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 937 records · Page 52Linked to original sources

PubMed2000

In vivo indomethacin treatment causes microglial activation in adult mice.

The current study was undertaken to study the role of prostaglandins in regulating microglial activation. Mice were treated with indomethacin (2 microg/ml) in their drinking water to selectively inhibit cyclooxygenase activity. After 4-8 days, the effect of inhibiting prostaglandin synthesis on microglial activity was evaluated. This was accomplished by analyzing microglial expression of Mac-1 (C3 complement receptor) as an indicator of activation. Mac-1 expression was assessed by immunohistochemistry of fixed brain cryosections, and by flow cytometric analysis of immunostained single cell suspensions. Both methods demonstrated that compared to age-matched, untreated controls, brains of indomethacin-treated mice had increased levels of Mac-1 expression, suggesting an increase in the state of microglial activation. These results demonstrate the importance of prostaglandins in down regulating microglial activity, and that inhibition of prostaglandin synthesis with indomethacin may act to increase the reactivity of the brain's immune system.

Animals↗

PubMed1985

Failure of local immunity. A potential cause of burn wound sepsis.

Destruction of the skin barrier by thermal injury removes the major local defense barrier to bacteria. To determine whether a local defect in immunity also existed, the opsonic activity of blister fluid against Staphylococcus aureus and Pseudomonas aeruginosa as well as neutrophil chemotaxis were measured. The results of these studies indicated that blister fluid could not opsonize Pseudomonas. A series of repletion experiments indicated that the opsonic defect for Pseudomonas was not due to the presence of inhibitors but was due to the lack of normal serum factor(s). Although both the level of immunoglobulins and complement components in the blister fluid was depressed, the cause of the opsoninopathy appeared to be due to local consumption of complement in the burn wounds. In addition to the opsoninopathy, both neutrophil chemotaxis and random migration were also depressed. In conclusion, a burn injury appears to cause severe impairment of both cellular and humoral local immunity, which could predispose these patients to burn wound sepsis.

Adolescent↗

PubMed1990

Modulation by interferons of the expression of monocyte complement genes.

Interferons-alpha, -beta and -gamma (IFNs-alpha, -beta and -gamma) stimulated the synthesis of the second complement component (C2), Factor B (B) and C1 inhibitor (C1-inh) by human monocytes in vitro. The degree of increase of the secretion rates of C2, B and C1-inh was dose-dependent and proportional to increases in the abundances of their respective mRNAs. IFN-gamma was the most effective at stimulating monocyte C1-inh synthesis, whereas IFN-alpha and IFN-beta were marginally more effective at stimulating monocyte C2 and B synthesis. Kinetic studies showed that the effect of the IFNs was rapid, with maximum stimulation occurring within 1-2 h for all three proteins. After the removal of IFNs from cultures the C1-inh mRNA abundance remained elevated for over 24 h in IFN-gamma-treated monocytes but returned to control levels within 8 h in IFN-alpha-treated and IFN-beta-treated monocytes. The abundances of C2 mRNA and B mRNA also returned to basal values within 8 h after removal of any of the three cytokines from the cultures. Both IFN-alpha and IFN-beta acted synergistically with IFN-gamma to stimulate synthesis of C1-inh and B. This synergistic effect only occurred when the cytokines were present in the cultures simultaneously. The effects of IFN-gamma plus IFN-alpha or IFN-beta on C2 synthesis appeared to be additive rather than synergistic. IFN-gamma inhibited synthesis of C3 by monocytes, but IFN-alpha and IFN-beta had no effect on the synthesis of this protein. Furthermore, none of the three cytokines had any effect on the expression of actin mRNA in monocytes.

Cells, Cultured↗

PubMed1989

Increase of glucose and lactate output and decrease of flow by human anaphylatoxin C3a but not C5a in perfused rat liver.

The complement fragments C3a and C5a were purified from zymosan-activated human serum by column chromatographic procedures after the bulk of the proteins had been removed by acidic polyethylene glycol precipitation. In the isolated in situ perfused rat liver C3a increased glucose and lactate output and reduced flow. Its effects were enhanced in the presence of the carboxypeptidase inhibitor DL-mercaptomethyl-3-guanidinoethylthio-propanoic acid (MERGETPA) and abolished by preincubation of the anaphylatoxin with carboxypeptidase B or with Fab fragments of an anti-C3a monoclonal antibody. The C3a effects were partially inhibited by the thromboxane antagonist BM13505. C5a had no effect. It is concluded that locally but not systemically produced C3a may play an important role in the regulation of local metabolism and hemodynamics during inflammatory processes in the liver.

Anaphylatoxins↗

PubMed2006

Statin-induced expression of CD59 on vascular endothelium in hypoxia: a potential mechanism for the anti-inflammatory actions of statins in rheumatoid arthritis.

Hypoxia, which leads to dysfunctional cell metabolism, and complement activation both play central roles in the pathogenesis of rheumatoid arthritis (RA). Recent studies have reported that mice deficient for the complement-inhibitory protein CD59 show enhanced susceptibility to antigen-induced arthritis and reported that statins have anti-inflammatory effects in RA. We hypothesized that the anti-inflammatory effect of statins in RA relates in part to their ability to increase CD59 expression in hypoxic conditions and therefore to reduce complement activation. Flow-cytometric analysis showed that CD59 expression on endothelial cells (EC) was unaffected by atorvastatin in normoxia (21% O2), whereas in hypoxic conditions (1% O2) an up to threefold dose-dependent increase in CD59 expression was seen. This effect of hypoxia was confirmed by treatment of EC with chemical mimetics of hypoxia. The upregulation of CD59 protein expression in hypoxia was associated with an increase in steady-state mRNA. L-Mevalonate and geranylgeraniol reversed the response, confirming a role for inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase and geranylgeranylation. Likewise, inhibition by NG-monomethyl-L-arginine and NG-nitro-L-arginine methyl ester confirmed that CD59 upregulation in hypoxia was nitric oxide dependent. The expression of another complement-inhibitory protein, decay-accelerating factor (DAF), is known to be increased by atorvastatin in normoxia; this response was also significantly enhanced under hypoxic conditions. The upregulation of CD59 and DAF by atorvastatin in hypoxia prevented the deposition of C3, C9 and cell lysis that follows exposure of reoxygenated EC to serum. This cytoprotective effect was abrogated by inhibitory anti-CD59 and anti-DAF mAbs. The modulation of EC CD59 and DAF by statins under hypoxic conditions therefore inhibits both early and late complement activation and may contribute to the anti-inflammatory effects of statins in RA.

Anti-Inflammatory Agents↗

PubMed1999

C3 and C4 allotypes in anti-neutrophil cytoplasmic autoantibody (ANCA)-positive vasculitis.

In ANCA-associated small vessel vasculitis few genetic factors have proven to be of importance for disease susceptibility, an exception being deficiency of alpha1-anti-trypsin, the main inhibitor of proteinase 3 (PR3). Alerted by our finding that myeloperoxidase has affinity for C3, and the finding of an increased frequency of the C3F allele in systemic vasculitis in a British cohort, we examined polymorphism of C3 and C4 in patients with ANCA+ small vessel vasculitis. After identification of all patients at our department with a positive ANCA test during the period 1991-95 and a diagnosis of small vessel vasculitis, blood samples were collected after informed consent. The 67 included patients were grouped according to ANCA serology and disease phenotype using the Chapel Hill nomenclature. The gene frequency of C3F was found to be increased (0. 32) compared with controls (0.20; P < 0.05) in the PR3-ANCA+ subgroup. The frequency of C4A3 was increased in the group as a whole, but no increase of C4 null alleles was seen. The findings imply a role for the complement system in the pathogenesis of ANCA-associated small vessel vasculitis.

Antibodies, Antineutrophil Cytoplasmic↗

PubMed1987

Coagulopathy in patients with hemorrhagic fever with renal syndrome.

Hemorrhagic fever with renal syndrome in Korea (Korean hemorrhagic fever) is an acute viral disease characterized by fever, hemorrhage and renal failure. In Korean patients, the disease manifests more distinctive bleeding tendencies than those of hemorrhagic fever with renal syndrome found in western countries. To investigate the nature and role of the coagulation, fibrinolysis, kinin and immune system in the pathogenesis of such a hemorrhagic manifestation, alterations of these systems were assessed from the early phase of the disease. Decreased platelet count and shortened platelet survival were observed with giant platelets in the peripheral blood. The marked prolongations of bleeding time, prothrombin time and partial thromboplastin time were noticed with the decreased plasma activities of coagulation factors II, V, VIII, IX and X. Shortened half life of fibrinogen, increased fibrinogen-fibrin degradation product, with decreased plasma levels and activities of plasminogen, alpha 2-plasmin inhibitor and antithrombin III were found. On thrombelastogram, the existence of procoagulant activity was confirmed, and prolonged reaction time and clot formation time with decreased maximum amplitude were observed. The appearance of circulating immune complexes was found along with decreased C3 and normal C4 in the serum. Significant decrease of serum C3 was evident in the patients with disseminated intravascular coagulation. These findings of coagulopathy were normalized within ten days of the illness in most cases. Therefore, it can be concluded that disseminated intravascular coagulation and thrombocytopenia in the early phase, and azotemia developing later might play an important role in the pathogenesis of bleeding tendency in Korean hemorrhagic fever.

Acute Kidney Injury↗

PubMed2004

Expression of complement factor H by lung cancer cells: effects on the activation of the alternative pathway of complement.

The complement system is important in immunosurveillance against tumors. However, malignant cells are usually resistant to complement-mediated lysis. In this study, we examine the expression of factor H, an inhibitor of complement activation, and factor H-like protein 1 (FHL-1), its alternatively spliced form, in lung cancer. We also evaluate the potential effect of factor H/FHL-1 in the protection of lung cancer cells against the activation of the complement cascade. By Northern blot analysis we demonstrate a high expression of factor H and FHL-1 in most non-small cell lung cancer cell lines, although neuroendocrine pulmonary tumors (small cell lung carcinoma and carcinoid cell lines) had undetectable levels. Western blot analysis of conditioned medium showed the active secretion of factor H and FHL-1 by cells that were positive by Northern blot. Expression of factor H/FHL-1 mRNA was also shown in a series of non-small cell lung cancer biopsies by in situ hybridization. Interestingly, many cultured lung cancer cells were able to bind fluorescence-labeled factor H to their surfaces. Deposition of C3 fragments from normal human serum on H1264, a lung adenocarcinoma cell line, was more efficient when factor H/FHL-1 activity was blocked by specific antibodies. Blocking factor H/FHL-1 activity also enhanced the release of anaphylatoxin C5a and moderately increased the susceptibility of these cells to complement-mediated cytotoxicity. In summary, we demonstrate the expression of factor H and FHL-1 by some lung cancer cells and analyze the contribution of these proteins to the protection against complement activation.

Blood Proteins↗

PubMed1987

Neutrophil lysosomal enzyme release and complement activation during cardiopulmonary bypass.

Complement activation and neutrophil degranulation were concomitantly studied during uncomplicated cardiopulmonary bypass (CPB). Plasma concentrations of complement factor C4, complement split product C3d, the neutrophil lysosomal enzyme elastase complexed with alpha 1-proteinase inhibitor (PI) and fibronectin were measured in 12 patients, C3d and elastase/PI increased significantly during CPB (volume-corrected results). The C3d rise was almost linear, whereas elastase/PI showed exponential increase. Mean elastase/PI and mean C3d concentrations at different times during CPB covaried closely. The study showed that during CPB neutrophil lysosomal enzyme release is intimately related to complement activation, although activation of the two systems may be caused by a common third activator within the extracorporeal circuit.

Adult↗

PubMed1993

[Complement analysis tests].

Although routine analysis of the complement system is rarely demanded, it is important from a diagnostical and therapeutical point of view to include the relevant tests when clinically required. Complement analysis should be performed when hereditary angioedema (C1 inhibitor deficiency) is suspected, and as part of investigation of patients with immunodeficiency (recurrent infections in childhood). Furthermore, complement analysis may be required in cases of recurrent systemic neisserial infections at any age, and to follow up certain autoimmune diseases. Only a few tests are available for routine purposes. These are reviewed briefly, with emphasis on collection and storage of samples prior to analysis. It is important that these guidelines be followed, to avoid misinterpretation of the results.

Angioedema↗

PubMed1996

Hereditary angio-oedema: new clinical observations and autoimmune screening, complement and kallikrein-kinin analyses.

OBJECTIVES: To study clinical and laboratory manifestations of hereditary angio-oedema (HAE). SUBJECTS: Thirty-three affected members of a kindred of 63. RESULTS: Oedematous attacks in the skin, mucous membranes and gastrointestinal tract with fluid displacement were elicited by mental and physical stress, minor traumas, dental and surgical procedures, eruption of teeth, tonsillitis, pregnancies, and use of oestrogen-containing pills including menopausal substitution. Every adult woman with symptomatic HAE (n = 11) showed symptoms of urinary tract infections in conjunction with the attacks (P = 0.010), and also experienced more spontaneous abortions or premature labours (P = 0.037) than healthy relatives. Patients with HAE of both sexes more frequently reported heartburn or peptic ulcers (P = 0.002). Rheumatic complaints were reported by 53% of HAE patients and 12% of their unaffected relatives (P = 0.013), but biochemical screening for 18 autoantibodies and quantitation of immunoglobulins did not reveal statistically significant differences between the two groups. C3, prekallikrein, total kininogen, high molecular weight kininogen (HK), alpha-2-macroglobulin and factor XII were not significantly different in HAE patients. In contrast, levels of C1-INH and C4 were depressed and cleaved HK increased in patients compared to unaffected relatives. CONCLUSIONS: HAE manifests in a variety of ways, and may influence risk of spontaneous abortions and premature labour.

Adolescent↗

PubMed2001

Regulation of in situ complement activation via the lectin pathway in patients with IgA nephropathy.

The lectin pathway, which is initiated by mannose-binding lectin (MBL) and MBL-associated serine protease (MASP), is one of the possible routes to activate the complement cascade in immunoglobulin A (IgA) nephropathy. The purpose of this study was to elucidate the regulatory mechanism of the pathway. Levels of complement activation products and regulatory proteins were measured in sera from 27 patients with IgA nephropathy, and generation of fluid-phase complement activation products in the presence of pooled normal human serum was quantified to evaluate activation in vitro. Although there were no significant differences in the serum levels and in vitro activation between the MBL-MASP positive (n = 14) and negative (n = 13) groups, there were positive correlations between complement activation products (Bb fragment and C4d fragment) and regulatory proteins (factor H, C4-binding protein, and C1 inhibitor) in the MBL-MASP-positive group. Furthermore, immunohistochemical studies demonstrated glomerular deposition of the regulatory protein (C4-binding protein, alpha2-macroglobulin, and factor H) in all patients in the MBL-MASP-positive group. These findings suggest that the regulatory proteins control in situ complement activation via the lectin pathway immediately, and continuous activation due to inadequate control will lead to the advanced glomerular injury.

Carrier Proteins↗

PubMed1991

FUT-175 as a potent inhibitor of C5/C3 convertase activity for production of C5a and C3a.

We examined the inhibitory effect of FUT-175 on the C3/C5 convertase activity of the cobra venom factor-derived enzyme CVF,Bb by measuring C5b6-mediated reactive lysis of unsensitized guinea pig erythrocytes and by measuring directly the released fragments C3-des-Arg and C5a-des-Arg. In this study, we showed that the concentration of 4.5 X 10(-6) M of FUT-175 caused 50% inhibition of C5 convertase activity of CVF,Bb in reactive hemolysis assays, and that 4.0 X 10(-6) M FUT-175 caused 50% inhibition of the production of C3a and C5a generated by the C3/C5 convertase activity of CVF,Bb.

Animals↗

PubMed2005

Hereditary angioedema: a family study.

Hereditary angioedema (HAE) is a rare, life-threatening, autosomal dominant disease characterized by recurrent episodes of angioedema, and caused by a deficiency of the plasma protein C1-esterase inhibitor (C1-INH). Clinical manifestation of HAE may first develop during childhood but typically presents around puberty with nonpruritic and non-pitting edema of the subcutaneous and mucosal tissues. Up to now, there has been no published report of HAE case in Taiwan. We reported a 33 year-old female patient who had recurrent painful swelling of face and hands since 27 years of age. She first suffered from sudden onset of painful swelling of the eyelids and lips in August 1998 when she was pregnant for the first time. Subsequently, similar episodes recurred for a few times. Her blood test disclosed that her C3 and C4 were 125 mg/dl and 6 mg/dl, respectively. Her uncle died of laryngeal edema at the age of 30 years. Her father and elder brother also had the similar history of recurrent facial and hand swelling. The C4 levels of her elder brother were 6 mg/dl and 13.3 mg/dl on two separate occasions. The C1-INH antigen serum level and functional assay of the index patient and ten other family members were studied. A total of seven members of the family were confirmed to have type 1 HAE as evidenced by the low C4 and low C1-INH antigenic level and functional activity. Two of the seven cases were asymptomatic up to the date of our report.

Adult↗

PubMed1979

C3d antiglobulin haemagglutination of human red blood cells. A demonstration of two types of cell-bound C3d by means of typsin digestion.

Washed human red blood cells from blood collected in EDTA were tested by Auto-Analyzer for a percentage of maximum antiglobulin haemagglutination (AH) using monospecific antisera to human C3d and C3c. The cells from normal persons were found to be agglutinated by anti-C3d but not by anti-C3c. To a fixed dilution of antiserum, the normal C3d AH values (X +/- 2 SD) were 34 +/- 19% for adult cells (n = 29) and 14 +/- 19% for cord cells (n = 19); the difference was significant (P less than 0.0001). By pretreatment of these cells with trypsin the C3d AH was either completely abolished or markedly reduced. Its difference between the adult and cord cells was eliminated as the observed values were 4 +/- 7% and 3 +/- 4% respectively (P = 0.15). The supernatant fluid of cell-trypsin mixture, treated with trypsin inhibitors, was found to be inhibitory to C3d AH but not to C3c AH. In contrast, the AH of C3d-coated red blood cells resulting from complement fixation in vivo (ie, cold agglutinin disease) or in vitro (eg, sucrose water reaction) was resistant to trypsin treatment. The difference between the trypsin-sensitive and trypsin-resistant cell-bound C3d is postulated to be at its attachment mechanism to the cell membranes. In addition, both the advantage and limitation of using trypsinised cells for C3d antiglobulin tests are demonstrated.

Adult↗

PubMed1996

Ligand-binding renders the 160 kDa Trypanosoma cruzi complement regulatory protein susceptible to proteolytic cleavage.

It has been previously shown that a surface complement regulatory protein (CRP) of Trypanosoma cruzi trypomastigotes binds human complement components C3b and C4b, and inhibits C3 convertase formation, thus contributing to the resistance of the bloodstage parasites to complement-mediated lysis. The blood stage parasites rapidly and spontaneously release a limited set of membrane glycoproteins, including CRP, and the modulation of release of CRP following ligand binding was investigated. Incubation of the parasites with C3b results in the release of CRP at a reduced apparent molecular mass. To determine if proteolytic processing was responsible for the reduction in apparent molecular mass of the released CRP, the proteolytic activity present in trypomastigote membrane preparations was examined. In addition to a well described cysteine protease, a novel 75 kDa protease was identified in tissue culture-derived trypomastigotes and axenically-derived metacyclic trypomastigotes membrane preparations. This protease was inhibited by aprotinin and leupeptin, but not L-trans-epoxysuccinyl-leucylamide-(4-guanidinobutane), N-[N-L-3-transcarboxyirane-2-carbonyl-L-leucinyl]-agmatine (E64). Treatment of the parasites with protease inhibitors did not affect spontaneous shedding of proteins, however, protease inhibitors abrogated the effect of C3b-binding on CRP degradation. These results indicate that binding of C3b to the CRP renders the CRP susceptible to cleavage by a parasite protease, possibly as a means of removing the CRP-C3b from the parasite surface. This process may represent an additional immune evasion mechanism which allows the parasite to avoid both complement-mediated lysis and clearance.

Animals↗

PubMed2003

Activation of complement mediates antiphospholipid antibody-induced pregnancy loss.

Although it is clear that the specific antigenic reactivity of antiphospholipid (aPL) antibodies is critical to their effect, the pathogenic mechanisms that result in injury in vivo are incompletely understood. We hyphothesized that aPL antibodies targeted to the placenta activate complement locally, generating split products that mediate placental injury and lead to foetal loss and growth retardation. To test this hypothesis, we used a murine model of APS in which pregnant mice are injected with human IgG containing aPL antibodies. Mice treated with inhibitors of complement activation and mice deficient in complement components were protected from aPL antibody-induced foetal damage. Although the cause of tissue injury in this disease is probably multifactoral, we have shown that complement activation is an absolute requirement for foetal loss and growth restriction and, therefore, thatthis pathway acts upstream of other important effector mechanisms. Identification of complement activation as a mechanism that is necessary for aPL-induced tissue damage and definition ofthe complement components necessary to trigger such injury is likely to lead to a better understanding of the pathogenesis of vascular and tissue injury in SLE and to new and improved treatments.

Abortion, Spontaneous↗

PubMed1980

Laboratory findings in patients with psoriasis, with special reference to immunological parameters, associations with arthropathy and sacro-iliitis.

Twenty-five male and 25 female consecutive patients hospitalized because of psoriasis were examined. The clinical and radiographical findings are presented in detail elsewhere. Increased serum IgA, C3, C4, and C3PA concentrations were found in patients both with and without arthropathy and/or sacro-iliitis. Increased IgG concentrations were found in patients without arthropathy, and of C1 inhibitor concentrations in patients with arthropathy and/or sacro-iliitis. IgG and IgA concentrations were lower in patients with arthropathy than in those without, the difference being most significant in patients with arthropathy of large joints. An association was found between increased C4 concentration and sacro-iliitis, increased CRP concentration and sacro-iliitis and increased C3 concentration and phalangeal joint arthropathy. C4 and CRP concentrations were not associated. A close association between CRP and SAA was observed. Our results indicate that psoriatic arthropathy is not a single uniform joint disease, but represents different forms of arthropathy.

Adolescent↗