SEARCH · PubMed Health

Results for “complement C3 inhibitor”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 901 records · Page 50Linked to original sources

PubMed2002

Elevated kallikrein activity in plasma from stable liver transplant recipients.

Extensive in vitro conversion of complement components C3 and C4 has been observed in EDTA plasma obtained from a number of stable orthotopic liver transplant recipients (LTR) [Clin. Chem. 45 (1999) 1190]. Consequently, we designed a chromogenic substrate (Ac-Ala-Gly-Leu-Thr-Arg-p-nitroanilide, AGLTR-pNA), based on the C1s cleavage site in complement component C4, in an attempt to identify the plasma proteinase(s) that cleaves C4 in vitro. Average peptidase activity in EDTA plasma obtained from stable LTR (n = 16) was significantly higher (P<0.01) than that in plasma from healthy non-transplant donors (n = 16). This peptidase activity was also detected using commercial substrates designed for specific coagulation proteinases. The plasma proteinase was not inhibited by hirudin, a thrombin inhibitor, but was inhibited by the plasma kallikrein inhibitor D-Phe-Phe-Arg-chloromethylketone, which fails to inhibit C1s. We concluded that the peptidase detected inLTR plasma, using chromogenic substrates including AGLTR-pNA, was plasma kallikrein. Western blot analysis confirmed the presence of kallikrein-alpha-2-macroglobulin complexes (alpha2M) in LTR plasmas. We also demonstrated that kallikrein was not the proteinase responsible for the in vitro cleavage of C4. Elevation of the plasma peptidase activity correlated significantly with recurrent hepatitis C virus (HCV) infection in these liver recipients with a P value <0.02. Significant correlation was not observed between complement activation (i.e. the C4a levels) and recurrent HCV infection (P>0.15); however, C4a levels did correlate with rejection (P<0.02). These results suggest that elevation in plasma peptidase activity and activation of complement do signal different pathological events in LTR, events that appear related to HCV-induced infection and immune tissue injury, respectively.

Adult↗

PubMed1991

Expression of decay-accelerating factor is reduced on hyperplastic synovial lining cells in rheumatoid synovitis.

Decay-accelerating factor (DAF), a membrane inhibitor of homologous complement activation, is present in synovial cells lining joint space and detected in synovial fluid. DAF is considered to protect synovial membrane from complement-mediated injury associated with articular inflammation. We studied the immunohistopathological features of DAF molecules in synovial membrane of rheumatoid synovitis using a DAF-specific monoclonal antibody, 1C6. Reacting molecules with the 1C6 antibodies in synovial tissue extracts formed a 70-kD band in Western blot analysis. DAF was strongly detected on the flat synovial lining cells, but weakly on the hyperplastic and multi-layered lining cells in rheumatoid synovitis. The latter cells reacted with anti-Leu-M3 antibodies specific for a cell surface marker of activated macrophages, sometimes accompanied by C3 and IgM deposition on the superficial synovial membrane. These results suggest that active rheumatoid synovitis characteristically with hyperplastic synovial lining cells is out of control by DAF, thereby permitting further complement-mediated injury.

Antibodies, Monoclonal↗

PubMed1980

Loss of Fc receptor activity after culture of human monocytes on surface-bound immune complexes. Mediation by cyclic nucleotides.

Human monocytes cultured on surface-bound immune complexes exhibited a loss of ability to form rosettes with IgG-sensitized sheep erythrocytes (EA). This loss was not a result of inhibition of Fc receptors by solubilized complexes nor of release of soluble factors by the cells. Loss of EA rosetting was not prevented by culture of monocytes at 4 degrees C, or by treatment with colchicine, cytochalasin B, or local anethetic agents. These results suggested that the loss was not secondary to capping or interiorization of Fc receptors. The results of other studies indicated that the Fc receptors were not damaged by lysosomal enzymes or oxygen radicals. Maintenance of EA rosetting ability of monocytes cultured on surface-bound immune complexes was seen after a 3-h preincubation of the cells in 100 mM 2-deoxy-D-glucose (2dG). A similar preincubation in ATP or in 8-bromoadenosine 3':5'-cyclic monophosphoric acid plus the phosphodiesterase inhibitor methyl isobutyl xanthine led to a partial loss of EA rosetting of cells on plain fibrin and to a partial reversal of the effects of 2dG seen with cells on complexes. We conclude that EA rosetting of monocytes cultured on surface-bound immune complexes is reduced by cyclic nucleotide-mediated effects on Fc receptor number or function.

Antigen-Antibody Complex↗

PubMed1975

Platelet aggregation induced by antilymphocyte serum. I. Differences between washed and unwashed platelets.

Horse antilymphocyte serum (ALS) induced active release of nucleotides and aggregation of washed human platelets. It also caused lysis of platelets in the presence of plasma. The sequence of lytic processes was studied by electron microscopy. Aggregation induced by ALS was not mediated through ADP in either washed or unwashed platelets, but was inhibited by those inhibitors of secondary platelet aggregation. In unwashed platelets heparin inhibited the cytolysis and aggregation completely, while prostaglandin E1 (PGE1) did not; in contrast, PGE1 completely inhibited the aggregation and release of nucleotides from washed platelets, while heparin did not. The possible mechanisms of ALS-induced aggregation are discussed.

Adenosine Diphosphate↗

PubMed2000

C1 inhibitor prevents capillary leakage after thermal trauma.

OBJECTIVE: In burned patients, activation of the complement and clotting systems is suggested to play an important role in the development of the capillary leak syndrome and inflammatory tissue destruction. In an animal model of thermal trauma, the possible protective effect of C1 inhibitor (C1Inh), a major control protein of both the complement and clotting systems, was investigated. DESIGN: Prospective, controlled study. SETTING: Animal model. SUBJECTS: Healthy pigs weighing 30 kg. INTERVENTIONS: Pigs were scalded for 25 secs with 75 degrees C hot water to achieve a 30% total body surface deep partial-thickness burn. The treatment group (n = 8) received C1Inh concentrate at an initial dose of 100 units/kg body weight immediately after thermal trauma, followed by three further applications every 12 hrs. Two control groups included animals that were either scalded (n = 8) or not scalded (n = 7) and treated with lactated Ringer's solution. MEASUREMENTS: Before and at various time points after trauma blood samples were analyzed for complement activation (APH50, CH50, SC5b-9, C3). Continuous monitoring of hemodynamic variables was performed and postmortem histologic examination of specimens from lung, heart, liver, kidney, stomach, duodenum, jejunum, ileum, and colon was carried out. Aseptically collected mesenteric lymph nodes were pooled and screened for bacterial translocation. For evaluation of the burn wound, biopsies from defined scalded and not scalded areas were taken daily. As a measure for edema formation, the weight of the animals was recorded every 2 hrs. RESULTS: After C1Inh treatment, which led to a significantly reduced complement activation, the clinical outcome was clearly improved, as indicated by vital signs and as demonstrated by reduced edema formation. Treated animals presented a diminished bacterial translocation. Pathologic alterations were clearly diminished in the burned skin, in shock-related organs, and in the intestines. CONCLUSION: Application of C1Inh appears to be an effective means to prevent capillary leakage and inflammatory tissue destruction after thermal trauma.

Animals↗

PubMed1989

Plasminogen activation in plasma of patients with systemic lupus erythematosus.

We measured alpha 2-plasmin inhibitor-plasmin complexes (PI-PC) in plasma of patients with systemic lupus erythematosus (SLE) to examine the plasminogen activation in SLE. The plasma PI-PC level in 23 patients with SLE was significantly higher than that in 18 normal subjects (P less than 0.001) and the SLE patients with nephrotic syndrome had higher plasma PI-PC levels than those without nephrotic syndrome (P less than 0.01). In addition, the plasma PI-PC level was significantly correlated with the level of plasma C3 breakdown products (iC3b/C3dg) in the patients with SLE (r = 0.53, P less than 0.01). These results suggest that plasminogen is activated in plasma of patients with SLE and that the plasminogen activation may be associated with the activation of complement in SLE.

Adult↗

PubMedDate not supplied

Pro-inflammatory complement activation by the A beta peptide of Alzheimer's disease is biologically significant and can be blocked by vaccinia virus complement control protein.

The amyloid plaque is the hallmark of Alzheimer's disease (AD). The transmembrane domain and a portion of the C-terminus (A beta) of the amyloid precursor protein, are known to form the nucleus of the amyloid plaque. It has been demonstrated recently, using in vitro assays, that the A beta peptide can activate both the classical (antibody-independent) and alternate pathways of complement activation. The proposed complement activation is due to the binding of A beta to the complement components C1q and C3, respectively, which initiate formation of the proinflammatory C5a and C5b-9 membrane attack complex. In this report, we have investigated the in vitro findings for the likely complement-dependent proinflammatory properties of the Alzheimer's disease A beta peptide. We have performed experiments using congenic C5-deficient and C5-sufficient mice injected with synthetic A beta and recombinant polypeptide (C-100) containing A beta. Injection of C-100 into C5-sufficient mice induced a clear increase in the number of polymorphonuclear cells (neutrophils) at the site of injection due to complement activation and the subsequent release of proinflammatory chemtoactic factors. In sharp contrast, the C5-deficient mice did not show any increase in cellular influx. The vaccinia virus complement control protein, an inhibitor of both the classical and alternate pathway can down-regulate the biologically significant activation of complement by A beta, as demonstrated by an in vitro immunassay. The therapeutic down-regulation of A beta-caused complement activation could greatly alleviate the progression of some of the chronic neurodegeneration characteristic of Alzheimer's disease.

Alzheimer Disease↗

PubMed1991

Induction of the paroxysmal nocturnal hemoglobinuria phenotype in normal human erythrocytes: effects of 2-aminoethylisothiouronium bromide on membrane proteins that regulate complement.

To investigate the mechanism by which treatment of normal human erythrocytes with the sulfhydryl reagent 2-aminoethylisothiouronium bromide (AET) induces susceptibility to complement mediated lysis, the effects of AET on the structural and functional integrity of decay accelerating factor (DAF), membrane inhibitor of reactive lysis (MIRL), and complement receptor type 1 (CR1) were examined. Following treatment with AET, erythrocyte MIRL and CR1 were no longer recognized in situ by antibodies, and antibody binding to DAF was diminished by approximately 50%. These studies indicated that the structural integrity of the three complement regulatory proteins was either partially (DAF) or completely (MIRL and CR1) disrupted by AET. Subsequent experiments showed that functional inactivation paralleled the structural disruption. Treatment of normal erythrocytes with AET induced susceptibility to cobra venom factor-initiated hemolysis, indicating that the functional activity of MIRL had been destroyed. The capacity of erythrocyte CR1 to serve as a cofactor for factor I-mediated cleavage of iC3b to C3c and C3dg was lost following treatment with AET. C3 convertase activity increase markedly following treatment of erythrocytes with AET, but convertase activity on AET cells was approximately 50% less than that observed when DAF function on normal cells was completely inhibited by antibody. Susceptibility of AET cells to acidified serum lysis was shown to be due primarily to inactivation of MIRL. Unexpectedly, in acidified serum the activity of the amplification C3 convertase of the APC was found to be controlled by MIRL as well as by DAF. These studies show that AET induces susceptibility to complement-mediated lysis by disrupting the structural and functional integrity of membrane constituents that regulate the activity of both the C3 convertases and the membrane attack complex of complement.

Antibodies↗

PubMed1987

[Quantitative determination of proteins in the contents of pseudocysts of the maxillary sinus].

The factors C 3c and C 4 of the complement system, the protease inhibitor alpha-1-antitrypsin (AAT) as well as the immunoglobulins IgA, IgG, IgM in the fluid of cysts of maxillary sinus were determined by means of single radial immunodiffusion. The concentration of these proteins was compared with the concentration in the serum obtained simultaneously. A decrease of C 3c, C 4 and AAT and an increase of IgA and IgG in fluid are indicators of active participation of the mucosa in defence processes.

Complement C3↗

PubMed1979

Human complement in thrombin-mediated platelet function: uptake of the C5b-9 complex.

Thrombin-mediated platelet aggregation and release is enhanced by the presence of C3, C5, C6, C7, C8, and C9 of human complement. The interaction of thrombin with its receptor on the platelet membrane initiates activation of complement on the platelet surface. Trypsin-mediated platelet function is not enhanced by the addition of complement, probably because trypsin has no receptor on the platelet surface so activation of complement is triggered in the fluid phase and not on the platelet surface. Activation of complement by thrombin led to production of dimers of the C5b-9 complex on the platelet surface. These complexes were eluted from the platelet membrane and were identified physicochemically and morphologically. The mechanism of complement-induced enhancement of platelet function is not clear, however, it probably is mediated via the arachidonic acid transormation pathway because this activity was blocked by known inhibitors of cyclo-oxygenase, namely, aspirin and indomethacin.

Antithrombin III↗

PubMed1981

Isolation and properties of a complement inhibitor from Naja haje venom, distinct from known anticomplementary factors in cobra venom.

A complement inhibitor (CI) has been isolated from cobra (Naja haje) venom which is distinct from the two known anticomplementary factors in cobra venom [1], in functional properties as well as structure. CI is a small (mol. wt 26,000, determined by sodium dodecyl sulphate gel electrophoresis), heat-labile glycoprotein; the amino acid composition is that of a globular protein. CI interferes at various steps of the complement sequence, including reactions of the classical and alternative pathway. No effect was observed on C4 fixation and on the assembly of the membrane attack complex from C6-9 (minor inhibiting effects, if present, have not been excluded). Initiation of the alternative pathway is inhibited by CI already at the stage of cleavage of factor B. CI binds to C4, C4b, C3 and C3b; since the major inhibitory action of CI is lost after washing of cell intermediates, complex formation and, as a consequence, steric hindrance may be responsible for the inhibiting effects of CI. CI also interferes with binding of C3b to C3b receptors on human erythrocytes. CI is non-toxic in mice when given intraperitoneally in doses of 5 microgram/g.

Amino Acids↗

PubMed1984

Control of the immune complex-complement interaction by protein H of the alternative complement pathway and the natural inhibitor heparin.

The potential of the negative regulatory protein H of the alternative complement pathway convertase and of heparin in modulating the complement-dependent capacity of fresh serum to inhibit immune complex precipitation (CIICP) between bovine serum albumin (BSA) and rabbit anti-BSA as well as tetanus toxoid (TT) and human anti-TT was assessed. Additions of purified H to serum to increase the intrinsic concentration of this protein by 80% (BSA-anti-BSA system) and 190% (TT-anti-TT system) resulted in an inhibition of CIICP by 50% and 60%, respectively, whereas further increase of the amount of H lead to a decrease of its inhibitory activity. A similar effect was observed with heparin: at a concentration of 400 U/ml a 90% inhibition of CIICP in the TT-anti-TT system was obtained which diminished at higher heparin concentrations. The effect of H on C3 deposition to immune aggregates was assessed through its influence on C3b-mediated immune adherence hemagglutination; factor H dose-dependently suppressed such hemagglutination induced by aggregated human IgG or preformed TT-anti-TT complexes when added to the immune complex-fresh serum mixture at the outset but not after 45 min of the 37 degrees C incubation period which means that H inhibited more likely decoration of immune complexes with C3b than it did inhibit the interaction of C3b-coated immune complexes with erythrocytes. This suppressive effect of H was reversed by the simultaneous addition of the activating protein B. Complement-mediated binding of tritiated C3 to latex-bound human IgG was assessed and H was found to dose-dependently inhibit such binding with a maximal inhibition of 37% at a H concentration of 7 micrograms/ml.

Animals↗

PubMed1996

Purification, characterization, and primary structure of Clostridium perfringens lambda-toxin, a thermolysin-like metalloprotease.

The lambda-toxin of Clostridium perfringens type B NCIB10691 was purified by ammonium sulfate precipitation, followed by size exclusion, anion-exchange, and hydrophobic interaction chromatography. The purified toxin had an apparent molecular mass of 36 kDa, as determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The toxin possessed casein-hydrolyzing activity, which was inhibited specifically by metal chelators, indicating that the toxin is a metalloprotease. The gene encoding the lambda-toxin (lam), which was shown by Southern analysis to be located on a 70-kb plasmid, was cloned into Escherichia coli cells. Nucleotide and N-terminal amino acid sequencing revealed that the lam gene encodes a 553-amino-acid protein, which is processed into a mature form, the molecular mass of which was calculated to be 35,722 Da. The deduced amino acid sequence of the mature enzyme contains an HEXXH motif characteristic of zinc metalloproteases and is homologous to other known enzymes belonging to the thermolysin family. The purified toxin degraded various biologically important substances, such as collagen, fibronectin, fibrinogen, immunoglobulin A, and the complement C3 component. It caused an increase in vascular permeability and hemorrhagic edema on injection into the dorsal skin of mice. These results suggest that the toxin contributes to the pathogenesis of histolytic infection by lambda-toxin-producing C. perfringens.

Amino Acid Sequence↗

PubMed1976

[Angioneurotic hereditary edema. 3 faimilial cases].

The study involved three families with hane. This disorder differs from the simple condition by its preferential visceral localisation (digestive and, above all, the glottis), its hereditary nature and the existence of a biological abnormality affecting the serum complement system (absence of enzyme activity of C1 esterase inhibitor in the serum of sufferers). The cases reported illustrate the serious prognosis of this condition (four deaths by asphyxia in one family) in the absence of specific therapy. This disorder, although rare, represents a fundamental problem in general pathology by virtue of the enzymatic, immunological and genetic processes which it involves.

Adolescent↗

PubMed2000

Acquired C1q deficiency caused by monoclonal paraproteinaemia.

Acquired C1q deficiency secondary to anti C1q auto-antibodies may result in the hypocomplementaemic urticarial vasculitis syndrome and may also be seen in active systemic lupus erythematosus. Some patients with acquired C1 inhibitor deficiency are found to have an underlying malignancy, most commonly lymphoma. We report a case of a 40-year-old man presenting with a lupus-like illness with acquired C1q deficiency secondary to a monoclonal paraprotein in the presence of splenic lymphoma with villous lymphocytes. His clinical symptoms correlated with the presence of the paraprotein. Relapse coincided with a rise in the paraprotein and fall in C1q, C3 and C4. There was no improvement in his clinical condition following combination chemotherapy. He remains on oral prednisolone.

Adult↗

PubMed1971

Modulation of function of the activated first component of complement by a fragment derived from serum. I. Effect on early components of complement.

An activity designated Kf can be separated from human serum and shown to give a 100-300% enhancement in the hemolytic activity of fully activated, fractionated C1. The enhancement of C1 activity is not because of activation of precursor C1 and it is not attributable to an effect on C1 binding. EAC42 or EAC4 intermediates interacted with C1Kf exhibit a greater T(max) and shorter Z(max) than when such intermediates are reacted with the same number of hemolytic units of C1. C3 consumption by the EAC1Kf42 intermediate greatly exceeds that of the EAC142 intermediate produced from the same EAC4 cells by comparable inputs of the other two complement components. Taken together, these findings suggest that Kf-treated C1 achieves more efficient utilization of C4 and C2 to create a larger number of 42 sites as appreciated on the intermediates by shorter T(max) and a greater Z(max), and an increased capacity to utilize C3. The capacity of Kf to enhance C1 upon introduction into whole serum of a patient with hereditary angioedema (HAE) in a manner comparable to its effect on fractionated C1 suggests that the effect of Kf may be pertinent to certain pathophysiologic conditions of man.

Angioedema↗

PubMedDate not supplied

[Humoral indices of the inflammatory process in psoriasis].

Immune complexes were determined in 104 patients with psoriasis, aged between 19 and 55 years. Duration of the disease, extension of lesions, and effects of infections preceding skin eruptions were considered. The studies showed the activation of immunological mechanism in psoriasis manifested by the increase in IgG and IgA levels, unchanged IgM levels, significantly more frequent negative values of IgD, significant increase in complement C4 component levels in all forms of the disease, and C3 activation in the acute and generalized chronic form. A significant increase in alpha 2 Mg was noted independently of the evolution and extension of skin lesions. An increase in alpha 1 AT was noted only in the initial phase of skin eruptions. An increase in Hp, Cr, CRP, and CIC was noted only during exacerbations. CIC were noted most frequently in postinfection psoriasis.

Adult↗

PubMed1994

Clusterin depletion enhances immune glomerular injury in the isolated perfused kidney.

Clusterin is a normal plasma protein, shown to be an inhibitor of reactive complement hemolysis and a component of the fluid phase SC5b-9 terminal complement complexes. It is a component of glomerular immune deposits in human and experimental glomerulonephritis. Using the complement-dependent isolated perfused rat kidney model of autologous phase passive Heymann nephritis, we have studied the effect of clusterin depletion of perfused plasma on the development of glomerular injury. Kidneys with planted glomerular sheep anti-rat Fx1A antibody were perfused with human plasma either depleted of clusterin to < or = 30%, or control plasma depleted of plasma fibronectin. Glomerular injury was then initiated by the addition of guinea pig anti-sheep immunoglobulins to the perfusate. Kidneys perfused with clusterin depleted plasma developed significantly greater proteinuria at all time points when compared to control kidneys. Glomerular antibody binding and C3 deposition were similar in the two groups, but terminal complement components were deposited in larger amounts in the clusterin depleted group. These data support a possible role for clusterin in vivo in the protection of complement-induced glomerular injury.

Animals↗