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PubMedDate not supplied

The effects of activated complement on myocardial performance in vitro.

Activated complement has been implicated in the dysfunction of several organ systems, but can it directly affect the myocardium? This possibility was studied using human right atrial trabeculae contracting isometrically "in vitro" in four solutions: Tyrode's (T), autologous arterial blood (B), plasma (P) and denaturated plasma (DP). Complement was activated by the addition of Zymosan while vehicle alone was used as control. Complement activation occurred in the blood and plasma solutions, as assessed by a significant drop in CH50 (p less than 0.05), while there was no detectable complement activity in either T or DP. Myocardial functional integrity was assessed by the change in contractile parameters with time. Subsequent resting forces, relative developed forces (DF), and rates of decay of DF were similar between muscles contracting in the four solutions. We conclude that activated complement has no direct effect on myocardial performance.

Blood↗
PubMed1979

Complement activation in acne vulgaris: consumption of complement by comedones.

Comedones, the contents of acne lesions, were shown to consume scomplement hemolytic activity in normal serum. This consumption was stimulated by the addition of serum from patients with inflammatory acne. Absorption of acne serum with Propionibacterium acnes cells removed all stimulating activity. Immunoelectrophoretic analysis of serum incubated with comedones revealed the conversion of C3 and factor B in normal serum. The addition of acne serum resulted in cleavage of C4. In serum treated with ethylene glycol-bis(beta-aminoethyl ether)-N,N'-tetraacetic acid, only C3 and factor B were converted. This indicates that comedones may activate complement by either the classical or the alternative pathway. It is suggested that P. acnes cells in comedonal material are responsible for the complement activation.

Acne Vulgaris↗
PubMedDate not supplied

Dialysis leukopenia and hypoxemia in a patient without measurable complement activity.

We have studied complement activity, total leukocyte counts, PO2 and acid-base balance during a single hemodialysis with cuprophan membranes in a patient with hereditary angioedema and C3NeF-positive chronic membranoproliferative glomerulonephritis. Before, during and after the dialytic procedure plasma complement activity (total hemolytic complement, classical and alternative pathway activities) was not detectable and no C3-conversion occurred, while profound leukopenia (from 8,500 to 1,800 leukocytes/microliter) and hypoxemia (from 101.8 to 86 mmHg PO2) were found within 20 min from the initiation of hemodialysis. Similar results were obtained by studying the same parameters during two additional hemodialytic procedures. In vitro experiments showed that the patient's C3 could not be converted, either by cuprophan or zymosan, a specific and potent complement activator, even under optimal experimental conditions. Our data demonstrate that complement activation is not the only possible mechanism responsible for early leukopenia (as well as hypoxemia) during dialysis with cuprophan membranes.

Acid-Base Equilibrium↗
PubMed1992

Regulation of complement activity by vaccinia virus complement-control protein.

A major protein secreted by vaccinia virus-infected cells has structural similarity to the super-family of complement-control proteins. This vaccinia complement-control protein (VCP) was studied to determine how it regulates complement activation. VCP was bound by C4b and C3b and served as a cofactor with factor I in cleaving these two molecules. VCP inhibited the formation and accelerated the decay of the classical C3 convertase. It also accelerated decay of the alternative pathway convertase, although higher concentrations were apparently needed. In vitro, therefore, VCP interfered with the classical and alternative complement pathways at several steps. In vivo, this interference may increase the virulence of vaccinia virus by enabling it to escape attack by the host's complement system.

Complement Activation↗
PubMed1988

A physical map of the human regulator of complement activation gene cluster linking the complement genes CR1, CR2, DAF, and C4BP.

We report the organization of the human genes encoding the complement components C4-binding protein (C4BP), C3b/C4b receptor (CR1), decay accelerating factor (DAF), and C3dg receptor (CR2) within the regulator of complement activation (RCA) gene cluster. Using pulsed field gel electrophoresis analysis these genes have been physically linked and aligned as CR1-CR2-DAF-C4BP in an 800-kb DNA segment. The very tight linkage between the CR1 and the C4BP loci, contrasted with the relative long DNA distance between these genes, suggests the existence of mechanisms interfering with recombination within the RCA gene cluster.

CD55 Antigens↗
PubMed1984

Increased expression of the C3b receptor by neutrophils and complement activation during haemodialysis.

Activation of complement and the relative number of C3b receptors expressed by neutrophils was assessed in patients undergoing haemodialysis with new and reused cellulosic membranes, and with polymethylmethacrylate (PMMA) membranes. Activation of complement was assessed by radioimmunoassay of plasma C3adesArg, and neutrophil C3b receptors were measured by fluorescent flow cytometry of cells indirectly stained with F(ab')2 anti-C3b receptor. During first use of cellulosic dialysis membranes by four patients, the mean expression of C3b receptors by neutrophils in blood taken from the afferent line of the extra-corporeal system after 10, 20, 60 and 120 min of dialysis increased to 127, 189, 255 and 296%, respectively. The mean plasma C3adesArg concentrations in the corresponding samples of blood were 225, 320, 236 and 160% of the pre-dialysis levels. During third and fifth use of the same membranes by these patients, the mean C3b receptor expression by neutrophils did not exceed 150% of the predialysis determination, and correspondingly minimal increases in plasma C3adesArg were observed. Analysis of blood taken simultaneously from the afferent and efferent lines of the first use cellulosic dialysis system indicated that the increase in C3b receptor expression by neutrophils and generation of C3adesArg occurred when blood came in contact with the dialysis membrane. Haemodialysis of four additional patients with the non-complement activating PMMA membrane caused only modest or no increases in neutrophil C3b receptors. Thus, complement activation in vivo is associated with up-regulation of neutrophilic C3b receptors, indicating that this cellular response previously described only in model, in vitro systems, is a physiological mechanism by which this cell can augment its capacity for responding to C3b opsonized material.

Biocompatible Materials↗
PubMed1987

Complement activation in peritonitis. Association with hepatic and renal perfusion abnormalities. First place winner: Conrad Jobst award.

The authors have shown that systemic activation of the complement system with either zymosan or cobra venom factor produces some of the hemodynamic changes characteristic of sepsis, specifically, a reduction in hepatic perfusion despite a normal or hyperdynamic systemic circulation. This study was undertaken to determine whether complement activation accompanied reductions in effective hepatic and renal blood flow (EHBF and ERBF, respectively) in a septic murine model previously demonstrated to be associated with flow redistribution. Rats underwent either cecal ligation and puncture (CLP) or sham laparotomy after a baseline blood sample was collected for complement assay. Eighteen hours later, thermodilution cardiac output, mean arterial pressure, heart rate, hematocrit, EHBF by galactose clearance, and ERBF by p-aminohippurate (PAH) clearance were determined. A second blood sample was collected for measurement of total hemolytic complement (CH50) by immune hemolysis of sheep erythrocytes and was compared to the t = 0 sample for calculation of per cent change in CH50. The cardiac output and hematocrit were normal in the CLP group relative to sham. The septic animals were tachycardic and slightly hypotensive, suggesting a diminished systemic vascular resistance. EHBF and ERBF fell dramatically in the septic group despite the normal cardiac output. Residual hemolytic complement activity was reduced to less than 40% of preseptic levels in the CLP group while sham values were no different than baseline, indicating massive complement activation in the septic animals. This study demonstrates an association between complement activation and hepatic and renal perfusion abnormalities in murine peritonitis. Work is underway to establish the temporal relationship between complement activation and visceral flow changes.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

The induction of plasma leakage in skin by histamine, bradykinin, activated complement, platelet-activating factor and serotonin.

Vascular leakage of [125I]-human serum albumin into the skin of sheep was measured in response to intradermal injection of histamine, bradykinin, zymosan-activated plasma (ZAP), platelet-activating factor (PAF) and serotonin. Potency of the mediators was PAF greater than ZAP greater than bradykinin approximately histamine greater than serotonin. Maximal leakage occurred in the first 10 min following injection of bradykinin, histamine and PAF, and for histamine and bradykinin had effectively ceased by 40 min. In contrast, ZAP and serotonin induced relatively constant plasma leakage over the first 40 min following their intradermal injection. Prostaglandins E1 and E2 enhanced plasma leakage induced by histamine and bradykinin thus confirming the applicability of the two-mediator hypothesis of vascular leakage to permeability responses in skin of sheep.

Animals↗
PubMed1991

Platelet-activating factor produces shock, in vivo complement activation, and tissue injury in mice.

We previously showed that TNF and endotoxin (LPS) synergize to activate the complement system and produce shock and bowel injury in normal mice. However, C5-deficient mice were protected from these adverse effects. In this study, we show that in mice, platelet-activating factor (PAF) antagonist prevents TNF- and LPS-induced complement activation, bowel injury, and death, indicating that PAF mediates the actions of TNF and LPS. We then examined the role of the complement system in PAF-induced shock and tissue injury. We found that 1) PAF (3 micrograms/kg) induces shock, hemoconcentration, bowel necrosis, and death in normal mice, whereas C5-deficient mice are protected from these effects. (Protection was abrogated when the dose of PAF was raised to 5 micrograms/kg.) Furthermore, when C5-deficient mice were reconstituted with normal serum, they also developed shock, bowel injury, and death in response to PAF. Thus, C5 is required for PAF to induce injury. 2) PAF activates the complement system in vivo, but not in vitro. The mechanism of complement activation by PAF is unclear. Inasmuch as PAF stimulates neutrophils to release protease that may activate the complement system, we examined the effect of neutrophil depletion on PAF-induced injury and complement activation. We found that neutrophil depletion fails to prevent PAF-induced complement activation, although PAF-induced lethality is much reduced. We conclude that PAF causes complement activation, and acts in synergy with active complement fragments to produce shock and tissue injury. Neutrophils probably do not play the pivotal role in PAF-induced complement activation.

Animals↗
PubMed1984

Pathways to complement activation during cardiopulmonary bypass.

Complement activation was assessed in 34 patients undergoing cardiopulmonary bypass. Arterial concentrations of complement fragments Ba and C3d rose in all patients, the increase in Ba preceding that of C3d. At the same time as complement fragments were being generated the arterial neutrophil count fell. These findings suggest (a) that complement activation is initiated by the alternative pathway during cardiopulmonary bypass and (b) that complement activation mediates loss of neutrophils during bypass. Complement mediated loss of neutrophils during the analogous setting of haemodialysis is the result of leucosequestration in the pulmonary vasculature. During cardiopulmonary bypass the lungs are out of circuit, so that activated leucocytes may sequester in other target organs. This may be an aetiological factor in the multi-organ failure occasionally seen after uneventful cardiopulmonary bypass.

Adult↗
PubMed1987

Comparison of complement activation by silicone intraocular lenses and polymethylmethacrylate intraocular lenses with polypropylene loops.

Silicone intraocular lenses are undergoing clinical investigation for use in the United States. We compared the ability of silicone intraocular lenses to activate the complement system in human sera with that of polymethylmethacrylate intraocular lenses with polypropylene loops using a radioimmunoassay that measures levels of activated complement fragments. Sera incubated with polymethylmethacrylate lenses with polypropylene loops had higher levels of C3a and C5a, but not C4a, than control sera incubated without intraocular lenses. On the other hand, there were no differences in levels of C3a, C4a, and C5a between sera incubated with silicone lenses and control sera. These results suggest that polymethylmethacrylate lenses with polypropylene loops activate the alternative pathway of complement, while silicone lenses do not.

Complement Activation↗
PubMed1992

Effects of complement activation in the isolated heart. Role of the terminal complement components.

The mechanisms of the complement-mediated myocardial injury associated with ischemia and reperfusion have not been elucidated fully. Complement activation may directly mediate injury through actions of the anaphylatoxins C3a and C5a or generation of the membrane attack complex C5b-9. A model was developed to examine the direct effects of complement activation on heart function, assess myocardial tissue damage, and determine which complement components mediate tissue injury. Isolated rabbit hearts were perfused with Krebs-Henseleit buffer by using a modified Langendorff apparatus. Human plasma was added to the perfusate as a source of complement. Rabbit tissue activates human complement. Treatment with 6% normal plasma resulted in complement activation as assessed by the generation of Bb, C3a, C5a, and SC5b-9. Functional changes in cardiac performance became apparent 7-15 minutes after plasma addition and developed fully over the next 20-30 minutes. The effects were dependent on the complement titer and included 1) an increase in the end-diastolic pressure, 2) a decrease in the developed pressure, 3) an increase in the coronary perfusion pressure, and 4) an increase in lymphatic fluid formation. These effects were not elicited when an inhibitor of complement activation (FUT-175) was present or when heat-inactivated plasma was used. The effects of complement activation on myocardial function could not be reproduced by treatment with recombinant human C5a, zymosan-activated plasma, or plasma selectively depleted of C8. Myocardial tissue accumulated sodium and calcium and lost potassium as a result of complement activation. Activation caused the release of creatine kinase from myocytes and an increase in the radiolabeled albumin space of the hearts. The data demonstrate that complement activation caused decrements in myocardial function and increased the coronary perfusion pressure and lymphatic fluid flow rate. The effects were not mediated by the anaphylatoxins but were dependent on the distal complement component C8, suggesting that C5b-9 was responsible for the physiological changes. Complement activation directly mediated tissue injury in a manner consistent with plasmalemmal disruption as a result of C5b-9 formation. The data suggest that the C5b-9 complex, which is known to form under conditions of ischemia, may contribute directly to myocardial cell injury.

Animals↗
PubMed1994

Complement activation by alginate-polylysine microcapsules used for islet transplantation.

A foreign body reaction is frequently observed around implanted microcapsules of alginate-polylysine. Since complement activation can play a role in this reaction, we checked in vitro the ability of empty alginate-polylysine microcapsules to activate complement. Human serum was incubated with microcapsules, and complement activation was evaluated by two methods: the complement hemolytic activity (CH50) and the assay of the C3adesArg fragment. The occurrence of complement activation in the presence of microcapsules was suggested both by a CH50 decrease and by high C3adesArg levels despite C3adesArg adsorption to the capsule membrane. Capsule membrane protection against the cytotoxic effects of complement was also tested. No hemolysis occurred when microencapsulated sensitized sheep erythrocytes were incubated with activated complement. In conclusion, the microcapsule membrane can protect cells against activated complement fragments. Nevertheless, alginate-polylysine microcapsules do activate complement, and this effect must be considered for its use as an implant.

Alginates↗
PubMed1994

Complement activation: a new participant in the modulation of fibrin gel characteristics and the progression of atherosclerosis?

The activation of the complement system has been implicated as an important mechanism in the progression of atherosclerosis. The relationship between fibrin gel characteristics and complement activation has, however, not been investigated. Zymosan-treated plasma with 87% complement activation as measured by C3a production using radioimmunoassay was found to induce changes in biophysical characteristics of fibrin network developed in both plasma and purified fibrinogen solution. Using already established methods to measure fibre thickness (mu T), permeability (T) and compaction, it was found that these networks are made of thinner fibres with increased tensile strength arranged into a matrix which renders the networks less permeable. Such networks are resistant to streptokinase-induced lysis. Fibrin networks with thin fibres in turn induced 3.7 times higher production of C3a than unmodified networks. These observations suggest the existence of positive feedback; complement activation induces major alterations in fibrin structure which in turn can induce further activation of the complement system. The detailed mechanism underlying this interrelationship is not clear at present, but this positive feedback system may play an important role in establishing a fibrin infrastructure ultimately responsible for the progression of atherosclerosis.

Arteriosclerosis↗
PubMed1989

Characterization of complement activity in turkeys: evidence for classical and alternative complement pathways.

Complement activity in turkey serum was examined by using inhibitors or activators of mammalian complement. Hemolytic test systems using sheep red blood cells sensitized with specific antibody (SSRBC) and horse red blood cells (HRBC) were developed to measure residual complement activity of turkey sera treated with the various inhibitors or activators. Lysis of SSRBC was blocked by treatment with 6-mM EDTA, 10-mM ethylene glycol-bis-beta aminoethylether N,N,N',N' tetraacetic acid (EGTA), and carrageenan. In contrast, lysis of HRBC was blocked by 6-mM EDTA, but not by 10-mM EGTA or carrageenan. Addition of magnesium to EGTA-chelated serum facilitated the lysis of HRBC but not the lysis of SSRBC. Treatment of serum with zymosan at 1 mg/mL and inulin at 5 mg/mL depleted hemolytic activity against both SSRBC and HRBC, suggesting depletion of components common to both pathways. Differences in the hemolytic activities of sera against SSRBC and HRBC after treatment with the various complement inhibitors and activators demonstrate the presence of two complement pathways in turkeys.

Animals↗
PubMed1984

Initiation of complement activation.

The complement system is an excellent one to look at as an example of a triggered enzyme system. It is found to use almost all the strategies of enzyme cascades and for initiation which were discussed in the introduction. The classical pathway is a fine example of an active zymogen form of activation and the alternative pathway is the canonical example of a tickover. Both may also be activated by exogenous enzymes from other systems. The strategies of enzymes waiting for substrates, of substrates waiting for enzymes, and of both waiting for modifying proteins are all seen in various stages of the reaction. There is an association of a linear cascade with the positive feedback amplification loop. This degree of evolutionary adaptation is not only aesthetically pleasing but must be taken to mean that the system is of considerable biological importance and has been over a long evolutionary time span.

Complement Activation↗
PubMed1982

Antibody-independent complement activation by myelin via the classical complement pathway.

Murine or rabbit whole brain homogenates were shown to activate human complement via the classical pathway by an antibody-independent reaction. This activity required Ca++ ions. Anticomplementary activity in fractionated murine brain was found to reside in the myelin fraction and in purified myelin. It was absent, however, both from highly purified myelin basic protein (MBP) and from the MBP-free residue. Because purified MBP is a monomer and this protein exists in brain tissue largely as a dimer, the ability of the cross-linked form of MBP to activate complement was investigated. MBP, dimerized with difluorodinitrobenzene, was highly anticomplementary. The murine brain, inactive when taken from the newborn mouse, was shown to first acquire the capacity to activate complement at 7 d after birth. This finding is consistent with the report that the synthesis of myelin protein has been shown to be initiated in murine brain 8 d after birth. Complement activation by MBP could play an important role in the pathological changes observed in neurological disorders.

Animals↗