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Results for “complement C3 inhibitor”

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PubMed1993

Monitoring of serum proteinase--antiproteinase balance and systemic inflammatory response in prognostic evaluation of acute pancreatitis. Results of a prospective multicenter study.

With the aim of studying the clinical usefulness and applicability of circulating levels of protease inhibitors, complement factors, acute phase reactants, and leukocytic enzymes in the prognostic evaluation of acute pancreatitis (AP), the present prospective multicenter study has been carried out. A total of 182 patients with AP have been included, to whom an exhaustive evolutive protocol has been applied from the time of their hospital admission (2-12 hr from the onset of the disease) until the 15th day of evolution in order to clearly define them. The severe episodes exhibit a greater consumption of alpha 2-macroglobulin, and C3 and C4 complement factors, as well as a greater increase of alpha 1-protease inhibitor, C-reactive protein and polymorphonuclear elastase than mild events, with regards to the underlying pathophysiological condition. The determination of the plasma levels of leukocytic elastase in the first hours of evolution allows a prediction of the severity of the acute pancreatitis event with a high reliability (predictive values that become higher than 90%). The clinical value of the remaining parameters analyzed, in this aspect, is less, being applicable to the monitoring of the disease.

Acute Disease↗

PubMedDate not supplied

Complement resistance of tumor cells: basal and induced mechanisms.

Clinical and experimental studies have suggested that complement may play a role in tumor cytotoxicity. However, the efficiency of complement-mediated tumor cell lysis is hampered by various protective mechanisms, which may be divided into two categories: basal and induced mechanisms. The basal mechanisms are spontaneously expressed in cells without a need for prior activation, whereas the induced mechanisms develop in cells subjected to stimulation with cytokines, hormones, drugs or with sublytic doses of complement and other pore-formers. Membrane-associated complement regulatory proteins, such as CD55 (DAF, Decay-Accelerating Factor), CD46 (MCP, Membrane Cofactor Protein), CD35 (CR1, Complement Receptor type 1) and CD59, which serve as an important mechanism of self protection and render autologous cells insensitive to the action of complement. appear to be over-expressed on certain tumors. Furthermore, tumor cells secrete several soluble complement inhibitors. Tumor cells may also express proteases that degrade complement proteins, such as C3, or ecto-protein kinases which can phosphorylate complement components, such as C9. Besides this basal resistance, nucleated cells resist, to some extent, complement damage by removing the membrane attack complexes (MAC) from their surface. Several biochemical pathways, including protein phosphorylation, activation of G-proteins and turnover of phosphoinositides have been implicated in resistance to complement. Calcium ion influx and activation of protein kinase C (PKC) and of mitogen-activated protein kinase (MAPK) have also been demonstrated to be associated with the complement-induced enhanced resistance to lysis. The complete elucidation of the molecular mechanisms involved in basal and induced tumor cell resistance will enable the development of strategies for interfering with these evasion mechanisms and the use of the cytotoxic complement system against tumor cells.

Animals↗

PubMed2006

Human complement-activating immunoglobulin (Ig)G3 antibodies are essential for porcine endothelial cell activation.

BACKGROUND: Complement-activating naturally occurring anti-porcine endothelial cell antibodies (Abs) are responsible for hyperacute rejection in porcine-to-primate transplantation, whereas the role of complement in acute vascular rejection, characterized by type II endothelial cell activation, is less well understood. We previously demonstrated a correlation between porcine type II endothelial cell activation, as detected by E-selectin expression, and human immunoglobulin (Ig)G3 anti-Gal alpha1-3Gal (Gal) Abs, which was not seen for IgG1, IgG2 or IgG4. The present study was undertaken to investigate whether there is a causal relationship between human anti-porcine IgG3 Abs and porcine endothelial cell activation. METHODS: IgG3 was isolated employing a Protein A column to 98.3% purity. Porcine endothelial cells were incubated with isolated human IgG3 or the combination of IgG1, IgG2 and IgG4. E-selectin expression and complement activation were investigated by flow cytometry and Western blotting, respectively. RESULTS: Purified IgG3, in contrast to the other IgG subclasses, induced a substantial increase in E-selectin expression. This activation was accompanied by complement activation as detected by C3 cleavage, and was abolished by heat inactivation or by adding the complement inhibitor FUT-175. Depletion of anti-Gal Abs reduced E-selectin expression by 60%, consistent with the presence of complement-activating anti-porcine non-Gal Abs of the IgG3 subclass. CONCLUSIONS: Collectively, these data strengthen the hypothesis that human anti-porcine endothelial cell Abs of the IgG3 subclass are essential for endothelial cell activation in porcine-to-human species grafts and demonstrate such activation to be partly independent of Gal epitopes.

Animals↗

PubMed1989

[Hereditary angioedema].

Hereditary angio-oedema (AOH) is a familial affliction that is most often hereditary, but sometimes acquired and linked to a deficiency of C1 esterase inhibitor. 8 cases have been examined, amongst which there was one attack in a young girl, without any clinical signs. Amongst the other 7, one had acquired AOH. The diagnosis was confirmed by the deficiency of C1 esterase inhibitor, associated with a significant reduction of the other fraction of complement c3-c4 and also total haemolytic complement. Strong doses of corticosteroids were used in 4 patients for urgent treatment. Basic treatment with DANAZOL was commenced in 3 patients.

Adolescent↗

PubMedDate not supplied

[Hereditary angioedema by defict of C1 esterase. Our experience in 8 cases].

Eight cases of hereditary angioedema, all of them with low values of C1-sterase inhibitor are analyzed. In 7 cases the C3 and C4 components of the complement were assessed; the results showed marked descent of C4. The 8 patients came from 4 different families; only 2 of them were males. Six patients presented digestive disorders, reporting colic pain, nausea and vomiting. In 1 of them the abdominal picture was the only evidence of the disease. In 5 patients the angioedema episodes occurred following traumatisms and in 3 because of emotional states. The duration of the attacks varied from several hours to six days. There was a familial history in all cases. Three of the patients had repeated episodes of pharyngolaryngeal angioedema, two of them requiring emergency tracheotomy because of suffocating crisis. Six patients were treated with Epsilon aminocaproic acid (16 to 20 gr daily) or with tranexamic acid (1 to 3 gr. daily). In 4 cases the results were excellent with either of these antifibrinolytic drugs. No side effects were observed in the tranexamic acid therapy whilst they were frequent in the treatment with Epsilon aminocaproic acid.

Adolescent↗

PubMed1978

Phospholipase A2 contamination of cobra venom factor preparations. Biologic role in complement-dependent in vivo reactions and inactivation with p-bromophenacyl bromide.

Cobra venom factor (CoF), the anticomplementary protein in Naja naja cobra venom, is usually purified by sequential ion exchange and gel filtration chromatography. CoF prepared in this manner contains small but significant quantities of phospholipase A2 activity. This acyl hydrolase activity can be simply and efficiently removed on a large scale by treatment of CoF with p-bromophenacyl bromide (BPB), an irreversible modifier of the histidine residue in the active site of phospholipase A2. BPB treatment does not alter the anticomplementary activity of CoF. In vivo experiments utilizing intratracheal injections of control and BPB-treated CoF, as well as pure phospholipase A2, revealed that contaminating phospholipase A2, and not the anticomplementary protein, was responsible for the observed acute neutrophil-associated lung injury. However, phospholipase A2 had no effect on the hypotensive and thrombocytopenic effects of CoF infected intravenously into rabbits. Depletion of circulating C3-C9 by intraperitoneal injections of CoF was not altered by removal of phospholipase A2 activity with BPB.

Acetophenones↗

PubMed1985

Lupus pregnancy. II. Unusual pattern of hypocomplementemia and thrombocytopenia in the pregnant patient.

To explore the causes of complications in pregnant women with systemic lupus erythematosus (SLE), we prospectively evaluated 34 pregnancies in 28 SLE patients, and 2 additional pregnancies in patients with lupus anticoagulant and positive antinuclear antibody, but no other manifestations of SLE. Nineteen pregnancies (55%) were complicated by marked proteinuria, thrombocytopenia, and/or lupus anticoagulant. Hypocomplementemia occurred in 18 pregnancies (52%). Neither thrombocytopenia-anticoagulant nor proteinuria was accompanied by an increase in antibody to double-stranded DNA or by clinical signs of active SLE. Antibody to Ro antigen did not predict fetal death. Both thrombocytopenia and proteinuria appeared abruptly during pregnancy and disappeared quickly after delivery. Fetal death was the result in 7 of 9 (77%) pregnancies in patients with anticoagulant, 6 of 10 (60%) in patients with thrombocytopenia, 6 of 18 (33%) in patients with hypocomplementemia, and 3 of 11 (27%) in patients with proteinuria. Twenty of 29 (68%) children were identified as male. The pathogenesis of hypocomplementemia was evaluated by a new assay, C1s-C1 inhibitor complex, which is thought to measure rate of complement activation by the classical pathway. Most pregnant patients with low CH50 levels and proteinuria had normal levels of C1s-C1 inhibitor complex, whereas nonpregnant patients with equivalent proteinuria and hypocomplementemia had high levels, as did pregnant patients with hypocomplementemia who did not have SLE. Pregnant and nonpregnant hypocomplementemic patients with proteinuria had similar levels of C3 and C4. In pregnant patients with SLE, C1s-C1 inhibitor complex was independent of CH50; in nonpregnant patients a linear relationship between C1s-C1 inhibitor complex and CH50 was seen.(ABSTRACT TRUNCATED AT 250 WORDS)

Antibodies, Antinuclear↗

PubMed2005

Role of Rho GTPase in astrocyte morphology and migratory response during in vitro wound healing.

Small Rho GTPases are key regulators of the cytoskeleton in a great variety of cells. Rho function mediates morphological changes as well as locomotor activity. Using astrocyte cultures established from neonatal mice we investigated the role of Rho in process formation during astrocyte stellation. Using a scratch-wound model, we examined the impact of Rho on a variety of morphological and functional variables such as stellation and migratory activity during wound healing. C3 proteins are widely used to study cellular Rho functions. In addition, C3 derived from Clostridium botulinum (C3bot) is considered selectively to promote neuronal regeneration. Because the latter requires a balanced activity of neurones and glial cells, the effects of C3 protein on glial cells such as astrocytes have to be considered carefully. Low nanomolar concentrations of C3 proteins significantly promoted process outgrowth and increased process branching. Besides enzymatic inactivation of Rho by ADP-ribosylation, changes in protein levels of the various Rho GTPases may also contribute to the observed effects. Furthermore, incubation of scratch-wounded astrocyte cultures with C3bot accelerated wound healing. By inhibiting the Rho downstream effector ROCK with the selective inhibitor Y27632 we were able to demonstrate that the accelerated wound closure resulted from both enhanced polarized process formation and increased migratory activity of astrocytes into the lesion site. These results suggest that Rho negatively regulates astrocytic process growth and migratory responses after injury and that its inactivation by C3bot in nanomolar concentrations promotes astrocyte migration.

Amides↗

PubMed1999

The NTR module: domains of netrins, secreted frizzled related proteins, and type I procollagen C-proteinase enhancer protein are homologous with tissue inhibitors of metalloproteases.

Using homology search, structure prediction, and structural characterization methods we show that the C-terminal domains of (1) netrins, (2) complement proteins C3, C4, C5, (3) secreted frizzled-related proteins, and (4) type I procollagen C-proteinase enhancer proteins (PCOLCEs) are homologous with the N-terminal domains of (5) tissue inhibitors of metalloproteinases (TIMPs). The proteins harboring this netrin module (NTR module) fulfill diverse biological roles ranging from axon guidance, regulation of Wnt signaling, to the control of the activity of metalloproteases. With the exception of TIMPs, it is not known at present what role the NTR modules play in these processes. In view of the fact that the NTR modules of TIMPs are involved in the inhibition of matrixin-type metalloproteases and that the NTR module of PCOLCEs is involved in the control of the activity of the astacin-type metalloprotease BMP1, it seems possible that interaction with metzincins could be a shared property of NTR modules and could be critical for the biological roles of the host proteins.

Amino Acid Sequence↗

PubMed1987

The complement system in type 1 (insulin-dependent) diabetes.

The complement proteins C1q, r, s, C2, C4, C3, factor B, C5, C6, and the inhibitors, C1 inhibitors, factors I and H were measured in 35 patients with recently diagnosed Type 1 (insulin-dependent) diabetes, 76 patients with longer-duration disease (30 with complications) and 43 first-degree healthy relatives. We found that C1q, C4 and C3 were reduced significantly in all groups of patients (p less than 0.001 for each protein in recent onset and uncomplicated patients; p less than 0.01, p less than 0.01 and p less than 0.05 respectively, for patients with complications) compared to 60 control subjects and that C4 was also reduced in healthy relatives (p less than 0.001). C4 allotypes were examined in 63 subjects (selected from the patient groups) in order to clarify the role of null alleles in the production of the C4 abnormality. These showed serum C4 to be reduced significantly in 50 patients without null alleles (patient mean 0.24 g/l; control subject mean 0.34 g/l) (p less than 0.0001), although levels were lowest in the 13 patients with one or more null alleles (mean 0.19 g/l). Finally, to examine the metabolic basis for the low concentrations of C4 and C3, the turnover of highly-purified, radiolabelled C4 and C3 was measured in seven recently diagnosed patients; four of these had low levels of C4. The data showed that three out of four of these patients had reduced synthesis of C3 and C4 and normal values for fractional catabolic rate. Two patients showed features of C4 hypercatabolism. We conclude that several early complement proteins are reduced in Type 1 diabetes, irrespective of duration or complications.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗

PubMed1991

High doses of intravenous Ig inhibit in vitro uptake of C4 fragments onto sensitized erythrocytes.

We have recently reported that intravenous Ig (IVIg) inhibits uptake of activated C3 fragments onto antibody-sensitized red blood cells (RBCs). To elucidate the mechanism by which IVIg exerts its effect on the complement system, we examined the possible interference with the C4 step of the classical complement cascade. We examined the capacity of autologous serum containing high concentrations of human IVIg to deposit C4 fragments onto model targets (guinea pig and/or human erythrocytes sensitized with rabbit anti-guinea pig/human erythrocytes IgG antibody). C4 binding was quantified with radiolabeled anti-C4. Guinea pig serum with added IVIg suppressed C4 uptake onto IgG-sensitized guinea pig erythrocytes at all time points (0, 5, 15, and 30 minutes). Using sera of guinea pigs treated with increasing doses of IVIg, this effect was shown to be dose-responsive. Serum from a patient treated with IVIg showed reduced C4 uptake onto sensitized homologous RBCs. In comparison with the serum from the same patient before IVIg therapy was administered, levels were decreased almost to background. C4 functional titers in those two samples were not different. C3 uptake was studied in parallel with C4 to compare the degree of inhibition using sera with increasing doses of IVIg in both the human and guinea pig system. C3 and C4 inhibition curves completely overlapped. Our findings suggest that IVIg is an effective inhibitor of deposition of early complement activation products (C4b, C3b) onto target surfaces and may indicate interference of IVIg with multiple sites of complement activation.

Animals↗

PubMed1999

Revisiting the role of fat mass in the life extension induced by caloric restriction.

One of the most robust observations in the biology of aging is that caloric restriction (CR) extends life in a variety of species. Although CR results in a severalfold decrease in fat mass (FM), the role of fat on life extension was considered to be minimal. Two main reasons accounted for this belief. First, although increased FM is associated with changes in substrate oxidation and in glucose homeostasis, in part through the effects of free fatty acids (FFA) and glycerol, several studies have suggested that longevity is determined independent of FM. Second, CR has systemic effects on a range of functions including neurological, endocrine, reproductive, immunological and antineoplastic, none of which have been historically linked to fat. In the last few years, an explosion of evidence has demonstrated that fat tissue is a very active endocrine gland which secretes a variety of peptides (such as leptin and plasminogen activating inhibitor-1), cytokines (such as tumor necrosis factor), and complement factors (such as D, C3, and B). This is in addition to the presence of substrates, such as glycerol and FFA, which are stored and released by fat cells and are known to have a major role in hepatic and peripheral glucose metabolism. We propose that many of the systemic effects of CR can now be explained by the chronic effects related to decreased plasma levels of peptides, cytokines, complement factors, and substrates. In fact, all of the benefits of CR on the neuroendocrine system and those related to the improvement in glucose homeostasis can be attributed to decrease in adipose cells and their products. Other evidence from epidemiological data in human obesity supports the role of fat mass and its body distribution as a risk factor for morbidity and mortality in humans due to impaired glucose metabolism (similar to rodents), for cancer (similar to rodents), and for the development of atherosclerotic vascular disease (in humans). If all or most of the life-extending benefits of CR can be attributed to decreased fat stores, the expression of specific candidate proteins may be explored and manipulated in the search for the most powerful adipose-dependent signals that modulate life expectancy.

Adipose Tissue↗

PubMed2006

Activation of complement C3, C5, and C9 genes in tumors treated by photodynamic therapy.

Cancer therapies, which deliver a rapidly induced massive tumor tissue injury, such as photodynamic therapy (PDT), provoke a strong host response raised for dealing with the inflicted local trauma. Activated complement system was identified as an important element of host response elicited by tumor PDT. The expression of genes encoding complement proteins C3, C5, and C9 was studied following tumor PDT mediated by photosensitizer Photofrin using mouse Lewis lung carcinoma (LLC) model. Treated tumors and the livers of host mice were collected at different times after PDT and the expression of the investigated genes was analyzed by RT-PCR. The results show a significant up-regulation of C3, C5, and C9 genes in PDT-treated tumors at 24 h after therapy, while no significant increase in the expression of these genes was found in the liver tissues. The expression of C3, C5, and C9 genes also became up-regulated in untreated tumor-associated macrophages (TAMs) co-incubated in vitro with PDT-treated LLC cells. This effect was abolished or drastically reduced in the presence of antibodies blocking heat shock protein 70 (HSP70), Toll-like receptor (TLR) 2 and TLR4, and specific peptide inhibitors of TIRAP adapter protein and transcription factor NF-kappaB. The presented study reveals that complement genes C3, C5, and C9 become up-regulated in tumors treated by PDT, but not in the host's liver. Tumor-localized up-regulation of these genes can be largely attributed to monocytes/macrophages invading the treated lesion after PDT. This effect appears to be induced by the recognition of danger signals from PDT-treated tumor cells such as HSP70 by TAMs that involve the TLR2- and TLR4-triggered signal transduction pathways leading to the activation of NF-kappaB.

Animals↗

PubMed2006

Effect of supraphysiologic levels of C1-inhibitor on the classical, lectin and alternative pathways of complement.

C1-inhibitor is increasingly used experimentally and clinically in inflammatory conditions like septicemia and ischemia-reperfusion injury. Several mechanisms may account for the anti-inflammatory effects of C1-inhibitor, including inhibition of complement. The aim of the present study was to investigate and compare the supraphysiologic effect of C1-inhibitor on the three complement pathways. Novel assays for specific evaluation of the classical, lectin and alternative pathways were employed using normal human serum supplemented with increasing concentrations of C1-inhibitor. Solid-phase classical- and lectin pathway activation was dose-dependently and significantly reduced up to 85% in the range of 2-28 times physiologic C1-inhibitor concentration. The lectin pathway was more potently inhibited than the classical at low doses. A functional lectin pathway assay demonstrated a significant reduction of C4 deposition up to 86% even at low concentration of C1-inhibitor and documented the effect to be at the level of MBL/MASPs. In contrast, C1-inhibitor had no effect on solid-phase alternative pathway activation, but significantly reduced cobra venom factor-induced fluid-phase activation up to 88%. The negative controls albumin and IgG had no effect on complement activation. The positive inhibitory controls compstatin (C3 inhibition), EDTA- or MBL-deficient sera reduced complement activation by 82-100%. We conclude that C1-inhibitor in high physiologic doses differentially inhibits all three-complement pathways. The inhibition pattern was strikingly different in the classical and lectin pathway, compared to the alternative. Previous studies interpreting the effects of C1-inhibitor as only due to classical pathway inhibition needs reconsideration. The data has implications for the therapeutic use of C1-inhibitor.

Complement C1 Inhibitor Protein↗

PubMed1999

Compstatin, a peptide inhibitor of C3, prolongs survival of ex vivo perfused pig xenografts.

Compstatin, a newly described C3-binding peptide, inhibits complement activation by blocking C3 convertase-mediated cleavage of C3. As the complement activation is an essential part of the rejection reaction, we evaluated the ability of Compstatin to delay or prevent hyperacute rejection in an ex vivo xenograft model. Pig kidneys were perfused with fresh human blood containing either Compstatin (n=6) or a control agent (n=6). Graft survival and activation of complement, leukocytes and platelets both in the fluid-phase and in the tissue were examined. The survival of the Compstatin-perfused kidneys (median, 380 min) was significantly (P=0.0036) longer than that of the controls (median, 90 min). The classical complement pathway (C1rs-C1inhibitor and C4bc) was significantly and equally activated in both groups during the first 60 min. C3 activation products increased fivefold and terminal complement complex eightfold in the control group, but no increase occurred in the Compstatin group during this period. Immunohistochemistry showed less C3 and fibrin deposition and immune electron microscopy showed less terminal SC5b-9 complement complex deposition in the Compstatin group. A significant change in total white cells, neutrophils, myeloperoxidase, and expression of the surface activation markers CD11b (CR3) and CD35 (CR1) and CD62L (L-selectin) was observed in both groups. Leukocyte activation was lower in the Compstatin group but the difference was not statistically significant. There were no differences in platelet counts, thrombospondin, soluble P-selectin or beta-thromboglobulin between the groups. We conclude that Compstatin prolongs graft survival and suggest that it may be a useful agent for attenuating hyperacute rejection by inhibiting C3 and thus terminal complement pathway activation.

Animals↗

PubMed1975

Complement component analysis in angiodema. Diagnostic value.

Complement component analysis is valuable for differentiating the various types of angioedema. Patients with hereditary angioedema have decreased levels of C1 esterase inhibitor and C4 in the presence of normal amounts of C3 and C1q. Acquired C1 esterase inhibitor deficiency secondary to malignant disease is also manifested by depressed C1 esterase inhibitor and C4, but decreased C1q levels distinguish it from hereditary angioedema. Normal values for these complement components are found in persons with allergic angioedema.

Angioedema↗

PubMed2001

A new type of acquired C1 inhibitor deficiency associated with systemic lupus erythematosus.

Acquired C1 inhibitor (C1-INH) deficiency with consequent angioedema is a rare condition that may indicate an underlying lymphoproliferative disorder. The defect is caused by increased catabolism, which is often associated with the presence of serum autoantibodies to C1-INH. The present report describes 3 patients with systemic lupus erythematosus who developed typical symptoms of acquired angioedema, characterized by recurrent swelling of subcutaneous and mucous tissues. The 3 patients demonstrated a major classical pathway-mediated complement consumption, with very low levels of C3 antigen and decreased levels of C1-INH antigen. Neither antibodies to C1-INH nor associated lymphoproliferative disease was found. No patient had clinical and biologic signs of lupus activity at the time the angioedema occurred. All patients were treated with steroids and exhibited a good response, without relapse of angioedema and with normalization of plasma levels of C1-INH. In lupus patients who present with an angioedema syndrome, acquired or hereditary angioedema must be sought by examining parameters of the classical pathway and levels of C1-INH. Our observations suggest the existence of a new form of acquired C1-INH deficiency associated with a major classical pathway-mediated complement consumption and systemic autoimmunity.

Adolescent↗

PubMed1997

Inhibiting the formation of classical C3-convertase on the Alzheimer's beta-amyloid peptide.

Amyloid plaques are the pathological hallmark of Alzheimer Disease (AD) brains, being found primarily in the hippocampus and neocortex, where AD pathology is most evident. Complement activation is associated with amyloid plaques which are made from fibrils of aggregated amyloid peptides, 39-42 amino acids long. In vitro studies show that aggregated amyloid peptides activate complement via the classical pathway, implying that amyloid plaques themselves cause complement activation in AD brains. In order to test this hypothesis, we sought to determine if a major peptide component of amyloid plaques, A beta 1-42, supports the formation of the classical pathway C3 convertase. Using normal human serum depleted of C3, we are able to detect C3 convertase activity on aggregated A beta 1-42 in vitro. The convertase activity is associated with the binding of C1q and activation of C4 on the aggregated peptide. Inhibitors of C1 esterase and the cation chelator EGTA both block the formation of the convertase activity. Congo red, a histochemical stain for amyloid deposits and an inhibitor of amyloid aggregation, reduces C3 convertase activity on aggregated A beta 1-42, indicated by decreased C3a production. Our results provide further evidence that aggregated A beta 1-42 alone is sufficient to serve as a nidus for complement activation, and thus may be involved directly in initiating the inflammation seen in AD brains.

Alzheimer Disease↗