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PubMed1990

C3a57-77, a C-terminal peptide, causes thromboxane-dependent pulmonary vascular constriction in isolated perfused rat lungs.

Pulmonary hypertension occurs after the intravascular activation of complement. However, it is unclear which activated complement fragments are responsible for the pulmonary vascular constriction. We investigated the 21-carboxy-terminal peptide of C3a (C3a57-77) to see if it would cause pulmonary vascular constriction when infused into isolated buffer-perfused rat lungs. Injection of C3a57-77 (225 to 450 micrograms) caused mean pulmonary arterial pressure (Ppa) to rapidly increase. However, the response was transient, with Ppa returning to baseline within 10 min of its administration. C3a57-77 also resulted in an increase in lung effluent thromboxane B2 (TXB2), concomitant with the peak increase in Ppa. C3a57-77 did not affect the amount of 6-keto-PGF1 alpha in the same effluent samples. Indomethacin inhibited the C3a57-77-induced pulmonary artery pressor response and the associated TXB2 production. Indomethacin also decreased lung effluent 6-keto-PGF1 alpha. The thromboxane synthetase inhibitors CGS 13080 and U63,357 inhibited the C3a57-77-induced pulmonary artery pressor response and TXB2 production without affecting 6-keto-PGF1 alpha. These inhibitors did not inhibit pulmonary artery pressor responses to angiotensin II. Tachyphylaxis to C3a57-77 occurred because a second dose of C3a57-77 administered to the same lung failed to cause a pulmonary artery pressor response or TXB2 production. The loss of the pressor response was not due to a C3a57-77-induced decrease in pulmonary vascular responsiveness because pressor responses elicited by angiotensin II were not altered by lung contact with C3a57-77. Thus, C3a57-77 caused thromboxane-dependent pulmonary vascular constriction in isolated buffer perfused rat lungs.

6-Ketoprostaglandin F1 alpha↗
PubMed2000

Reduction of neutrophil activation by vitamin E modified dialyzer membranes.

BACKGROUND/AIM: Transient leukopenia during hemodialysis due to neutrophil activation is attributed to bioincompatibility of the dialysis membrane, but the mechanism remains unclear. We studied the mechanism of neutrophilic activation by comparing a vitamin E modified membrane (CLEE) and a regular cellulose membrane (CLSS). METHODS: (1) CLSS and CLEE membranes were used in a crossover clinical study in 7 chronic hemodialysis patients. Neutropenia, CD11b expression, and plasma C3a and myeloperoxidase concentrations were compared between the two dialyzer membranes. (2) Normal blood was circulated through CLEE and CLSS minimodels, and the same parameters were compared. (3) Blood samples with modified complement activities (EDTA: both classical and alternative pathways inactivated; EGTA+Mg: classical pathway inactivated; heating: alternative pathway inactivated; control: no modification) were incubated in the CLSS minimodel, and the neutrophilic activation was compared. RESULTS: In clinical hemodialysis, neutropenia, CD11b expression, and C3a and myeloperoxidase levels were significantly lower when CLEE membranes were used. The same tendency was observed in minimodels. However, the degrees of inhibition in clinical dialysis, especially at the venous line, were significantly higher than in minimodels. As compared with controls, CD11b expression and myeloperoxidase level were significantly lower when both classical and alternative pathways were inactivated or when the classical pathway alone was inactivated, but were not significantly different when the alternative pathway alone was inactivated. CONCLUSIONS: Vitamin E modification of the dialyzer reduces some reactions of neutrophilic activation, such as CD11b expression and myeloperoxidase release, more effectively in the clinical situation than in ex vivo models, suggesting a possible effect of vitamin E in inhibiting bioreactions due to pyrogen in the dialysate. The classical complement pathway is required in membrane-induced neutrophilic activation, at least during the initial stage.

Adult↗
PubMed1971

Complement-derived leukotactic factors in inflammatory synovial fluids of humans.

A large per cent of rheumatoid synovial fluids contain chemotactic activity for rabbit granulocytes (neutrophilic). The chemotactic activity is, in large part, related to the fifth (C5) and sixth (C6) components of human complement; a combination of physical-chemical techniques indicates the activity to be attributable to C567 and C5a, a cleavage product of C5. Many rheumatoid synovial fluids contain a C5-cleaving enzyme which, on the basis of substrate specificity and susceptibility to inhibitors, is very similar to an enzyme extractable from lysosomal granules of human and rabbit granulocytes. Inflammatory nonrheumatoid synovial fluids contain chemotactic activity that is related to cleavage products (C3a) of the third component of human complement (C3). Also found in these fluids is a C3-cleaving enzyme capable of producing C3a. Of the other synovial fluids examined, lupus fluids were remarkable by their total lack of chemotactic activity. These findings record for the first time the presence of complement-derived chemotactic factors in pathological human fluids.

Antigen-Antibody Reactions↗
PubMed2000

Complement activation induced by ischemia-reperfusion in humans: a study in patients undergoing partial hepatectomy.

BACKGROUND/AIM: Activation of the complement system is induced by ischemia-reperfusion (I/R) in animal models. Whether I/R also induces complement activation in humans is not known. Here, we investigated complement activation in patients undergoing major liver resection. METHODS: In 11 of 17 patients, the hepatoduodenal ligament was clamped, making the liver transiently ischemic (HEMI+; mean ischemia time, 42 +/- 18 min); 6 patients were operated without clamping (HEMI-). Activation at plasma level (circulating activation products) was studied in blood samples collected prior to surgery and 5, 24 and 48 h thereafter. Parameters analyzed were C4b/c and C3b/c, C4d and C3d, C3a, as well as complexes between complement and C-reactive protein (CRP), which reflect CRP-induced complement activation. Activation at tissue level (C3 and C4 fixation) was studied in liver biopsies obtained before and after resection. RESULTS: In plasma, post-operative levels of C4b/c and C3b/c were not different from baseline levels in both groups. Mean plasma levels of C4b/c and C3b/c were significantly decreased at 24 h post-surgery in the HEMI+ group (p=0.02 and p=0.07). At the same time, levels of C4d-CRP and C3d-CRP were significantly increased (p<0.01 for both parameters). At tissue level, activated complement fragments were observed intracellularly in some pericentral hepatocytes. In I/R livers, large numbers of hepatocytes were positively stained for all complement activation products. CONCLUSIONS: Our data show that in situ complement activation via the classical route occurred during liver resection and that ischemia and/or reperfusion may have contributed to activation. Levels of complement activation products in the circulation were low, showing that transient ischemia had no severe influence on systemic complement activation, suggesting a locally contained response.

Adult↗
PubMed1989

The human C3b receptor (CR1).

The human complement system is comprised of 19 plasma components and regulatory proteins and of at least 9 distinct cellular receptors for these proteins or their activation fragments. The important role of complement in host defense against infection is related to its capacity to opsonize microorganisms, lyze target cells, and induce the release of inflammatory mediators from leukocytes. Complement participates in the processing and clearance of immune complexes and in regulation of the immune response. Most of the biologic effects derived from complement activation depend on ligand-receptor interactions between complement proteins or their cleavage fragments and specific receptors on cells. Two types of ligands are generated during complement activation: soluble low-molecular-weight ligands, such as the anaphylatoxins C3a and C5a, and so-called bifunctional ligands that attach both to the target of complement activation (opsonins) and to the appropriate receptor on effector cells. The most abundant complement protein in plasma is C3. Activation of the classic and alternative complement pathways generates C3 convertases that cleave C3 into an anaphylatoxic fragment, C3a, and a major fragment, C3b, which is capable of forming a covalent linkage with the targets of complement activation. Surface-bound C3b is the preferential ligand for the C3b receptor, CR1 (CD 35), which is expressed on most peripheral blood cells. The receptor plays an important role in the processing of immune complexes, the phagocytosis of C3b-bearing microorganisms, and regulation of the immune response. The cellular expression of the molecule is decreased in patients with systemic lupus erythematosus (SLE) and in patients infected with the human immunodeficiency virus (HIV).

Antigen-Antibody Complex↗
PubMed1984

Plasma lactoferrin reflects granulocyte activation via complement in burn patients.

Complement activation and neutropenia have been observed in thermally injured animals. In burn patients, granulocyte chemotaxis and morphological loss of specific granules occur. We conjectured that complement is activated in humans and, in turn, induces granulocytes to secrete lactoferrin (LF), a marker of granulocyte activation. Twenty burn patients were evaluated for absolute granulocyte count (AGC), plasma levels of anaphylatoxins (C3a, C4a, C5a), and lactoferrin. The AGC directly correlated with the extent of the burn on day 1. Similarly, plasma LF on day 1 correlated with the percent burn. Those with greater than 30% burn had plasma LF between 10 and 40 micrograms/ml (normal LF = 1.5 +/- 1.8 micrograms/ml). In five patients without further complications followed serially, plasma LF did not return to normal until 2 to 5 weeks. In all patients, there was evidence of complement activation; C4a ranged between 283 and 13,064 ng/ml and C3a between 19 and 852 ng/ml. In some patients, C5a was detectable, but the values correlated inversely with the extent of burn. On the other hand C3a and C4a levels did not correlate with the extent of burn but threefold to fivefold rises of C3a levels on days 7 and 9 predicted gram-negative sepsis. Although plasma LF did not predict sepsis, levels greater than 12 micrograms/ml on day 1 heralded the onset of neutropenia on day 3 in 60% of patients with 30% burn. Six of 20 patients developed pulmonary radiographic changes and, in five of the six, the changes occurred by day 3. Plasma LF in all six patients on day 1 was greater than 17 micrograms/ml. In two patients with greater than 50% burn, depletion of granulocyte LF was demonstrated histochemically. These studies indicate that complement is activated in burn patients, which is associated with granulocyte secretion. Measurement of plasma anaphylatoxins and LF may serve as useful aides in clinical management of these patients.

Adult↗
PubMed1994

Assessment of blood substitutes: II. In-vitro complement activation of human plasma and blood for safety studies in research, development, industrial production and preclinical analysis.

Animal safety study cannot predict the effects of blood substitutes in human response. Response of human, especially in immunology and complement activation, need not be the same as those in animals. We have earlier reported an in-vitro preclinical screening test based on testing the effects of modified hemoglobin on complement activation of human plasma or blood in vitro. In this test, modified hemoglobin is added to human plasma in a test tube. Complement activation is followed by the C3a levels. Since this directly measures the effect of modified hemoglobin on human plasma, it would be the closest response in human next to injecting this into human. Thus, this could be an important bridge before clinical use in patients. However, why wait for the completion of research, industrial production and preclinical animal studies? Why don't we do this test right at the beginning during the research stage? If a new system is found to cause complement activation at this stage, one can avoid tremendous waste of time and money in further development, industrial production and preclinical animal study. This paper analyzes this approach in research, development, industrial production and preclinical analysis.

Blood Substitutes↗
PubMed1990

Effects of homologous and heterologous stroma-free hemoglobin and polyhemoglobin on complement activation, leucocytes and platelets.

This is a study of the effects of stroma-free hemoglobin(Hb) and polyhemoglobin on C3 and C3a levels and on blood cell counts. The effects of membrane stroma from red cells and endotoxins on complement activation were also investigated. Plasma samples from rats were incubated with hemoglobin solutions or control solutions. C3 was measured using anti-rat C3 by nephelometric method. C3a was measured using radioimmunoassay. C3 and C3a were also determined in rats receiving hemoglobin solutions, red cell stroma solutions, or a solution containing complement activators (membrane stroma and bacterial endotoxins). There were no significant differences in C3 or C3a levels between the plasma incubated with hemoglobin solutions and the control plasma incubated with saline (P greater than 0.05). Compared with the saline incubated plasma, C3 was significantly lower and C3a significantly higher in the zymosan treated plasma (P less than 0.01). In hemoglobin infused rats, there was no significant difference between pre-versus post-infusion values in C3 and C3a. There was a significant increase in C3a in the rats receiving stroma suspension (P less than 0.05) or stroma and endotoxins (P less than 0.02). Polyhemoglobin and stroma-free hemoglobin did not cause significant changes in total leucocyte, differential, or platelet counts. Our study suggests that purified stroma-free Hb and polyHb do not activate complement, and that C3a is a more sensitive parameter for monitoring complement activation than C3. On the other hand, contaminates in hemoglobin preparations, such as membrane stroma or endotoxins, activate the complement system.

Animals↗
PubMed2004

Antibody, complement and accommodation in ABO-incompatible transplants.

Many facets of accommodation have been explored since this process was first observed in ABO-incompatible renal allografts over 17 years ago. Intriguing new pieces of the puzzle have emerged to be fitted into the picture in several places. For example, vascular endothelial cells can be stimulated to secrete substantial amounts of blood group A and B antigens linked to von Willebrand factor; the antibody response to A and B antigens stimulated by ABO-incompatible renal allografts can show epitope spreading; complement can inhibit inflammation through actions of some complement split products, particularly iC3b and C3a; endothelial cells can upregulate various cytoprotective mechanisms; and clinically, new protocols for achieving accommodation have been implemented with improved results.

ABO Blood-Group System↗
PubMed1993

Use of finger-prick human blood samples as a more convenient way for in-vitro screening of modified hemoglobin blood substitutes for complement activation: a preliminary report.

Safety test of modified hemoglobin in animals does not always reflect safety in human. We have earlier reported an in-vitro preclinical screening test based on in-vitro complement activation of human plasma In this test, modified hemoglobin is added to human plasma in a test tube. Complement activation is followed by the C3a levels. Since this directly measures the effect of modified hemoglobin on human plasma, this could be an important bridge before clinical use in patients. The use of plasma is suitable for research, development and industrial applications. However, there are many extra steps involved and may not be convenient for population or patient screening on a large scale bases. The present study shows that it is possible to use small sample of whole blood obtained directly from finger pricks and use immediately for analysing complement activation using an ELISA enzyme immunoassay method.

Blood Specimen Collection↗
PubMed1989

Induction of interleukin-1 production in patients undergoing cardiopulmonary bypass.

Systemic reactions resembling inflammation occur in patients undergoing cardiopulmonary bypass. We now report that interleukin-1, an endogenous pyrogen and a key mediator of inflammation, is transiently and consistently generated in vivo by circulating monocytes within hours after cardiopulmonary bypass. Interleukin-1 production was assessed by measuring interleukin-1 functional activity and interleukin-1 beta antigen concentration in cell lysates from monocytes of patients during and after bypass. There was no increase in intracellular interleukin-1 activity during bypass and within the first hours after bypass, possibly because of a suppressive effect of hypothermia on interleukin-1 production, as documented in vitro. Maximal generation of interleukin-1 was observed 24 hours after extracorporeal circulation, concomitantly with the occurrence of a peak in body temperature. The amount of interleukin-1 generated at that time was linearly correlated with the increase in patients' body temperature. The peak in interleukin-1 production followed by 20 hours the peak in complement activation as assessed by determining C3a desArg and C5a desArg concentrations in patients' plasma. These results indicate that interleukin-1 may be involved in the pathogenesis of adverse systemic reactions associated with cardiopulmonary bypass.

Adult↗
PubMed1997

Coating of human decay accelerating factor (hDAF) onto medical devices to improve biocompatibility.

In passing blood through an artificial circulatory system, the blood is exposed to surfaces that result in activation of the complement system. The consequences of the activation of complement can be extremely serious for the patient ranging from mild discomfort to respiratory distress and even anaphylaxis. An entirely novel approach was to express recombinant GPI anchored human decay accelerating factor (hDAF) using the baculovirus system and then coat the recombinant protein onto the surfaces of these materials to reduce complement activation. Expression of hDAF in Sf9 cells was shown by ELISA, FACS analysis, and Western blot. Functional activity was tested by CH50 assay. For the coating experiments a small scale model of a cardiovascular bypass circuit constructed from COBE tubing was used. hDAF was either coated onto the circuit using adsorption or covalently linked via the photoreactive crosslinker, p-azidobenzoyl hydrazide. After coating, heparinised human blood was pumped around the circuit and samples were collected into EDTA collection tubes at different time points. Complement activation was measured using a Quidel C3a-des-arg EIA. The photolinked circuits gave a reduction in C3a production of 20-50%, compared to 10-20% seen with an absorbed hDAF circuit. Furthermore, the inhibition of complement was seen over the whole time scale of the photolinked circuit, 60-90 min, whilst in the adsorbed circuit inhibition was not seen to a significant degree after 60 min. The time scale of a standard cardiac bypass is 45-90 min, therefore, the photolinked circuit results are encouraging, as significant inhibition of complement activation is seen within this time frame.

Adsorption↗
PubMed1997

Inflammatory mediators in BAL fluid as markers of evolving pneumonia in leukocytopenic patients.

STUDY OBJECTIVES: Pneumonia during chemotherapy-induced leukocytopenia is a major cause of overall treatment failure in patients with hematologic malignancies. To improve outcome in these high-risk patients, early diagnosis of pulmonary infiltrates and institution of adequate antimicrobial treatment are mandatory. To identify patients with evolving pneumonia, we have prospectively studied the prognostic value of cytokine and complement measurements in early BAL samples from febrile leukocytopenic patients. DESIGN: Prospective, comparative study. SETTING: Hematology/oncology section of a university hospital. PATIENTS: Twenty-one patients with leukocytopenia (WBC count < 1.000/microL) following cytoreductive chemotherapy for malignant disorders. INTERVENTION: Early BAL sampling primarily for microbiologic diagnostic purposes. MEASUREMENTS AND RESULTS: Proinflammatory cytokines and activated complement components were measured in the BAL aspirates and the results were related to the prevalence or subsequent evolution of overt pneumonia. Of the 21 patients studied, 10 patients presented with overt pneumonia at BAL sampling (group A), 5 patients developed objective signs of pneumonia 3 to 5 days after BAL (group B), and 6 patients remained free of pneumonia during follow-up (group C). In comparison with group C, patients in groups A and B both had distinctly elevated bronchoalveolar levels of tumor necrosis factor-alpha, interleukin-6, granulocyte colony-stimulating factor, C3a, and C5a. CONCLUSIONS: Cytokine and complement determinations in early BAL samples may aid in the identification of febrile leukocytopenic patients with evolving pneumonia 3 to 5 days prior to the manifestation of diagnostic clinical and radiographic signs.

Adult↗
PubMed2003

Complement activation in a model of chronic fatigue syndrome.

BACKGROUND: A need exists to identify biological markers in chronic fatigue syndrome (CFS). OBJECTIVE: To use an exercise and/or allergen challenge to induce the symptoms of CFS and to identify a biological marker that correlates with these symptoms. METHODS: Patients with CFS (n = 32) and age-matched, normal control patients (n = 29) exercised for 20 minutes on a stationary bike at 70% of their predicted max work load (Watts). Patients from each group with positive skin test results were also challenged with intranasally administered relevant allergens. Symptoms were recorded for 2 weeks before and 1 week after each challenge, using 3 different instruments. Blood samples were taken before, and 0, 1, 6, and 24 hours after challenges. Levels of complement split products, cell-associated cytokines, and eosinophilic cationic protein were measured. Mean preexercise and postexercise symptom scores were evaluated for each group. RESULTS: Exercise challenge induced significant increases of the complement split product C4a, but not C3a or C5a, at 6 hours after exercise only in the CFS group (P <.01), regardless of allergy status. Mean symptom scores were significantly increased after exercise through the use of a daily diary (P <.03) and a weekly diary (P <.01) for the CFS group only. Mean scores for the Multidimensional Fatigue Inventory categories "reduced activity" and "mental fatigue" were significantly increased in the CFS group only (P <.04 and P <.02, respectively). CONCLUSIONS: Exercise challenge may be a valuable tool in the development of diagnostic criteria and tests for CFS. Establishment of a role for complement activation products as markers or participants in production of illness require further study.

Adult↗
PubMed2000

Galalpha(1,3)Gal epitope in porcine small intestinal submucosa.

Small intestinal submucosa (SIS) is a naturally occurring, acellular biomaterial derived from porcine jejunum, which promotes constructive tissue remodeling when applied as a xenogeneic graft material. Galactosyl-alpha(1,3)galactose (Gal) is a cell-associated epitope responsible for hyperacute rejection of porcine whole-organ xenografts in primates. Because SIS is harvested from porcine tissue, it may contain the Gal epitope. The goals of this study were to determine if Gal is present in SIS and, if it is present, to determine if human serum complement can be activated in vitro following exposure to porcine-derived SIS. SIS was probed for Gal by immunohistochemical methods and by lectin-peroxidase staining. SIS stained strongly positive with human serum, which contains naturally occurring antibodies to Gal, followed by anti-immunoglobulin G (IgG) or anti-IgM peroxidase conjugate. Blocking with the lectin I-B(4), which is specific for the Gal epitope, decreased the intensity of staining. Exposure of SIS to alpha-galactosidase reduced staining to negligible amounts. The Gal epitope is distributed transmurally throughout the SIS material. Subtyping of the immunoglobulins that bind to SIS showed that IgG(2) is the major immunoglobulin of human plasma that binds to SIS. SIS did not activate complement in vitro as measured by radioimmunoassay for C3a.

Animals↗
PubMed2004

Complement and autoimmune glomerular diseases.

The renal glomerulus is the specialized structure in the kidney responsible for generating over 150 liters of plasma ultrafiltrate per day in humans. Certain characteristics of this structure favor involvement in autoimmune diseases. Formation of immune complexes in the glomerulus, either deposited from the circulation or generated in situ, can activate the complement system. Active products of this system include the anaphylatoxins C3a and C5a, C3b, which covalently associates with immune complexes, and the C5b-9 membrane attack complex. If complement is activated in a site accessible to blood constituents, such as in the subendothelial and mesangial regions, generated C3a, C5a and C3b can interact with their respective receptors on inflammatory cells to lead to an exudative lesion. In addition, intrinsic glomerular cells bearing relevant receptors may also be activated and can proliferate to contribute to the inflammation. In a privileged site such as the subepithelial region, complement activation products are not accessible to blood cells, and as such, the resultant pathology is noninflammatory. In this setting, effects of C5b-9 predominate, which include activation and injury of cells through still incompletely characterized pathways. Various means to alter the complement pathway are now available, including antibody inhibitors and recombinant proteins based upon naturally occurring complement regulators. The use of these agents, as well as mice in which individual components of the complement system have been deleted, has given a great deal of insight into how the complement system is involved in glomerular disease. The ability to manipulate the complement pathway is now a reality in a clinical setting, yet conclusive human studies are difficult to achieve.

Animals↗
PubMed1991

Biomedical polymers differ in their capacity to activate complement.

Conventionally, complement activation by biomedical polymers has been evaluated by determining the C3a concentration in the fluid phase only. According to this criterion, biomaterials such as hemodialysis membranes made from cellulosic or various synthetic polymers were classified as activators or nonactivators of complement. Since certain membranes bind large quantities of C3a from the fluid phase, classification based on fluid-phase C3a concentration has in some instances been inaccurate. As follows from the comparison of complement activation by cuprophane and polyacrylonitrile membranes, the capacity of a biomedical polymer to activate complement is not determined by the number of potential covalent binding sites on its surface. Biomaterial itself may lack hydroxyl and/or amino groups, and yet it may activate C3 in human serum very efficiently. Some of the biomaterials may also bind unactivated/unfragmented C3 whether in the absence or presence of other serum proteins. In addition, binding of factor B (a promotor of C3 activation) and binding of factor H (an inhibitor of C3 activation) to certain biomaterials have been found to be independent of complement activation and unaffected by the presence or absence of C3. Thus, it is becoming apparent that the requirements for the formation and stability of the C3 convertase on artificial surfaces differ from those on biological membranes, and that the relative magnitude of binding of factor B and factor H to the surface per se cannot be used as a reliable indicator of the capacity of the biomaterial to activate complement. Further studies are necessary to elucidate the molecular mechanisms of C3 and C5 activation on the surfaces of biomedical polymers.(ABSTRACT TRUNCATED AT 250 WORDS)

Blood Proteins↗