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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↗
PubMed1994

Adsorption of anaphylatoxins and platelet-specific proteins by filtration of platelet concentrates with a polyester leukocyte reduction filter.

Anaphylatoxins generated during storage of platelet concentrates (PCs) may potentially have side effects on platelet transfusion. We evaluated the anaphylatoxin-scavenging abilities of white blood cell reduction filters. Among the commercially available filters for PCs, one made with polyester fiber (PL50) dramatically adsorbed C3a and C4a anaphylatoxins to the respective mean level of 1,721-208 ng/ml and 1,240-141 ng/ml in 3-day-old PCs. C3a and C4a were measured as the native and des Arg form of each complement by radioimmunoassay. C3a and C4a anaphylatoxins in the supernatant plasma fraction from 3-day-old PC again decreased from 1,136 to 114 ng/ml and from 1,086 to 65 ng/ml, respectively. The filter also adsorbed 85% of platelet factor 4 (PF4) and 31% of beta-thromboglobulin (beta-TG), which had been released from platelets into the plasma during storage. The plasma levels of adhesive proteins such as fibronectin, fibrinogen, and von Willebrand factor, and plasma lactate dehydrogenase activity did not decrease after filtration. Another polyester filter (PL5A), on the other hand, significantly increased C3a and C4a levels with filtration. In addition, there was no PF4 adsorption ability during the filtration. The filters for red cells (RC50, BPF4, and R500A) had no anaphylatoxin adsorption capabilities. The observed specific adsorption of anaphylatoxins might be attributed to the electrostatic force between the positively charged anaphylatoxins with high pI and the possibly negatively charged filter membranes. Since PF4 and beta-TG have positively charged moieties in the C-terminal position, the same adsorption mechanism might operate.(ABSTRACT TRUNCATED AT 250 WORDS)

Adsorption↗
PubMed1993

Rapid quantification of C3a and C5a using a combination of chromatographic and immunoassay procedures.

Monoclonal antibodies were isolated which reacted specifically with the complement cleavage products C3a, C3adR, C5a, and C5adR but not with the parent molecules C3 or C5. In both cases the mAbs showed a higher affinity towards the desArg forms. These mAbs were used as capture antibodies in immunoassays for C3a/C3adR and C5a/C5adR. The immunoassays are based on the ABICAP technology which ensures for a rapid measurement. Due to the large binding capacity and the very short diffusion pathways in the gel-matrix the binding equilibrium between capture antibodies and the antigen is reached whilst the sample is flowing through the column. Therefore this test represents an endpoint assay offering the possibility of using a single calibration curve for a large number of measurements. With the C3adR assay concentrations down to 16 ng/ml C3adR can be detected. The lower detection limit of the C5adR assay is 1 ng/ml C5adR. The tests for C3a/C3adR, and C5a/C5adR can be performed in 20 to 25 min and this rapid processing of plasma samples should permit the application of these parameters for diagnostic purposes and patient management.

Amino Acid Sequence↗
PubMed1986

Patient reactions and granulocyte degranulation during hemodialysis with cuprophane and polycarbonate membranes. A double-blind study.

During dialysis with cuprophane or polycarbonate filters, a fall in neutrophil and eosinophil cell counts is observed. Total complement remains unchanged, but C3a increases indicating complement activation. Release of granular granulocyte proteins is observed indicating granulocyte activation. Patient reactions or biochemical findings indicate no significant difference when polycarbonate or cuprophane membranes are used, except perhaps less complement activation with polycarbonate. The biochemical observations may be due to complement activation or cell contact with the membrane.

Adult↗
PubMed1991

[Complement fragments in patients with bronchial asthma].

In this study, we investigated the pharmacological reactions induced by ibudilast to the complement system with the aim of clarifying the functional relation of the complement system to allergic reactions and pathology in patients with bronchial asthma. Complement hemolytic activities (CH50 and ACH50), complement profile, anaphylatoxins (C3a and C5a) and complement fragments (Bb, iC3b and C4d) were measured in 20 patients with bronchial asthma. One of antiasthmatic activities induced by ibudilast was concluded to be brought about though inactivation of the alternative complement pathway working on type III allergic reaction. Ibudilast increased the complement fragment Bb in the patients' plasma with the fairly controlled bronchial asthma. This increase in circulating Bb was suspected to be a result of inactivation of intermediate complement complexes, for example C3b.Bb.P, because the amounts in plasma of C3 and C5 showed no changes, while those of factor, B, P, H and I were decreased by ibudilast administration in patients with fairly controlled bronchial asthma. This antiasthmatic ability of ibudilast was restrained in those patients whose peripheral leukocytopenia was advanced before ibudilast administration, and in those whom ibudilast did not provoke an increase in the plasma level of iC3b, or did not prevent the serum level of C5 from increasing. In those unfairly controlled cases, enough anaphylatoxins, especially C5a might be produced to make the margination of peripheral neutrophils to the lung and increase CR3 on neutrophils binding with iC3b.

Adult↗
PubMed1985

Angiography and complement activation. Evidence for generation of C3a anaphylatoxin by intravascular contrast agents.

The potent anaphylatoxin C3a was measured in the peripheral blood of eleven patients receiving radiocontrast agents whilst undergoing coronary angiography. In seven patients C3a levels were raised during this procedure and in three of these the anaphylatoxin was increased between four and tenfold. In four patients C3a levels remained within the normal range. In vitro tests of five contrast agents revealed marked heterogeneity in their ability to generate C3a from serum.

Anaphylatoxins↗
PubMed1988

Human malignant ascites and histamine-induced protein leakage from the normal microcirculation.

The accumulation of malignant ascites is a significant cause of morbidity and mortality in patients with intraabdominal malignancies. However, the cause of malignant ascites is unknown. In this study, we used the rat cremaster muscle preparation to determine if and how malignant ascites could produce protein leakage from normal blood vessels which would lead to fluid accumulation in the peritoneal cavity. The rat cremaster muscle, with nerves and blood vessels to the animal intact, was prepared for microscopic observations of the microcirculation. Serum albumin was tagged to fluorescein isothiocyanate and injected into the rat. Fluorescent microscopy was used to quantitate leakage of the tagged albumin into the interstitial tissue. Malignant ascites was collected from a patient with metastatic breast cancer. The ascites fluid was placed on the cremaster muscle and it induced protein leakage from the normal blood vessels of this tissue. Protein leakage was partially blocked by diphenhydramine (10(-4) M) and by mast cell depletion with compound 48/80. There was a high level of C3a in the malignant ascites solution but C3a did not increase during the exposure period. These data suggest that activated complement in malignant ascites may release histamine from mast cells to cause protein leakage of the normal vasculature. The movement of protein into the peritoneal cavity would be followed by water, thus increasing the volume of the ascites and exacerbating the clinical condition.

Animals↗
PubMed1992

Assay for opsonin activity based on chemiluminescence of a Cypiridina luciferin analog.

Opsonin activity (OA) was investigated in serum samples from cord blood of 11 full-term newborn infants and 12 healthy adult volunteers by the method of luminol-dependent chemiluminescence (L-CL) and Cypiridina luciferin analog-dependent chemiluminescence (CLA-CL) together with the measurement of complement components (C3, C4, C3A and properdin). CL and complement components of cord samples were significantly lower than that of healthy adult blood. CLA-CL showed a significant correlationship to C3 and C3A. L-CL also displayed a significant correlationship to C3A but the relationship to C3 was not significant. From these results, when OA is measured by CL, CLA-CL is preferred to L-CL as a technique.

Adult↗
PubMed1993

Complement activation during saturation diving.

In this study, the levels of activated complement fragments C3a and C5a were measured on 11 U.S. Navy divers as they performed a 28-day saturation dive to a pressure equivalent of 1,000 feet of seawater (fsw, 31.3 atm abs). Two subjects developed symptoms consistent with the high pressure nervous syndrome (HPNS) and three were treated for type I DCS (joint pain only). These events allowed us to test two hypotheses: a) alterations in C3a or C5a levels during compression are related to the occurrence of HPNS and b) increases in complement fragments are an indicator of decompression stress associated with type I DCS. There was no correlation between changes in C3a and C5a levels during compression and the diagnosis of HPNS. Our results suggest that an increase in C3a and C5a levels during saturation diving correlates with decompression stress and the clinical diagnosis of type I DCS.

Analysis of Variance↗
PubMed1984

Active site of C3a anaphylatoxin: contributions of the lipophilic and orienting residues.

Activation of the serum complement cascade generates C3a anaphylatoxin, a primary mediator of inflammation. The active-site pentapeptide from the COOH terminus of C3a, Leu-Gly-Leu-Ala-Arg (residues 73-77), exhibits the inflammatory activities and specificity of the native 77-residue polypeptide. Functionally important features of this active site were studied by testing the ability of 22 synthetic analogues of this pentapeptide to contract isolated muscle strips from guinea pig ileum and to desensitize this tissue to contraction induced by human C3a or C5a. The C3a receptors on mast cells and basophils probably contain lipophilic groups that interact with the lipophilic side chains of Leu-73 and Leu-75 and charged groups that interact with the carboxylate and guanidinium groups of Arg-77. The lipophilic contribution of Leu-73 is modest and sterically nonspecific while that of Leu-75 is substantial and sterically specific. Gly-74 and Ala-76 appear to position and orient the adjacent residues Leu-73, Leu-75, and Arg-77 for optimal receptor binding. The contribution of Gly-74 is neither conformationally nor sterically specific while that of Ala-76 is both conformationally and sterically specific. The cellular C3a receptors evidently interact most efficiently with peptides ending in -Leu-Ala-Arg-OH.

Anaphylatoxins↗
PubMed1996

A new biologic role for C3a and C3a desArg: regulation of TNF-alpha and IL-1 beta synthesis.

The complement activation products C3a and C3a desArg are generated in the course of trauma, infection, tissue injury, and ischemia. We have investigated the effects of C3a and C3a desArg on gene expression and protein synthesis of TNF-alpha and IL-1 beta in PBMC. Neither C3a nor C3a desArg alone induced detectable protein or mRNA levels for TNF-alpha and IL-1 beta. C3a modulated LPS-induced TNF-alpha and IL-1 beta synthesis. In nonadherent PBMC, C3a suppressed LPS-induced synthesis of TNF-alpha (20-71% decrease by 0.2-10 microgram/ml of C3a, p less than 0.01) and IL-1 beta (19-57% decrease by 0.5-10 microgram/ml of C3a, p less than 0.01), independently of endogenous production of PGE2. C3a also suppressed LPS-induced mRNA levels for TNF-alpha and IL-1 beta. In contrast, in adherent PBMC, C3a at 5 to 20 microgram/ml enhanced LPS-induced TNF-alpha (75-188% increase, p less than 0.001) and IL-1 beta (119-274% increase, p less than 0.001) synthesis. C3a enhanced TNF-alpha and IL-1 beta mRNA levels in LPS-stimulated adherent cells. Furthermore, C3a desArg shared with C3a the ability to modulate LPS-induced mRNA and protein synthesis for TNF-alpha and IL-1 beta. These results suggest that C3a, thought to be proinflammatory, and C3a desArg, thought to be biologically inactive, are modulators of inflammation. Both C3a and C3a desArg may enhance cytokine synthesis by adherent monocytes at local inflammatory sites, while inhibiting the systemic synthesis of proinflammatory cytokines by circulating cells.

Cell Adhesion↗
PubMed1986

Determination of plasma C3a des Arg levels after blood contact with foreign surfaces.

The products of complement activation, including C3a, C4a, C5a, and their des Arg derivatives, have been used by many investigators as indicators of blood or foreign surface bioincompatibility, e.g., during hemodialysis. One problem encountered is that after extracorporeal circulation over some dialysis membranes very high C3a levels (5,000-10,000 ng/ml) are generated. To the authors' knowledge the only presently available C3a des Arg RIA kit is provided by Upjohn Diagnostics (Kalamazoo, MI, U.S.A.), which covers an assay standard range of 20-500 ng/ml. Since Upjohn's assay procedure manual does not contain a recommended dilution technique the authors undertook a study to determine the best method. The diluents tested include physiologic saline, normal plasma, phosphate-buffered saline-gelatin, and the Upjohn precipitating agent provided in their kit. The results show that only dilution by normal plasma gave reliable results. The use of the other three diluents resulted in an overestimation of C3a levels. Therefore it is important to know the dilution technique used when comparing the results of membrane C3a generating ability presented by different authors. Furthermore, comparison of different membranes where plasma samples in some cases do not require dilution (e.g., polyacrylonitrile membranes) with those requiring dilution (e.g., regenerated cellulose membranes) will lead to distorted results if an accurate technique is not used.

Biocompatible Materials↗