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PubMed1993

Rheumatoid factor expression and complement activation in children congenitally infected with human immunodeficiency virus.

Rheumatic disease manifestations and autoimmune phenomena are common in adults infected with human immunodeficiency virus (HIV). On the other hand, rheumatic disease manifestations are rare in children congenitally infected with HIV. We studied the relationship between autoimmune phenomena and rheumatic diseases by examining HIV-infected children for the presence of rheumatoid factors (RFs), immune complexes, and complement activation fragments. RFs (principally IgA) were detected in 12 of the 24 HIV-infected patients (50%) and in none of the uninfected (HIV-exposed, seroreverted) controls (n = 22). Mean levels of complement activation fragments C3a and Bb were elevated in the HIV-infected children compared with the controls. A correlation was seen between the presence of IgA RF and alternative complement pathway activation as measured by plasma levels of Bb. None of the children had clinical or laboratory evidence of rheumatic disease.

Antigen-Antibody Complex↗
PubMed1992

[Activation of complement and serial changes of anaphylatoxin (C3a, C5a) in patients for open-heart surgery using a membrane oxygenator].

Activation of complement and serum changes in anaphylatoxin (C3a and C5a) were studied in 8 patients who underwent open-heart surgery using a membrane oxygenator. C1 esterase inhibitor (C1-EI), C3, C5, CH50, C3a and C5a were measured serially at 7 points. C1-EI, C3, and C5 were measured by single radial immunodiffusion, CH50 by Mayer's method, and C3a and C5a by radioimmunoassay. Levels of C1-EI, C3 and C5 decreased significantly from 10 min after initiation to 120 min after the end of CPB compared with base line values. Degree of activation of complement increased in proportion to duration of CPB. Significant decreases of C3 and C5 continued until first postoperative day. Level of C3a increased significantly 10 min after initiation of CPB, and gradually increased till immediately after the end of CPB, when the level was maximum (4625 +/- 560 ng.ml-1) among 7 points. Level of C3a decreased gradually till 120 min after end of CPB. C5a was not detected during whole course. No patient showed respiratory distress of pulmonary edema. In conclusion, membrane oxygenator activated classical pathway of complement at 10 min after initiation of CPB. C3a increased significantly from 10 min after initiation of CPB to 120 min after end of CPB, but C5a was not detected at all during the whole course. The significant activation of complement continued till first postoperative day.

Aged↗
PubMed1983

Vascular permeability changes induced by complement-derived peptides.

The polypeptides C3a and C5a are released as protein cleavage byproducts during activation of the complement system. These substances are able to release histamine from mast cells and this has generally been thought to be the link between complement activation and increased microvascular permeability in inflammatory reactions. Recent observations of inflammatory responses in the skin suggest that there is another link, which does not involve histamine. This is potentially of more general importance since antihistamines have limited effects on the majority of inflammatory reactions. One of the complement protein fragments, C5a (with or without carboxyl terminal arginine which is necessary for histamine release), is very potent in increasing vascular permeability. However, protein leakage leading to tissue oedema in skin is difficult to detect unless an arteriolar dilator is present. There is evidence that C5a and a vasodilator prostaglandin can be generated together extravascularly in response to a microbial stimulus. Unlike histamine, C5a does not act directly on venular endothelial cells, but triggers a very rapid interaction between circulating polymorphonuclear leukocytes and venular endothelial cells which, by an unknown mechanism, results in elevated venular permeability to plasma proteins.

Animals↗
PubMed1992

Activation of complement in normal serum by hydrogen peroxide and hydrogen peroxide-related oxygen radicals produced by activated neutrophils.

Neutrophils activated by soluble particulate stimuli generate superoxide anion and subsequently form hydrogen peroxide and other oxygen radicals. The effect of hydrogen peroxide on the complement system in normal serum was investigated. Treatment of normal serum with hydrogen peroxide resulted in a diminution of the haemolytic activity of the total and alternative complement pathways and the haemolytic titres of C3 and C5 but not of C2, in normal serum. These decreases in complement activity depended on the concentration of hydrogen peroxide added to the serum. Immunoelectrophoretic analysis of hydrogen peroxide-treated serum showed that C3 and C5 proteins were activated. Complement degradation products C3a and C5a were produced in normal serum treated with hydrogen peroxide, and 20 mM EDTA abolished C3a and C5a production in hydrogen peroxide-treated serum but 20 mM Mg-EGTA did not. Catalase completely abolished and dimethylsulphoxide and D-mannitol, hydroxyl radical scavengers, partially inhibited the hydrogen peroxide-mediated complement activation. Hypochlorite, incubated with normal serum, significantly inhibited serum haemolytic activity, and sodium thiosulphate, a reducing agent, abolished the effect of hypochlorite. Normal serum incubated with activated neutrophils showed neutrophil chemotactic activity and decreased serum haemolytic activity, and the addition of catalase or methionine (5 mM) completely abolished the effects of activated neutrophils. These results suggest that hydrogen peroxide activates complement via an alternative pathway of complement activation and that hydroxyl radicals and other hydrogen peroxide-related species such as hypochlorite are most likely involved in hydrogen peroxide-mediated complement activation. Complement activation by oxygen radicals produced by activated neutrophils may be one of the mechanisms by which complement is activated in human immune complex diseases.

Complement Activation↗
PubMed1981

Characterization of human C4a anaphylatoxin.

Human C4a anaphylatoxin was isolated from a Cls digest of the fourth component of complement. Isolation required a two-step procedure involving ion-exchange chromatography on CM-Sephadex C-50 and gel filtration on Sephadex G-50. Characterization of C4a indicated it is a highly cationic polypeptide (pI = 9.0-9.5) containing 77 residues with Mr = 8,759. C4a is devoid of tryptophan, histidine, and carbohydrate. Judged by the shape and magnitude of its circular dichroism spectrum, 54% of the polypeptide backbone of C4a assumes an alpha-helical conformation. Partial NH2-terminal sequence determination of C4a revealed a sequence identical with that published by Bolotin et al. (Bolotin, C., Morris, S., Tack, B., and Prahl, J. (1977) Biochemistry 16, 2008-2015) for the NH2 terminus of the alpha-subunit of human C4. Comparison of the NH2-terminal sequence of C4a with the sequences of complement activation fragments C3a (Hugli, T.E. (1975) J. Biol. Chem. 250, 8293-8301) and C5a (Fernandez, H.N., and Hugli, T.E. (1978) J. Biol. Chem, 253-6955-6962) showed that of the first 24 NH2-terminal residues of C4a, 6 were identical with those of C3a (25% homology) and 8 were identical with those of C5a (33% homology). These data represent the first chemical evidence for the existence of an evolutionary relationship among anaphylatoxins C3a, C4a, and C5a, and imply that a similar relationship exists among their precursor proteins.

Amino Acids↗
PubMed1987

Anaphylotoxin levels following thermal injury.

Following thermal injury, anaphylotoxins (C3a and C5a) are generated by complement activity. We measured C3a and C5a levels serially in 18 seriously burned patients (mean burn size = 37.9 per cent body surface area) over the initial 3 weeks following injury. Values for C3a were significantly increased when compared with normal controls, with maximum levels during the second week, while C5a levels were slightly elevated initially. These levels did not correlate with the extent of tissue injury, the development of septic complications or the clinical outcome. However, it appears likely that C3a and C5a may be responsible for some of the pathophysiological alterations observed following thermal injury.

Adult↗
PubMedDate not supplied

In vitro function of granulocyte concentrates following passage through an electromechanical infusion pump.

Six units of granulocytes stored for 18 hours at 20 to 24 degrees C without agitation were passed through an electromechanical infusion device pump system (test) (Abbott) and through a 170-micron filter (control). To determine the effect of needle gauge, a 19 or 23 gauge needle was attached to the end of the pump administration set. After passage through the pump, granulocytes were evaluated for signs of cytolysis and functional loss, red cells for hemolysis, platelets for release of beta-thromboglobulin, and plasma for C3a and C5a complement activation. There was no evidence (mean +/- 1 SD) of hemolysis (less than 1.0 vs. less than 1.0 mg/dl), loss of granulocytes (123 +/- 38 X 10(3)/microliters vs. 118 +/- 29 X 10(3)/microliters), changes in any of several tests of neutrophil function, increased release of beta-thromboglobulin (15.8 +/- 5.8 vs. 17.0 +/- 6.6%), or C3a complement activation (483 +/- 221 vs. 500 +/- 200 ng/ml) after passage through the pump system (p greater than 0.05). No significant differences were seen between the use of a 19 or 23 gauge needle. Based on these in vitro data, we conclude that this pump system is acceptable for use in clinical practice when control over rate and volume of granulocyte administration is important.

Cell Survival↗
PubMedDate not supplied

Biocompatibility and performance of a modified cellulosic and a synthetic high flux dialyzer. A randomized crossover comparison between cellulose triacetate and polysulphon.

The biocompatibility and performance of two high flux membranes (modified cellulosic: cellulose-triacetate (CTA), and a synthetic material: polysulphon [PS]) were assessed in 31 stable patients on hemodialysis (HD) in a randomized crossover study. Parameters evaluated included leukocytes, complement activation products C3a and C5a, cytokines, lymphocyte subpopulations, urea, creatinine, phosphate, and beta 2 microglobulin. Considering biocompatibility, the drop in the number of leukocytes was more pronounced during CTA HD compared with PS (p = 0.045), although both were low in comparison with cuprammonium dialysis in the same patients, as observed during a separate study. Both membranes induced a low and transient state of complement activation. Interleukin 1 beta and interleukin 6 could not be detected at all, whereas tumor necrosis factor alpha levels were marginally elevated before and after HD with both membranes. During the first 30 min of HD with either membrane, the numbers of CD8+ cells decreased significantly, resulting in an increase in the CD4/CD8 ratios; in addition, the number of NK cells decreased. Performance, as measured by extraction ratios for small molecular weight solutes and Kt/V urea, was significantly better during CTA dialysis (p < 0.001), but almost similar after correction for membrane surface area. On the basis of these data, it seems justified to conclude that, whereas biocompatibility of the PS dialyzer appeared slightly superior to CTA, performance of both dialyzers was comparable.

Adult↗
PubMed1992

Patterns of blood response during cardiopulmonary bypass.

Monitoring of cardiopulmonary bypass (CPB) in terms of alterations to the concentrations of selected blood constituents leads to contrasting patterns of response. This has been verified by determining the influence of CPB on the activation of fibrinolysis, complement, leucocytes and the contact phase of coagulation. Fibrinolytic activity was determined by fibrin degradation products (X-FDP's), complement activation by C3a and C5a, leucocyte activation by granulocyte elastase and contact activation by factor XII-like activity (FXIIA). Five patients undergoing elective coronary artery surgery using a bubble oxygenator and pulsatile perfusion were studied. X-FDP's rose gradually during CPB and remained elevated. Similar patterns were observed for elastase and FXIIA. In contrast, C3a rose sharply with peak values at 1 1/2-2h of bypass while C5a did not show significant changes during bypass. The data obtained have enabled the establishment of response patterns for parameters in CPB which will provide information relevant to the clinical application of biomaterials.

Biocompatible Materials↗
PubMed1987

Activation of human serum complement with allergens. I. Generation of C3a, C4a, and C5a and induction of human neutrophil aggregation.

To understand the relevance of allergens in generation of C3a, C4a, and C5a in normal human serum, we studied extracts of several allergens (house dust, house dust mite, Aspergillus fumigatus, and perennial ryegrass). Known complement activators zymosan and endotoxin were used as controls. Generation of C3a, C4a, and C5a (determined by radioimmunoassays) occurred with extracts of house dust and Aspergillus more than with house dust mite and ryegrass. Anaphylatoxins were produced both in dose and time-dependent fashions. Serum activated with house dust and Aspergillus extracts induced neutrophil aggregation when this serum was added to neutrophil suspensions. Less aggregation occurred when house dust mite and perennial ryegrass extract-activated sera were added to human neutrophils. We propose that some allergens may induce biologic responses by activation of sera and generation of anaphylatoxins as well as by IgE-mediated responses.

Adult↗
PubMed1986

Immunopharmacology of anaphylatoxin-induced bronchoconstrictor responses.

The complement anaphylatoxin peptides, C3a and C5a, are potential mediators of immediate hypersensitivity reactions, eliciting many of the same actions on isolated tissue and cell preparations as specific antigen. Instilled intratracheally in experimental animals, the peptides induce acute bronchospasms and are sometimes lethal. In vitro, they cause dose-dependent contraction of isolated lung tissue preparations, a response which correlates well with bronchospasms observed in vivo, and our current understanding of the cellular and molecular mechanisms of this action are reviewed here. C5a and its catabolic derivative, C5ades Arg, stimulate contraction of isolated guinea pig lung parenchymal strips in part by production of leukotrienes that constitute SRS-A, and by release of histamine. Leukotrienes in turn release thromboxane from lung tissue, and evidence indicates that at least part of the spasmogenic activity of these peptidolipids is mediated by this effect. C3a is considerably less potent than C5a in contracting lung tissues and appears to act primarily by causing the release of spasmogenic cyclooxygenase metabolites. Both peptides may additionally have direct action on contractile cells within the tissue. Platelet-activating factor (PAF), an unusual phospholipid mediator released from inflammatory cells stimulated with C5a and other agents, also contracts isolated lung parenchymal tissues. PAF stimulates release of significant quantities of thromboxane from guinea pig lung; however, indomethacin does not block contractile responses of the tissue. Recent evidence indicates that PAF may act on parasympathetic neurons in lung to release endogenous acetylcholine, and this action may be a major component of tissue responses to this mediator. Thus the complement anaphylatoxins stimulate release of many of the same mediators from lung tissues as are released by antigen challenge of sensitized tissue, and may, therefore, play an important role in the pathogenesis of allergic bronchospasms.

Anaphylatoxins↗
PubMed1994

Safe use of heparin-coated bypass circuits incorporating a pump-oxygenator.

Durable, covalently bonded, heparin-coated cardiopulmonary bypass (CPB) circuits with oxygenators have been developed. Proposed advantages of heparin-coated CPB circuits include improved biocompatibility and thromboresistance. The purpose of this study was to evaluate our experience with heparin-coated CPB circuits in 20 patients. Heparin was given to maintain an activated clotting time equal to or greater than 200 seconds, while flow rates were kept equal to or greater than 2 L/min. Indications for use of this circuit included recent stroke, posttraumatic injuries, recent gastrointestinal bleeding, protamine allergies, combined cardiac and noncardiac procedures, and ventricular assist. Mean heparin dosage was 0.50 +/- 0.18 mg/kg and protamine dosage was 57.14 +/- 39.36 mg. Postoperative blood loss and transfusion requirements were minimal. Postoperative complement levels of C3a and C5a were normal, suggesting excellent biocompatibility. There were no deaths or perioperative complications. Heparin-coated CPB circuits using a pump oxygenator can be used safely with low-dose heparin administration in select patients requiring CPB.

Adolescent↗
PubMed1991

Acute reversible hypoxemia in systemic lupus erythematosus.

OBJECTIVE: To determine the frequency of unexplained reversible hypoxemia in patients with systemic lupus erythematosus and to assess the relation between hypoxemia and elevated plasma levels of complement split products. DESIGN: Cohort study. SETTING: Inpatient and outpatient facilities of the New York University Medical Center/Bellevue Hospital and the Hospital for Joint Diseases. PATIENTS: Case patients were 22 patients hospitalized with disease exacerbation and no evidence of parenchymal lung disease on chest roentgenogram. Four patients with stable disease were followed in the outpatient clinic, and five healthy normal volunteers served as controls. MEASUREMENTS: Plasma levels of complement split products (C3a, factor Bb fragment), alveolar-arterial (A-a) Po2 gradients, and pulmonary function were measured. MAIN RESULTS: Nine episodes of hypoxemia or hypocapnia (mean A-a gradient, 30.4 +/- 4.8 mm Hg) or both (despite normal chest roentgenogram results) were noted in six hospitalized patients (group 1). Gas exchange improved within 72 hours of steroid therapy (mean A-a gradient, 11.6 +/- 4.3 mm Hg; P less than 0.01). These patients had an elevated initial mean C3a level (938.4 +/- 246.8 ng/mL) that decreased within 72 hours (407.8 +/- 80.9 ng/mL; P less than 0.01), concomitant with improved oxygenation. Ventilation-perfusion scans, obtained for four of six group 1 patients, excluded pulmonary emboli. Four hospitalized patients (group 2) had a normal A-a gradient (mean, 7.5 +/- 2.7 mm Hg). The mean C3a level of this group (358.3 +/- 39.2 ng/mL) was lower than that of group 1 (P less than 0.05). Four patients with stable disease (group 3) had a mean A-a gradient and a mean C3a level of 3.3 +/- 2.7 mm Hg and 237.8 +/- 105.7 ng/mL, respectively, similar to values found in five normal volunteers, in whom the mean A-a gradient was 3.7 +/- 1.7 mm Hg and the mean C3a level was 124.8 +/- 9.2 ng/mL. CONCLUSION: A syndrome of reversible hypoxemia, unassociated with parenchymal lung disease, is unexpectedly common in acutely ill, hospitalized patients with systemic lupus erythematosus. The pathogenesis of this syndrome is unclear, although the data are compatible with the hypothesis that hypoxemia may be related to pulmonary leukoaggregation.

Acute Disease↗
PubMed1989

Decreased releasability of basophils from patients with cold urticaria after cold exposure.

Histamine release from peripheral blood basophils challenged with C5a, f-met-peptides and calcium ionophore was studied in patients with cold urticaria before and after exposure to low environmental temperatures. Compared to healthy controls, stimulated mediator release before cold exposure was increased in 7 of 11 patients. When challenged by cold exposure mediator release from in vitro-stimulated basophils was decreased. This decrease was more pronounced after stimulation with receptor-mediated stimuli (e.g. C5a) as compared to receptor-unrelated stimuli, e.g. calcium ionophore. In 4 of 11 patients stimulated mediator release before cold exposure was moderately increased. Also after cold exposure only a weak decrease of stimulated histamine release was seen. Levels of activated complement components (C3a) before and after cold exposure failed to provide evidence for complement activation in vivo. Also the number of circulating basophils as well as their cellular histamine content remained normal after cold exposure. The results show that in these patients release of histamine is altered before and after cold exposure. These changes in basophil responsiveness are not due to complement activation in vivo.

Basophils↗
PubMed1989

Plasmin activity and complement activation during storage of citrated platelet concentrates.

Platelet concentrates were studied for evidence of plasmin activity and complement activation during a 7-to-10-day storage period. When measured by an amidolytic activity assay, plasmin reached a level of 845 +/- 540 nkats/L on day 7 (n = 9). Fibrin(ogen) degradation product (FDP) levels became markedly elevated on the tenth day of storage, rising to 45 +/- 22 micrograms/ml (n = 5). Antiplasmin levels decreased in platelet concentrates by 18% +/- 6% (n = 5) over 7 days, but there was no significant decrease in stored platelet-poor plasma (-1.7%, n = 5, p = 0.5). The amount of plasminogen in platelet concentrate converted to plasmin was estimated to be less than 3% by assay of total plasminogen. Supernatant plasma from stored platelet concentrates was examined for the presence of the complement activation peptides C3a and C5a. From day 0 to day 10 of storage, mean C3a levels rose from 327 ng/ml to 6690 ng/ml. An equivalent increase in C3a levels, from 336 ng/ml at day 0 to 6866 ng/ml at day 10, was also observed in stored platelet-poor plasma. C5a was not detected (less than 10 ng/ml) at any point during the storage period; however, we noted a small decrease of borderline significance (p = 0.04) in total C5 from day 0 (117 micrograms/ml) to day 10 (108 micrograms/ml). Only trace amounts of C3 fragments were found on stored platelets, and there was no evidence of the membrane attack complex. These findings indicate the presence of plasmin activity and conversion of C3 during storage of platelet concentrates.

Blood Platelets↗
PubMed1990

Cardiac dysfunction caused by recombinant human C5A anaphylatoxin: mediation by histamine, adenosine and cyclooxygenase arachidonate metabolites.

We had found previously that complement-derived anaphylatoxins C3a and C5a function as mediators/modulators of cardiac immune hypersensitivity reactions. The purpose of this study was to determine the secondary mediators responsible for the cardiac effects of C5a. Recombinant human C5a (rhC5a) caused dose-dependent tachycardia, slowing of atrioventricular nodal conduction, a short lasting increase followed by a prolonged decrease in left ventricular contractility, and coronary vasoconstriction. These changes were associated with the release of histamine, thromboxane A2 and adenosine into the coronary effluent. Our data indicate that the positive inotropic and chronotropic effects of rhC5a are mediated by histamine release and consequent activation of H2-receptors, the coronary-vasoconstricting effect is due to thromboxane release and the negative dromotropic effect is associated with adenosine release. Furthermore, the decrease in contractility caused by rhC5a is likely to result from the H1-mediated negative inotropic effect of histamine compounded by the ischemic conditions created by the coronary vasoconstricting effects of thromboxane A2 and, perhaps, leukotrienes. Our findings demonstrate that C5a has marked cardiac effects at concentrations approximating those attained in vivo in a multitude of pathophysiological conditions in which complement is activated, including myocardial infarction. Thus, anaphylatoxins may play a role in the development of ischemic cardiac dysfunction.

Adenosine↗