[C1-inhibitor].
Explore the source record for details and available documents.
Complement C1 Inactivator Proteins↗
SEARCH · Search PubMed
Results for “Complement C1 Inhibitor Protein”
Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.
Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.
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↗
Candidate inhibitors of porcine complement.
Therapeutic complement inhibition is a promising strategy for treatment of a number of diseases as judged from rodent studies. The species distance from rodents to humans may limit the clinical relevance of these studies. The pig is an alternative animal for studies of human diseases like sepsis and ischemia/reperfusion injury. However, available complement inhibitors for use in pigs are scarce. The aim of the present study was to investigate and compare the efficacy of selected candidate inhibitors of porcine complement in vitro for possible future application in vivo. Sera from three different pigs were each incubated with three different activators of the complement system (zymosan, heat-aggregated immunoglobulin G (HAIGG) and Escherichia coli). Three groups of complement inhibitor candidates were tested: serine protease inhibitors (FUT-175 and C1-inhibitor), monoclonal antibodies (anti-factor B (fB) and anti-factor D (fD)) and a recombinant regulatory protein (vaccinia virus complement control protein (VCP)). Read-out was the terminal C5b-9 complement complex (TCC). The serine protease inhibitors FUT-175 and C1-inhibitor dose-dependently inhibited TCC formation in zymosan-, HAIGG- and E. coli-activated porcine sera, but with different efficacy. Complete inhibition of TCC was obtained using 0.2 mg/mL FUT-175, but required 16 mg/mL of C1-inhibitor. The monoclonal anti-fB and -fD antibodies both inhibited TCC formation dose-dependently, but in different ways. Anti-fB at high dose (1 mg/mL) completely inhibited TCC formation in sera activated with zymosan and virtually completely in sera activated with HAIGG, but not in sera activated with E. coli. Anti-fD inhibited all three activators at low dose (0.05 mg/mL), and approximately 50% TCC reduction was obtained. The recombinant complement regulatory protein VCP efficiently and dose-dependently inhibited TCC formation with a complete inhibition found at 0.05 mg/mL for all three activators. All candidates tested inhibited porcine complement activation, but in different ways and to different degrees. Of the complement-specific candidates, VCP inhibited all activators completely at low doses.
Animals↗
Kinetic analysis of immune complex solubilization: complement function in relation to disease activity in SLE.
Solubilization of preformed bovine serum albumin (BSA) rabbit anti-BSA complexes in serum with kinetic analysis, haemolytic complement function, complement proteins C1q, C4, C3 and complexes containing C1 inhibitor (C1 INH-C1r-C1s-C1 INH) were serially investigated in relation to disease activity in 25 patients with systemic lupus erythematosus (SLE). Clinical assessment of disease activity was expressed using a validated global index (SLEDAI). Markedly decreased capacity to solubilize immune complexes in serum was mainly found in sever disease. By serial analysis, evidence of fairly persistently impaired classical pathway function was found in most of the patients. In partial contrast, impaired alternative pathway function was more clearly associated with active severe disease. Immune complex solubilization during short incubation (5-10 minutes) correlated with classical and alternative pathway-mediated haemolysis. Solubilization during long incubation (40 minutes) was correlated with haemolytic alternative pathway function. In some patients gradual impairment of solubilization during short incubation, and reduced classical pathway haemolytic activity were detectable 2-4 months before clinical manifestations prompted therapeutical intervention. SLEDAI was negatively correlated with solubilization during prolonged incubation (40 minutes) and with haemolytic alternative pathway function, further emphasizing involvement of the alternative pathway in severe disease. The findings emphasize the importance of impaired complement function due to complement activation in SLE. Assays for immune complex solubilization or other complement functions appear to be useful for monitoring disease activity in SLE.
Antigen-Antibody Complex↗
Clusters of intragenic Alu repeats predispose the human C1 inhibitor locus to deleterious rearrangements.
Frequent alterations in the structure of the complement component C1 inhibitor gene have been found in patients affected by the common variant of hereditary angioedema, characterized by low plasma levels of C1 inhibitor. This control protein limits the enzymic activity of the first component of complement and of other plasma serine proteases. Sequence comparisons of a 4.6-kilobase-long segment of the normal gene and the corresponding gene segments isolated from two patients carrying family-specific DNA deletions point to unusually long clusters of tandem repeats of the Alu sequence family as a source of genetic instability in this locus. Unequal crossovers, in a variety of registers, among Alu sequences of the clusters result in deletions of variable length that encompass exon 4. In a third family, exon 4 was instead found to be duplicated along with the same tracts of flanking introns lost in one of the deletions. In addition to undergoing Alu-mediated partial deletions and duplications, the gene is also a target for more recent retroposition events. Gross alterations in the C1 inhibitor gene account for about 20% of the hereditary angioedema chromosomes and consequently make this gene a prime example of the mutagenic liability of Alu repeats.
Amino Acid Sequence↗
Complement regulatory proteins on the sperm surface: relevance to sperm motility.
PROBLEM: To determine whether complement regulatory proteins are present on human spermatozoa and whether antibodies to these proteins adversely affect sperm motility. METHOD OF STUDY: Human sperm membrane proteins were solubilized and subjected to polyacrylamide gel electrophoresis followed by Western blot analysis against antibodies to complement component 1 inhibitor (C1-INH), decay-activating factor (DAF; CD55), membrane cofactor protein (MCP; CD46), and homologous restriction factor (HRF; CD59). Spermatozoa, obtained by a swim-up technique, were incubated in medium (control 1) and medium supplemented with antibodies to human albumin (control 2) and antibodies to these complement regulatory proteins. We used a computerized sperm motion analysis to determine the effect of these antibodies on sperm motion characteristics. RESULTS: Complement regulatory proteins such as C1-INH, CD55, CD46, and CD59 were found in the sperm extracts as shown by Western blot analysis. The heat-treated (56 degrees C, 30 min) IgG fraction of antibodies to these proteins significantly reduced sperm motility in general and other motion parameters. Addition of complement did not affect these results except in the antibodies to CD46 in which the reducing action was further amplified. CONCLUSIONS: Our data suggest that C1-INH, CD55, CD46, and CD59 are present on the sperm surface. These proteins may have biological functions, such as affecting sperm motility, besides the complement regulatory functions. In infertile men and women with antibodies that recognize one or more of these complement regulatory proteins, there may be problems related to poor sperm motility and survival in the reproductive tracts.
Antigens, CD↗
Irreversible enzyme inhibitors. Inhibitors of guinea pig complement derived by quaternization of substituted pyridines with benzyl halides.
A series of 83 compounds derived from hydrocarbon-substituted pyridines by quaternization with PhCH2Br usually containing a 2-SO2F or 6-Cl-2-SO2F group was synthesized and evaluated as inhibitors of guinea pig complement and in most cases its C1 component. The most active compounds were 3-(4-phenylphenylbutyl)-N-(6-choro-2-fluorosulfonylbenzyl) pyridinium bromide (43) and 3-(4-phenylphenylbutyl)-N-(2-fluorosulfonylbenzyl) pyridinium bromide (44), each showing 50% inhibition at 7.8 muM. The most effective irreversible inhibitor of the C1 component was N-(6-chloro-2-fluorosulfonylbenzyl)-5,6-benzoquinolinium bromide (87), which showed 50% inhibition at 4 muM.
Animals↗
Complement and IgG subclasses in agammaglobulinemic patients.
Complement and IgG subclass analysis was performed in six agammaglobulinemic patients suffering from recurrent bacterial infections. Complement analysis included functional activity of the classical (CH50) and the alternative pathway (APH50) of complement, the complement proteins C3, C4, factor B, the regulators C1-inhibitor, factors H and I as well as the C3-derived split product C3dg/C3d. Plasma concentrations of total IgG ranged between < 0.01 and 297 mg/dl. IgM and IgA were almost undetectable. Levels of all IgG subclasses, which in most cases were measurable only by sensitive ELISA, were markedly reduced in all patients. A pronounced activation of the complement system was observed in all patients as revealed by reduced titers of hemolytic function and elevated levels of C3dg/C3d. Despite the fact that complement activation by itself was the major reason for decreased C4 levels, from depressed plasma concentrations of the common allotypic variants C4A and C4B, a heterozygous C4 deficiency could not be excluded in 2/6 patients. Our data clearly show that, by application of sensitive analytical methods, agammaglobulinemic patients vary considerably in their ability to synthesize immunoglobulins. This may, at least in part, explain the heterogeneous pattern of clinical symptoms. The increased susceptibility of agammaglobulinemic patients to bacterial infections is reflected by a highly activated, and thereby depleted complement system.
Adolescent↗
Hepatitis C virus NS3 serine protease interacts with the serpin C1 inhibitor.
Both NS3 protein (1007-1657) and its protease moiety (NS3p, 1027-1207) were able to interact in vitro with C1 Inhibitor (C1Inh) to give a 95-kDa Mr C1Inh cleavage product similar to that obtained upon proteolysis by complement protease C1s. High-Mr reaction products were also detected after incubation of C1Inh with NS3 but not with NS3p; they correspond to ester-bonded complexes from their hydroxylamine lability. Similar reactivity of NS3 was observed upon incubation with alpha2-antiplasmin. Serpin cleavage was prevented by treatment of NS3 with synthetic serine protease inhibitors. This interaction between viral NS3 and host serpins suggests that NS3 is likely to be controlled by infected cell protease inhibitors.
Complement C1 Inactivator Proteins↗
Protease inhibitors in the treatment of hereditary angioedema.
Deficiency of C1 Inhibitor leads to unopposed activation of complement, with localized, unpredictable, and sometimes life-threatening attacks of angioedema. Treatment with plasma-derived C1 Inhibitor rapidly aborts attacks, and may be lifesaving, but is expensive, requires use of a pooled blood product, may need to be repeated and may not be effective in autoantibody mediated angioedema. The antifibrinolytic agents aprotinin, tranexamic acid, and epsilon-aminocaproic acid are useful for prophylaxis and treatment of angioedema, likely by inhibiting plasmin. Specific drugs to replace the deficient C1 Inh have not been reported. The kallikrein inhibitor DX-88 (Dyax) has received orphan drug status in Europe and is undergoing clinical trial in Europe and the USA.
Aminocaproic Acid↗
Demonstration of modified inactive first component of complement (C1) inhibitor in the plasmas of C1 inhibitor-deficient patients.
The first component of complement (C1) inhibitor plays a critical role in the regulation of the classical complement pathway and the contact system, and the deficiency of C1 inhibitor protein or function is associated with recurrent angioedema. In this study we evaluated the size of the C1 inhibitor antigens present in the plasmas of C1 inhibitor-deficient patients. We found that the C1 inhibitor in the plasmas existed in three forms: high molecular weight forms in complex with proteases, native 110-kD C1 inhibitor, and a modified inactive 94-kD form. The proportion of the total C1 inhibitor in the 94-kD form was 28% in nine hereditary angioedema patients, 92% in five acquired C1 inhibitor-deficiency patients, and 1.2% in five normal controls. In vitro activation of normal plasma with kaolin, but not heat-aggregated gamma-globulin generated 94-kD C1 inhibitor from 110-kD C1 inhibitor. Neither kaolin activation nor heat-aggregated gamma-globulin activation generated 94-kD C1 inhibitor in Hageman factor-deficient plasma. These results suggest that 94-kD C1 inhibitor is generated in vitro by activation of the contact system. The in vivo mechanism of 94-kD C1 inhibitor generation in C1 inhibitor-deficient patients is not known.
Angioedema↗
The role of complement and gp120-specific antibodies in virus lysis and CD4+ T cell depletion in HIV-1-infected patients.
The substantial virus lysis was induced by HIV-1-infected patient serum and normal human complement serum in the presence of purified patient IgG. Non-infected CD4+ T cells coated with the whole virus or with a recombinant HIV-1 envelope gp120 and sensitised with patient IgG were also shown to be susceptible to complement-dependent lysis. The serum level of complement regulatory protein in a fluid phase, the C1-esterase inhibitor, was significantly correlated with serum concentration of C1q-circulating immune complexes (P=0.0062), but inversely with CD4+ T cell count (P < 0.0001). Accordingly, the disease progression in HIV-1-infected patients was significantly correlated with the level of complement activation as determined by serum level of C1-esterase inhibitor (P=0.0001), and inversely correlated with CD4+ cell count (P < 0. 0001) and gp120-specific antibody titre (P=0.0086). These results strongly suggest that the complement activation by gp120-specific antibodies play a very important role in virus clearance, but also in depletion of infected as well as gp120-coated non-infected CD4+ bystander T cells during the course of HIV-1 infection.
Animals↗
C1, the first component of complement: structure-function-relationship of C1q and collectins (MBP, SP-A, SP-D, conglutinin), C1-esterases (C1r and C1s), and C1-inhibitor in health and disease.
Explore the source record for details and available documents.
Amino Acid Sequence↗
Hereditary angioedema complicated with chronic renal failure: report of sibling cases.
Hereditary angioedema (HAE) is known as a deficiency state of C1 inhibitor (C1 INH), an important protease inhibitor protein involved in the complement system. As with other components of the classical pathway of the complement system, a state of its deficiency often causes clinical immunoregulatory disorders. A 45-yr-old brother and a 63-yr-old sister with HAE both developed chronic renal failure, probably due to chronic glomerulonephritis, and required regular hemodialysis. This is, to our knowledge, the first report of sibling cases of HAE associated with chronic renal failure.
Angioedema↗
[Immunochemical studies on proteinase inhibitor of co-precipitation after euglobulin fraction of plasma (author's transl)].
Explore the source record for details and available documents.
Chemical Precipitation↗
A study of complement functions in a family with hereditary angioneurotic edema.
A study of some complement functions was performed in two patients affected with hereditary angioneurotic edema (HAE) - mother and daughter - from a Southern Italy family (Apulia) and in three of their relatives. A decreased level of the C1 esterase plasma inhibitor was found in both the patients, who were treated with tranexamic acid with a slight, but definite improvement. However, the disease could not be traced beyond two generations in the pedigree and a couple of ascendants was found who were free from HAE both from the clinical standpoint and from that of the laboratory evaluation of complement functions. The possibility that HAE arose in the family through a mutational event is discussed.
Adolescent↗
Targeting complement in therapy.
With increasing evidence that complement activation significantly contributes to the pathogenesis of a large number of inflammatory diseases, strategies that interfere with its deleterious action have become a major focus in pharmacological research. Endogenous soluble complement inhibitors (C1 inhibitor, recombinant soluble complement receptor 1, antibodies) blocking key proteins of the cascade reaction, neutralizing the action of the complement-derived anaphylatoxin C5a, or interfering with complement receptor 3 (CR3, CD18/11b)-mediated adhesion of inflammatory cells to the vascular endothelium have successfully been tested in various animal models over the past years. Promising results consequently led to clinical trials. Furthermore, incorporation of membrane-bound complement regulators (decay-accelerating factor (CD55), membrane co-factor protein (CD46), CD59) in transgenic animals has provided a major step forward in protecting xenografts from hyperacute rejection. At the same time, the poor contribution of complement to the antitumor response, which is caused by multiple resistance mechanisms that hamper the efficacy of antibody-based tumor therapy, is increasingly recognized and requires pharmacologic intervention. First attempts have now been made to interfere with the resistance mechanisms, thereby improving complement-mediated tumor cell destruction.
Anaphylatoxins↗
Effect of factor Xa inhibitors on thrombin formation and complement and neutrophil activation during in vitro extracorporeal circulation.
BACKGROUND: Even when large doses of heparin are administered during cardiopulmonary bypass, thrombin is produced. Thrombin is a powerful protease that is associated with the thrombotic and bleeding complications of open heart surgery and is produced by cleavage of prothrombin by factor Xa. This study assessed the ability of a specific inhibitor of factor Xa, recombinant tick anticoagulant peptide (rTAP), alone or in combination with standard heparin and a low-molecular-weight heparin, enoxaparin, to suppress thrombin formation and activity during in vitro extracorporeal circulation. METHODS AND RESULTS: Fresh, anticoagulated human blood was recirculated for 2 hours in an extracorporeal membrane oxygenator perfusion circuit at 37 degrees C. Four anticoagulant protocols were evaluated; porcine heparin (3.75 U/mL); enoxaparin (17.5 U/mL); rTAP (4 mumol/L); and porcine heparin plus rTAP (2 mumol/L). Blood samples were obtained for analysis from the donor, after anticoagulation, and after 5, 30, 60, and 120 minutes of recirculation. There were no significant differences between groups in platelet count, response to adenosine diphosphate, or prothrombin fragment (F1.2) production. rTAP plus heparin reduced beta-thromboglobulin release; fibrinopeptide A concentrations were significantly higher with rTAP alone. Enoxaparin strongly and significantly inhibited complement C5b9 production and neutrophil elastase release and was associated with significantly increased concentrations of C1-C1 inhibitor and kallikrein-C1 inhibitor complexes. CONCLUSIONS: rTAP does not reduce thrombin formation or activity during in vitro extracorporeal circulation. Enoxaparin markedly inhibits formation of the complement membrane attack complex and neutrophil elastase release, possibly by accelerating C1 inhibitor activity.
Adenosine Diphosphate↗