blood-contacting applications.

Adsorption↗
PubMed1991

The anaphylatoxins C3a and C5a are vasodilators in the canine coronary vasculature in vitro and in vivo.

The effect of complement fragments on coronary blood flow in vivo and the contraction of coronary arteries in vitro was determined. In pentobarbital anesthetized dogs, intraarterial bolus injection of C3a and C5a, zymosan-activated serum and methylcholine in the coronary vascular bed caused transient and dose-dependent increases in coronary blood flow. Similar increases were obtained with 25 micrograms of C3a (104 +/- 13%, n = 5) and 0.1 microgram of methylcholine (102 +/- 4%, n = 3). Smaller increases in blood flow were elicited by 25 micrograms of C5a (41 +/- 18%, n = 4) and 0.2 ml of zymosan-activated serum (48 +/- 5%, n = 4). None of these responses were associated with significant changes in left ventricular contractile force measured with a strain gauge, arterial blood pressure, and heart rate. C3a dilated the coronary vascular bed in conscious dogs with an activity equal to or greater than that observed in anesthetized dogs. Isolated canine coronary arteries that were precontracted with serotonin relaxed in response to C3a, whether or not the endothelium was intact. Overall these data suggest that physiologically high doses of anaphylactic complement fragments vasodilate the canine coronary circulation.

Animals↗
PubMed1988

Detection of the terminal complement complex in patient plasma following acute myocardial infarction.

The mechanisms of inflammation responsible for the myocardial tissue damage seen after an acute myocardial infarction (AMI) have not been clearly identified. Recent lines of evidence, demonstrating depressed sera levels of individual complement components in patients after myocardial infarction, have suggested involvement of the complement (C) system in micro- and macrovascular injury subsequent to AMI. The present study assessed the role of complement as a mediator of myocardial inflammation by quantifying products of complement activation including, the terminal complement complex (TCC) the cytolytic component of the complement system, C1rC1s-C1 inhibitor complex and C3bBbP complex, formed following activation of the classical and alternative pathway, respectively, and anaphylatoxins C3a and C5a in 41 patients following AMI. Plasma TCC and C1rC1s-C1 inhibitor complex concentrations increased up to 32-fold (P less than 0.001) and 8-fold (P less than 0.001), respectively, while the C3bBbP complex, C3a des-Arg and C5a des-Arg each increased over 2-fold (P less than 0.001) 16 h after AMI, and were only minimally detectable during non-inflammatory myocardial conditions. Furthermore, TCC concentrations increased over 150% (P less than 0.001) one day after patients reinfarcted, subsequent to hospitalization for a primary AMI. These results demonstrate activation of complement after AMI and suggest that inflammatory mediators of the complement system may contribute to myocardial tissue damage during the infarction process.

Adult↗
PubMed1992

Generation of iC3 at the interface between blood and gas.

Earlier studies have shown that C3 can be denatured when blood comes in contact with a polystyrene surface. This study was undertaken to see if similar denaturation of C3 occurs at the gas-plasma interface which is found in all kinds of oxygenator used during cardio-pulmonary operations. An in vitro system consisting of gas bubbling through human blood, serum or plasma was used. The generation of C3a, as an indicator of complement activation, and iC3 and iC3 fragments were monitored. Both C3a and iC3/iC3 fragments levels were increased during bubbling. In contrast to the C3a level, no reduction in iC3/iC3 fragments formation was seen in the presence of EDTA, indicating that it was independent of complement activation. The rate of iC3/iC3 fragments generation was unaffected by the composition of the gas (pure oxygen, pure nitrogen or air), suggesting that the denaturation of C3 indeed occurred at the serum-gas interface. C3 and iC3/iC3 fragments were isolated from bubbled EDTA-chelated serum by PEG precipitation and chromatography on FPLC, using a Mono S column and detected by two ELISAs, specific for native C3 and iC3/iC3 fragments. After 240 min approximately 20% of the total amount of C3 consisted of intact iC3 and it was confirmed that this population bound to human erythrocytes.

Blood↗
PubMed1993

Blood activation during neonatal extracorporeal life support.

Cardiopulmonary bypass for heart operations is associated with a whole body inflammatory reaction. The main factors involved in this reaction are the contact system and the complement system. The activation of the contact system is considered mainly responsible for impaired hemostasis because it affects platelet function. The activation of the complement system is considered the main cause for organ dysfunction, particularly of the lung, due to activation of leukocytes. This study in 10 neonates was undertaken to evaluate if there are effects of activation of the contact and the complement systems in neonatal extracorporeal life support comparable to those during cardiopulmonary bypass for cardiac operations. Two periods of blood activation during extracorporeal life support could be distinguished. The initial blood-material interaction at the onset of extracorporeal life support resulted in activation of both the contact and the complement systems. The contact activation was apparent by elevated factor XIIa-C1 esterase inhibitor complexes, decreased kallikrein inhibitory capacity, thrombin-antithrombin III formation, and moderate generation of fibrin(ogen) degradation products. The complement activation was characterized by elevated C3a, decreased leukocyte count, elastase release, and tumor necrosis factor-alpha production. This initial activation pattern subsided by 24 hours. A second activation period was observed 72 hours after the onset of extracorporeal life support, which was characterized only by increased clotting and fibrinolytic activity while no activation of the complement system was observed. We conclude that the initial activation pattern in extracorporeal life support is similar to that observed during cardiopulmonary bypass for cardiac operations. The contact activation that affects platelets might explain the continuous platelet consumption observed during extracorporeal life support. In this period, as in cardiopulmonary bypass, aprotinin given in the pump prime might be effective to prevent platelet consumption and impairment of hemostasis also in extracorporeal life support. The complement activation and leukocyte inflammatory reaction during the initial period are able to cause a capillary leak syndrome and might therefore explain the frequently observed temporary compromised lung function in extracorporeal life support. This reaction, as in cardiopulmonary bypass, might be reduced by the use of specific drugs or heparin coating also in extracorporeal life support. The cause of the second period of activation during extracorporeal life support requires further studies before adequate measures can be recommended.

Acute-Phase Proteins↗
PubMed2006

Complement mediators in ischemia-reperfusion injury.

BACKGROUND: Ischemia-reperfusion (I/R) injury occurs when a tissue is temporarily deprived of blood supply and the return of the blood supply triggers an intense inflammatory response. Pathologically, increased complement activity can cause substantial damage to blood vessels, tissues and also facilitate leukocyte activation and recruitment following I/R injury. Herein, previously published studies are reported and critically reviewed. METHODS: Medline and the World Wide Web were searched and the relevant literature was classified under the following categories: (1) Complement pathways; (2) The complement system and the inflammatory response; (3) Complement in ischemia-reperfusion injuries; and (4) Therapeutic approaches against complement in I/R injuries. RESULTS AND CONCLUSIONS: I/R injury is a common clinical event with the potential to seriously affect, and sometimes kill, the patient and is a potent inducer of complement activation that results in the production of a number of inflammatory mediators. Complement activation leads to the release of biologically active potent inflammatory complement substances including the anaphylatoxins (C3a and C5a) and the cytolytic terminal membrane attack complement complex C5b-9 (MAC). The use of specific complement inhibitors to block complement activation at various levels of the cascade has been shown to prevent or reduce local tissue injury after I/R. Several agents that inhibit all or part of the complement system, such as soluble complement receptor type 1 (sCR1), C1 inhibitor (C1-INH), C5a monoclonal antibodies, a C5a receptor antagonist and soluble CD59 (sCD59) have been shown to reduce I/R injury of various organs. The novel inhibitors of complement products may eventually find wide clinical application because there are no effective drug therapies currently available to treat I/R injuries.

Animals↗