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PubMed1997

Anaphylatoxins in fresh-frozen plasma.

BACKGROUND: Fresh-frozen plasma (FFP) is widely used in patients with coagulation disorders and simultaneous complement activation. Complement activation in FFP itself is poorly investigated. STUDY DESIGN AND METHODS: The concentration of anaphylatoxins C3a and C5a, the complement precursors C1q and factor B, and complement function were measured in 40 consecutively administered FFP units in two pediatric neonatal intensive care units. In 12 samples, the measurements were also performed after incubation with inulin. RESULTS: In 15 of 40 FFP units, both anaphylatoxin concentrations were below the upper cutoff levels reported for healthy humans (C3a, 500 microg/L; C5a, 5 microg/L). Anaphylatoxin levels were higher in FFP units produced by apheresis than in those from blood donation. Complement activation of FFP by inulin increased anaphylatoxin concentration, whereas C1q and factor B levels, and complement function remained unchanged. CONCLUSION: Elevated concentrations of anaphylatoxin are frequently found in FFP units produced by apheresis. Studies are necessary to investigate the reasons for complement activation and the possibilities of prevention during apheresis. As the concentrations of complement precursors and complement function did not change with activation in FFP, these studies should include measurement of the anaphylatoxins C3a and C5a.

Anaphylatoxins↗
PubMed1997

Complement activation by heparin-protamine complexes during cardiopulmonary bypass: effect of C4A null allele.

OBJECTIVES: The first objective was to determine the effect of inherited differences in the classic pathway complement protein C4 on complement activation by heparin-protamine complexes in cardiac surgery. Specifically, we hypothesized that patients with heterozygous C4A null phenotype (A0BB), who have decreased amounts of C4A, may have increased complement activation because of reduced clearance of heparin-protamine complexes. The second objective was to determine whether heparin-protamine-induced complement activation correlated with postoperative pulmonary shunt fractions. METHODS: C4 typing was performed by agarose gel immunofixation and crossed immunoelectrophoresis. Complement activation was measured by radioimmunoassay of C3a and C4a before cardiopulmonary bypass, after bypass, and after protamine infusion. Shunt fractions were calculated from blood gases. RESULTS: Of the 79 patients, 18 expressed heterozygous C4A null allele (A0BB), 16 had heterozygous C4B null allele (AAB0), three had homozygous C4B null alleles (AA00), and the rest expressed both C4A and C4B alleles (AABB). Patients with heterozygous C4A null allele had significantly increased plasma levels of C4a after protamine neutralization of heparin (C4a of 2862 +/- 375 ng/ml; mean +/- standard error of the mean) when compared with patients with normal expression of C4 alleles (AABB) (C4a of 1580 +/- 141 ng/ml) or heterozygous C4B null allele (C4a 1526 +/- 208 ng/ml). Pulmonary shunt fractions obtained after the operation correlated with the classic pathway complement activation by heparin-protamine complexes, but not with alternative pathway complement activation during cardiopulmonary bypass. CONCLUSIONS: Patients with heterozygous C4A null phenotype have increased complement activation by heparin-protamine complexes during cardiac operations, possibly because of their defective clearance. The classic pathway complement activation by heparin-protamine interaction correlates with postoperative pulmonary shunt fractions.

Alleles↗
PubMed1999

Neutrophils from patients with advanced human immunodeficiency virus infection have impaired complement receptor function and preserved Fcgamma receptor function.

Interleukin (IL)-8 production by human polymorphonuclear leukocytes (PMNL) to Cryptococcus neoformans is related to complement activation. Generation of the bioactive fragments C3a and C5a is responsible for IL-8 release. IL-8 production was analyzed in response to C. neoformans by PMNL from persons with early- and late-stage (>400 and <200 CD4 cells/mm3, respectively) human immunodeficiency virus (HIV) infection who were at high risk for cryptococcosis. IL-8 release by PMNL from persons with early-stage infection and from healthy donors was similar; however, PMNL from persons with late-stage HIV infection had significantly impaired IL-8 production, which correlated with reduced IL-8 response to C3a and C5a proteins and decreased CD88 expression. Addition of murine monoclonal antibody (MAb) 18B7 promoted phagocytosis and restored IL-8 release consistent with integrity of FcgammaRIII. These results provide evidence for a selective defect in CD88 expression on PMNL from persons with late-stage HIV infection. However, Fcgamma receptor expression in PMNL appears to be intact and allows MAb to glucuronoxylomannan to positively influence PMNL function.

Adult↗
PubMed2000

Usefulness of pleural complement activation products in differentiating tuberculosis and malignant effusions.

OBJECTIVE: To determine whether measurement of the complement activation products SC5b-9 and C3a-desArg in pleural fluid can reliably differentiate tuberculous from malignant pleural effusions. DESIGN: Twenty-four patients with tuberculous pleuritis, 29 with malignant pleural effusion, and 30 control subjects with transudates were enrolled in the study. SCSb-9 and C3a-desArg were measured in pleural fluid using commercial ELISA tests, and their performances were evaluated using receiver operating characteristic (ROC) analysis. RESULTS: Patients with tuberculous pleuritis had higher mean levels of pleural SC5b-9 (5052 microg/L) and C3a-desArg (7436 microg/L) than those with malignant effusions (1048 and 2835 microg/L, respectively), whereas only SC5b-9 concentrations in the latter were comparable with controls. The area under the ROC curve (AUC) was 0.84 for SC5b-9 and 0.81 for C3a-desArg. Pleural SC5b-9 showed an accuracy of 80.8%, compared with 78.8% for C3a-desArg, when cut-off points of 1500 and 4500 microg/L, respectively, were used. Using a stepwise logistic regression model, the combination of pleural SCSb-9 > or =1500 microg/L, age < or =35 years, and pleural monocyte percentage > or =90% provided the highest accuracy for tuberculous pleurisy (88.5%, AUC 0.95). CONCLUSION: This pilot study suggests that pleural SC5b-9 is clinically useful for differentiating tuberculous and malignant pleural effusions.

Adult↗
PubMed1997

Serum complement and familial combined hyperlipidemia.

Familial combined hyperlipidemia (FCHL) is one of the most common inherited lipid disorders. Resistance of adipocytes to the effects of acylation stimulating protein (ASP) may contribute to ineffective triglyceride synthesis and thereby prolonged postprandial lipemia and increased fatty acid flux to the liver seen in FCHL patients. Interestingly, ASP is identical to C3a-desArg, fragment of the third component of complement. We examined the relationships between serum levels of complement components C3 and C4 and markers of lipid and glucose metabolism in 11 large FCHL families (n = 53). Median serum C3 levels were 38% higher in affected compared to non-affected male FCHL family members (1.90 g/l vs. 1.38, P = 0.0027). The strongest correlations were observed between serum complement C3 and apolipoprotein B levels, reaching 0.77 in males. These relations were not confounded by obesity or impaired glucose tolerance. In conclusion, serum levels of the main complement components C3 and C4 correlated significantly with serum lipid levels. Further studies are needed to clarify the importance of disturbances in the complement system on the pathogenesis of FCHL and other lipid disorders.

Adipocytes↗
PubMed1987

Pulmonary dysfunction is common during a cytomegalovirus infection after renal transplantation even in asymptomatic patients. Possible relationship with complement activation.

In 24 patients with a cadaveric renal allograft, serial measurements after transplantation were made of the diffusing capacity for carbon monoxide (DLCO) together with serial measurements of C3d, the stable conversion product of the complement factor C3, and determinations of the anaphylatoxin C3a. Twelve patients were studied during an active cytomegalovirus (CMV) infection, and 12 patients were studied during allograft rejection or during a stable phase after renal transplantation (control subjects). No patients had pulmonary symptoms nor abnormal chest radiographs or arterial blood gas determinations. During an active CMV infection, DLCO was significantly reduced compared with the measurements made during allograft rejection or during a stable phase after renal transplantation. This was true both with (p less than 0.01) and without (p less than 0.01) correction for the hemoglobin concentration. Serum C3d levels were increased in 8 of the 12 patients with a CMV infection, but not in any of the patients in the control group. In 8 patients with a CMV infection, measurements were made of the anaphylatoxin C3a, and were found to be significantly higher than the levels in the control population (p less than 0.01). We conclude that our data are consistent with pulmonary dysfunction in every patient with an active CMV infection. The concomitant findings of complement activation and formation of anaphylatoxins suggest a causal relationship of the complement activation and a decreased DLCO, although further studies are warranted to determine the exact role of complement in the pulmonary events during an active CMV infection after renal transplantation.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1987

Complement and dengue haemorrhagic fever/shock syndrome.

The complement system is activated in DHF/DSS. The peak of activation and the presence of C3a and C5a anaphylatoxins coincided with the onset of shock and leakage. The levels of C3a correlated well with disease severity. This indicated an important role of the complement system in the pathogenesis of shock. Circulating immune complexes as assayed by two standard techniques were not detected in the majority of patients, and if detected were found in small amount. The role of circulating immune complexes in the activation of complement in DHF/DSS needs to be reinvestigated, and other possible mechanisms leading to complement activation should be sought.

Antigen-Antibody Complex↗
PubMed1997

Generation of anaphylatoxins through proteolytic processing of C3 and C5 by house dust mite protease.

BACKGROUND: The group 3 allergen of Dermatophagoides species (Der p 3 and Der f 3) has been identified as a 30 kd trypsin-like protease of the house dust mite. We previously showed that the 30 kd protease from Dermatophagoides farinae (Df-protease) could activate the bradykinin-generating cascade and exacerbate inflammatory reactions. OBJECTIVE: The purpose of this study was to determine whether Df-protease could enzymatically generate anaphylatoxins from complement components C3 and C5. METHODS: Df-protease was incubated with human serum C3 or C5 in a purified system, and the anaphylatoxin activity produced was assayed by measuring enhancement of vascular permeability and release of histamine from mast cells triggered by C3a and by assessing chemotaxis of polymorphonuclear cells caused by C5a. We also attempted to determine whether protease isolated from house dust could cause release of C5a from C5. RESULTS: Df-protease showed strong activation of C3 and C5, producing C3a and C5a by proteolytic cleavage of the complements. An appreciable amount of Df-protease was recovered in the house dust extract, and the house dust protease caused C5a release from C5. CONCLUSION: Df-protease activated the complement system to produce anaphylatoxins. Thus it is suggested that house dust mite proteases may contribute to the pathogenesis of allergic and inflammatory diseases caused by house dust allergens.

Air Pollution, Indoor↗
PubMed1984

Complement activation and hypersensitivity reactions to dialysis membranes.

Certain patients receiving hemodialysis experience recurrent chest pain, dyspnea, and hypotension during exposure to new cuprophane-membrane dialyzers (the "first-use syndrome"). Because activation of complement may be involved in these events, we examined in vivo complement activation with new cuprophane membranes and in vitro activation by zymosan in 6 such patients, and compared them with 10 patients who did not have symptoms during dialysis. All patients with the first-use syndrome had maximal complement activation 10 minutes after initiation of dialysis, with C3a des-arginine (desArg), the stable metabolite of C3 activation, equal to 8533 +/- 157 ng per milliliter (mean +/- S.E.M.). In asymptomatic patients the maximal C3a desArg value occurred at 15 minutes and was only 2907 +/- 372 ng per milliliter (P less than or equal to 0.0001). At a concentration of 3.8 x 10(-5) g of zymosan per milliliter, patients with the first-use syndrome had a C3a desArg level of 29.6 +/- 1.4 micrograms per milliliter, whereas it was only 16.6 +/- 2.3 micrograms per milliliter in asymptomatic patients (P less than or equal to 0.0001). Two other patients, who experienced cardiopulmonary collapse during the first two minutes of dialysis, had a C3a desArg level of 18,900 and 7800 ng per milliliter, respectively. We conclude that the occurrence of adverse symptoms associated with new cuprophane-membrane dialyzers correlates with complement activation.

Adult↗
PubMed1995

Soluble complement receptor 1 inhibits both complement and granulocyte activation during ex vivo hemodialysis.

Hemodialysis with cellulosic membranes results in both complement and granulocyte activation. We investigated the effects of soluble complement receptor 1 (sCR1), a potent complement inhibitor, on both complement and granulocyte activation in an ex vivo model of dialysis. Measurements were made of complement activation (radioimmunoassay for C3a desArg) as well as granulocyte activation (flow cytometric measurements of reactive oxygen species production, granulocyte CD11b/CD18 (MAC-1) expression and CD62L (L-selectin) expression). sCR1 completely abolished the generation of plasma C3a desArg during ex vivo hemodialysis. Without sCR1, C3a desArg levels rose from 968 +/- 373 ng/ml to 4961 +/- 40 ng/ml by the end of the ex vivo procedure (p < 0.001). sCR1 also completely inhibited MAC-1 upregulation and L-selectin shedding from granulocytes during ex vivo hemodialysis. With sCR1 there was still a statistically significant increase in granulocyte reactive oxygen species production (from 2.42 +/- 0.1 fluorescence channels to 6.47 +/- 0.7 fluorescence channels, p < 0.01) but a 50% inhibition when compared with experiments without sCR1 (3.15 +/- 0.5 to 11.2 +/- 1.9, p < 0.01). We conclude that sCR1 completely abolishes complement activation and changes in granulocyte cell adhesion molecules during ex vivo hemodialysis with cellulosic membranes. sCR1 partially inhibits granulocyte reactive oxygen species formation.

Anaphylatoxins↗
PubMed1994

Serum complement levels and severity of sepsis.

The activities (C3a, C4a, C5a) and concentrations (CH50, C3, C4, C5) of serum complement were measured to evaluate the involvement of complement in sepsis. We studied 27 patients with sepsis who were divided into the survivors (Group 1) and the nonsurvivors (Group 2). The levels of C3a, C4a, and C5a were all significantly higher in Group 2 than in Group 1 and closely reflected the severity of sepsis. Levels of C3 and C4 were significantly lower in Group 2 than in Group 1, presumably because these components were consumed as a result of activation of both the alternative and classical pathways. The levels of CH50 and C5 did not differ significantly between the two groups. These findings suggest that complement is closely involved in the exacerbation of the condition of septic patients, and that the measurement of complement activity is useful for evaluating the severity of sepsis.

Adult↗
PubMed1990

Complement activation in systemic sclerosis.

The use of a synthetic protease inhibitor, nafamstat mesilate, has enabled reliable estimations of in vivo complement activation to be made in patients with systemic sclerosis. Elevations of C3a and C4a anaphylatoxins were found in 2 and 24 out of 30 patients respectively, indicating that complement activation, predominantly by the classical pathway, is a common occurrence in the disease, even though complement C3 and C4 levels were within the reference range.

Adult↗
PubMedDate not supplied

Modified cellulosic dialyzer membranes: an investigative tool in thrombogenicity studies.

We have previously demonstrated that chemical modification of cellulosic membranes with dimethyl-amino-ethyl (DEAE) groups significantly improves membrane properties in terms of biocompatibility. Here, we show that DEAE substitution also alters the membrane's thrombogenic properties, and cellulosic membranes with various amounts of DEAE substitution were produced. Clinical dialyzers were constructed using two experimental membrane materials: modified cellulose-low (MC-low) and MC-high; standard unsubstituted cellulose was used as a control. Six patients were treated for a period of 3 weeks with each type of dialyzer and a heparin dose of less than 6000 IU/treatment. MC-low exhibited less extracorporeal beta-thromboglobulin and thromboxane B2 release than MC-high or Cuprophan. In addition, residual blood volume after clinical use was lower in the MC-low type. MC-low and MC-high induced less complement activation than Cuprophan, as characterized by extracorporeal C5a and C3a plasma concentrations (75% less C5a generation and 50 to 70% less C3a generation than unsubstituted cellulose).

Cellulose↗
PubMed1995

Complement levels and exposure in the hypobaric chamber.

Decompression sickness sometimes occurs in routine hypobaric chamber runs. Susceptibility to decompression sickness has been correlated with increases in C3a and C5a metabolites of complement activation by air bubbles. If personnel susceptible to decompression sickness show changes in C3a and C5a after decompression, then measurement of these metabolites may be useful in assisting diagnosis. C3a and C5a metabolites of complement activation were measured in 11 male and 2 female volunteers 1 h before (A), 1 h after (B), and 24 h after (C) exposure in routine hypobaric chamber runs to 25,000 ft equivalent altitude. The results were compared with 4 controls (3 males and 1 female). A one-way analysis of variance showed no significant difference between the experimental and control groups overall (p = 0.308; p > 0.05; N = 17). T-tests at each of the results further suggest non-significant differences between the experimental and control groups (p = 0.473; p = 0.341; p = 1.051; p > 0.05; N = 17) at results A, B, and C, respectively. The C5a assay was less than 10 micrograms.L-1 in all individuals, and the particular kit used was not sensitive below 10 micrograms.L-1. As none of the participants developed decompression sickness, it would be useful to determine levels of C3a and C5a in individuals who subsequently develop decompression sickness. One member of the experimental group who had undergone many chamber runs had much higher pre- and post-chamber run levels of C3a. This raises the question of the effect of repeated exposure in low pressure chambers on complement activation, and requires further study.

Adult↗
PubMed1990

Anaphylatoxin and terminal complement complexes in red cell salvage.

Thirteen patients undergoing elective orthopedic surgery were studied regarding anaphylatoxin (C3a and C5a) and terminal complement complex (TCC) formation in association with red cell salvage. The auto-transfusion equipment gave a centrifuged and washed erythrocyte fraction. The concentrations of C5a and TCC were not increased but elevated C3a levels were found in the suspension. After infusion of the erythrocyte fraction to the patient, no signs of systemic complement activation were observed. Thus, plasma levels of C3a, C5a and TCC were within the normal range in all the patients before and after autotransfusion. This study indicates that the complement system is activated in the cellsaver equipment. The washing procedure, however, seems to eliminate most of the anaphylatoxins and terminal complement complexes. No extensive systemic activation of complement seems to occur in association with autotransfusion to patients undergoing elective surgery.

Aged↗
PubMed1983

Anaphylatoxin formation during hemodialysis: effects of different dialyzer membranes.

Measurable complement activation resulting in the formation of both C3a and C5a anaphylatoxins was observed in 12 patients undergoing maintenance dialysis treatment with cuprophan hollow fiber dialyzers. Specific radioimmunoassay measurements demonstrated that these patients displayed significantly elevated levels of C3a antigen in the venous (outflow) line of the dialyzer after only 2 min of dialysis. During hemodialysis, venous plasma C3a levels continued to increase and became maximally elevated after 15 min. Thereafter, C3a concentrations gradually declined, suggesting that the rate of complement activation abates with continued cuprophan hemodialysis. Complement activation, as judged by venous plasma C3a levels, was also temporally correlated with hemodialysis leukopenia. The factor believed to be responsible for pulmonary vascular leukosequestration, C5a, could also be detected in venous plasma, but levels of this antigen were not strikingly elevated until the later stages of dialysis. By contrast, six patients dialyzed with polyacrylonitrile dialyzers failed to exhibit hemodialysis leukopenia and displayed only very modest increases in their plasma C3a levels during the initial phases of hemodialysis. These observations provide direct evidence that anaphylatoxin formation during hemodialysis is a transient phenomenon and indicate that the biocompatibility of dialysis membranes, as reflected by their complement activating potential, may be significantly different.

Acrylic Resins↗
PubMed2001

Light and electron microscopic analyses for ischaemia-reperfusion lung injury in an ovine cardiopulmonary bypass model.

An experiment to study the role of contact-activation leukocyte sequestration in the formation of ischaemia-reperfusion injury (I-R injury) was carried out. The study was conducted using light and electron microscopic analyses in an ovine cardiopulmonary bypass (CPB) model using a membrane oxygenator. Five adult sheep were used in the study. The CPB circuitry consisted of a roller pump and a membrane oxygenator. During CPB, flow rates ranged from 50 to 60 ml/kg/min with mild hypothermia. The CPB time was fixed at 120 min. Ten minutes after the start of CPB, total CPB was established. Thereafter, total CPB was performed for 100 min, followed by another 10 min of partial CPB. Lung biopsy specimens for light and electron microscopy were obtained from the upper lobe of the right lung before CPB, 109 min after the start of CPB (just before reperfusion) and 30 min after weaning (after reperfusion). A portion of the lung biopsy specimen was taken for a water content measurement at the same time intervals. For measuring the left and right atrial leukocyte counts, blood samples were taken before thoracotomy, 5 and 109 min after the start of CPB, and 30 and 120 min after weaning. C3a was measured before thoracotomy, 109 minafter the start of CPB, and 30 and 120 min after weaning. Plasma malondialdehyde (MDA) was checked before thoracotomy, 109 min after the start of CPB and 30 min after weaning. On both light and electron microscopic examination, mild to moderate acute lung change was observed after ischaemia-reperfusion. Interstitial oedema, leakage of erythrocytes into the alveolar space and endothelial cell swelling were the main findings. However, few neutrophils were seen. Water content of the lung showed a slight increase after the start of CPB, but there was no statistical significance. Neither significant differences in the transpulmonary gradients of leukocytes nor a significant complement activation, expressed by C3a levels, was observed. The MDA level did not display a significant change related to lung reperfusion despite an increase in MDA after the start of CPB. These findings indicate that I-R injury during CPB may not be from complement-activation leukocyte sequestration, but from another source of oxygen free radicals related to CPB.

Animals↗