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PubMed1970

C1 inactivator inhibition by plasmin.

Plasmin incubated with partially purified C[unk] inactivator produced a decrease in inhibitory activity which was related to the time of incubation and to the concentration of plasmin. This effect of plasmin was not influenced by the purity of the inhibitor preparations. Soybean trypsin inhibitor and tosyl arginine methyl ester (TAMe), substances which block the active enzymic center of plasmin, prevented the plasmin-induced inactivation. Double diffusion analysis of the functionally deficient, plasmin-treated C[unk] inactivator using a specific antibody, showed a reaction of identity with the untreated inhibitor. Agarose and acrylamide gel immunoelectrophoresis of a plasmin, inhibitor mixture showed the appearance of an additional precipitin band with immunologic reactivity similar to that of the untreated inhibitor. These results demonstrate that plasmin alters both the functional and immunoelectrophoretic properties of C[unk] inactivator, and that the active proteolytic site of plasmin is necessary for this interaction. Since C[unk] inactivator has been shown to inhibit several different proteolytic enzymes including C[unk], kallikrein, PF/Dil, and plasmin, this investigation provides a theoretical relationship between the fibrinolytic, kallikrein, and complement systems which may have pathophysiologic relevance to various human disease states.

Arginine↗
PubMed1981

Hormone binding globulin levels in patients with hereditary angiooedema during treatment with Danazol.

Five patients with hereditary angiooedema were treated with Danazol for periods up to 10 months. This therapy resulted in normalization of serum levels of the inhibitor of the first complement component and disappearance of clinical disease symptoms in all patients. Although a variety of hormones were measured, only those of the pituitary-gonadal axis altered during treatment: a moderate decrease in leuteinizing hormone levels and a sharp fall of testosterone in adult men were observed. In all patients, however, both sex hormone binding globulin and thyroxine binding globulin concentrations were considerably suppressed during Danazol therapy. However, levels of corticosterone binding globulin and thyroxine binding globulin concentrations were considerably suppressed during Danazol therapy. However, levels of corticosterone binding globulin remained unchanged. The fraction of endogenous testosterone not bound to sex hormone binding globulin invariably increased. The possible relevance of these findings to the understanding of the mode of action of Danazol both in these patients and in general, are discussed.

Adult↗
PubMed1990

The increased rate of activation of factor XII in late pregnancy can contribute to the increased reactivity of factor VII.

The amidolytic activity of enzymes derived from factor XII (XIIa) was 3-fold higher in plasmas collected during pregnancy than from control subjects. Factor VII coagulant activity (VIIc) and XIIa increased in both kinds of plasmas on incubation on ice for 24 h (cold activation). These increases could be attributed to the decreased potency of C1 inhibitor (C1INH). However, variations in the concentration of C1INH and of factor XII could not explain the differences in VIIc and in XIIa between late pregnancy and control plasmas following cold activation under the same conditions. It is concluded that in vitro the increased amount of contact surface in the late pregnancy plasma promotes a higher rate of generation of XIIa and consequently a higher rate of activation of factor VII. The increased amount of contact surface could also be responsible for the increased concentration of XIIa in non-treated plasma from late pregnancy and could contribute in vivo to the higher reactivity of factor VII in this condition.

Amides↗
PubMed1979

Substrate modulation as a control mechanism in the activation of plasma multienzyme systems.

Since plasma is a homogenous fluid its biochemical systems need special control mechanisms to prevent their unlimited and continuous activity. In general, enzymic activity is not preformed but generated by trigger processes. Activation is then enhanced by cascade reactions. It can be controlled by enzyme inhibitors, by enzymes which destroy co-factors, or by spontaneous decay or enzyme complexes involved in the system. In addition, in some reactions of the complement and Hageman factor-dependent systems the necessity of substrate modulation controls the extent of activation. Thus, factor B of the properdin system is activatable by factor D only when bound to the activated third component of complement, and C3b fragment; similarly C2 is activated and forms the C3 converting complex, C42, only when bound to C4b prior to its cleavage by C1; C5 can be activated by either of the two convertases only when bound to surface-fixed C3b; and the mutural activation of Hageman factor and pre-kallikrein on surfaces proceeds efficiently only when HMW-kininogen is present which complexes with pre-kallikrein and possibly with Hageman factor.

Complement C3↗
PubMed1990

Hereditary angioedema: therapeutic effect of danazol on C4 and C1 esterase inhibitors.

Hereditary angioedema (HAE) is an inherited deficiency of C1 esterase inhibitor (C1 inh). The two types of genetic C1 inh deficiency are type I, which is quantitative, and type II, which is functional. For the purpose of the present study, four HAE patients were selected. None of them had received any androgenic therapy. The group included three type I and one type II cases. All patients that entered the protocol received danazol, 400 mg/day for 14 days. The complement system was evaluated by monitoring C4, hemolytic complement 50% (CH50), circulating immune complexes (CIC), and antigenic and functional C1 inh during the study. The level of complement factors at the beginning and at the end of this period demonstrated a statistically significant increase in C4 and CH50 and the disappearance of CIC, while C1 inh remained unmodified. These results suggest that the therapeutic effect of danazol may have two mechanisms of action: (1) promotion of C4 synthesis by anabolic effect resulting in an improvement of the complement system with the disappearance of CIC and (2) a minor increase in C1 inh level primarily due to the lack of its consumption.

Adult↗
PubMed1993

The contact system in human malignant and benign ascites.

The plasma contact system was studied in ascites and plasma from patients with gastrointestinal cancer and patients with liver failure. Our study demonstrates the presence of factor XII, factor XI, and prekallikrein and their main inhibitors in ascites and plasma from both patient groups. Both factor XII-like and plasma kallikrein-like activities were detected in the malignant ascites. The kallikrein-like activity in malignant ascites was found in complex with alpha 2-macroglobulin. In plasma samples from the patients functional values of factor XII and prekallikrein were decreased compared to controls. In benign ascites the proenzyme levels were significantly lower than in malignant ascites. Functional inhibition values in ascites and plasma from patients were unexpectedly high. Our findings indicate that the plasma contact system is activated in the ascites from cancer patients. Activation of the contact system generates vasoactive mediators, which may play a role in the accumulation of malignant ascites.

Aged↗
PubMed2004

Potentiation of C1 esterase inhibitor by StcE, a metalloprotease secreted by Escherichia coli O157:H7.

The complement system is an essential component of host defense against pathogens. Previous research in our laboratory identified StcE, a metalloprotease secreted by Escherichia coli O157:H7 that cleaves the serpin C1 esterase inhibitor (C1-INH), a major regulator of the classical complement cascade. Analyses of StcE-treated C1-INH activity revealed that surprisingly, StcE enhanced the ability of C1-INH to inhibit the classical complement-mediated lysis of sheep erythrocytes. StcE directly interacts with both cells and C1-INH, thereby binding C1-INH to the cell surface. This suggests that the augmented activity of StcE-treated C1-INH is due to the increased concentration of C1-INH at the sites of potential lytic complex formation. Indeed, removal of StcE abolishes the ability of C1-INH to bind erythrocyte surfaces, whereas the proteolysis of C1-INH is unnecessary to potentiate its inhibitory activity. Physical analyses showed that StcE interacts with C1-INH within its aminoterminal domain, allowing the unaffected serpin domain to interact with its targets. In addition, StcE-treated C1-INH provides significantly increased serum resistance to E. coli K-12 over native C1-INH. These data suggest that by recruiting C1-INH to cell surfaces, StcE may protect both E. coli O157:H7 and the host cells to which the bacterium adheres from complement-mediated lysis and potentially damaging inflammatory events.

Animals↗
PubMed1992

Antithrombin III, C1 inhibitor, methylglyoxal, and polymorphonuclear leukocytes in the development of vascular complications in diabetes mellitus.

Under conditions closely approximating those in vivo (100 mM sodium carbonate pH 7.3 with 0.9% NaCl, 37 degrees C), antithrombin III (AT III) and the C1 inhibitor (C1-INH) are inactivated by methylglyoxal (MG) with pseudofirst-order kinetics and second-order rate constants of 25.2 and 7.8 M-1 min-1, respectively. A study of the functional status of neutrophils from patients with diabetes mellitus (DM) prompts an idea that under hyperglycemia in the diabetic organism the polymorphonuclear leukocytes (PML) endure 'arousal' that is identical or analogous to their activation. Indeed, nonstimulated PML from DM patients display (i) an almost sixfold higher luminol-dependent chemiluminescence and (ii) a double rate of oxygen uptake as compared with those from healthy donors, and (iii) are capable of MG formation in the presence of acetoacetate, which in vivo may be an additional source of this inactivator of AT III and C1-INH in diabetic patients. Conditions leading to ketosis or lactic acidosis are discussed, and a probable scenario is proposed for the organismic deterioration in DM.

Acetoacetates↗
PubMed2000

Frequent de novo mutations and exon deletions in the C1inhibitor gene of patients with angioedema.

BACKGROUND: Cases of angioedema with no family history but with functionally low levels of C1 inhibitor and recurrent attacks are often observed. Clinical and biochemical data do not distinguish these cases from proven inherited forms of hereditary angioedema. OBJECTIVE: We sought to test the hypothesis of de novo mutations in patients affected by angioedema without a family history of the disease. METHODS: Among 137 independent kindreds followed for hereditary angioedema, 45 (32.8%) patients with early onset of the disease were registered as sporadic cases. Nineteen patients with unaffected parents were screened for point mutations and microdeletions-insertions by using fluorescence-assisted mismatch analysis. The biologic paternity of these patients was verified by determining their alleles at 4 microsatellite loci. Gross deletions were detected with Southern blot analysis. RESULTS: C1 inhibitor plasma levels measured in both parents of 24 sporadic patients were normal in all but 3 patients. Among the 19 patients studied at the DNA level, 9 de novo single nucleotide substitutions and 6 de novo microdeletions were found. De novo exon deletions were detected in 3 additional patients with Southern blot analysis. CONCLUSIONS: De novo C1inhibitor mutations and exon deletions account for at least 25% of all unrelated cases of angioedema. This finding has implications relevant to the genetic epidemiology and genetic counseling of this disease. The observation that 5 of the 9 de novo point mutations reproduce previously reported changes underlines the presence of multiple hot spots, two of which contain a CpG dinucleotide.

Angioedema↗
PubMed1990

[A simplified method for the assessment of C1 esterase inhibitor function].

From the result that the activated form of C1-s(C1-s) prolonged the kinetics of hemolysis via complement, this assay was applied to assess C1 esterase inhibitor (C1INH) function. In the kinetic assay, the complement hemolytic activity was evaluated by the time which required to cause 50% reduction of the initial turbidity of sensitized sheep erythrocytes, and was expressed as T1/2. (1) T1/2 of pooled normal human sera (p-NHS) showed dose-dependent prolongation by the addition of various amounts of C1-s. (2) Preincubation of various amounts of functionally pure C1INH with the constant amounts of C1-s inhibited dose-dependently the prolongation of T1/2 by C1-s. (3) The C1INH activity of NHS was 840 +/- 80 units/ml (n = 6) and that of the C1INH deficient serum was 80 units/ml, which were calculated from the standard curve established by the addition of various amounts of purified C1INH. This test requiring only C1-s and sensitized sheep erythrocytes is simple technically and high in sensitivity, and seems to be useful for the routine assay for C1INH function of human sera.

Animals↗
PubMed1990

Methylprednisolone induces activation of the contact system in a dose-dependent manner. An in vitro study.

The effect of methylprednisolone sodium succinate (MP) on the contact system of plasma was studied in human citrated pool plasma. Contact activation was demonstrated by the presence of plasma kallikrein (KK) activity and activated Hageman factor (FXIIa) and/or KK in complex with C1 inhibitor (C1inh), detected by chromogenic peptide substrates or radioimmunoassays, using monoclonal antibodies directed to neodeterminants exposed on complexed C1inh, respectively. When plasma and different doses of MP were incubated for a period of 24 hours, the highest dose of MP (10 mg/ml) gave rapid and marked increases in KK activities and concentrations of C1inh complexes. MP at 5 mg/ml plasma also induced activation of the contact system, although this activation was less pronounced. Even the lower dose of MP (1 mg/ml), which is equivalent to doses used in humans, increased plasma concentrations of KK-C1inh complexes. In conclusion, this in vitro study shows that MP in a dose-dependent way activates the contact system of plasma.

Complement C1 Inactivator Proteins↗
PubMed1988

Dose dependence of endotoxin-induced activation of the plasma contact system: an in vitro study.

The dose and time dependence of endotoxin-induced activation of the plasma contact system have been studied. Citrated pool plasma was incubated at 37 degrees C with endotoxin doses of 2.10(5), 2.10(6), 2.10(7), and 2.10(9) ng/l (lipopolysaccharide B, E. coli 026: B6, Difco Laboratories, Detroit, MI) for 24 hr. Samples for determination of components of the contact system were obtained prior to incubation and at 1, 2, 4, 6, 12, and 24 hr. Plasma kallikrein (KK) activity markedly increased at 12 hr in test plasma containing the highest dose of endotoxin (2.10(9) ng/l). Coincident with the elevated KK activity, reductions of both plasma prekallikrein (PKK) and functional kallikrein inhibition (KKI) were seen as assayed by chromogenic peptide substrate analyses. Also, functionally determined alpha 2-macroglobulin (alpha 2-M) and C1 inhibitor (C1INH) values were decreased, confirming the reduction of KKI values. Changes of Hageman factor (FXII), PKK, and high molecular weight kininogen (HMWK) values were also found at the same time point when assayed by immunochemical techniques. The same pattern of changes was seen in test plasma containing 2.10(7) and 2.10(6) ng/l of endotoxin. These changes, however, were less pronounced and not seen until 24 hr after beginning incubation. In control plasma and in plasma containing the lowest dose of endotoxin (2.10(5) ng/l), no changes were seen in any factors of the contact system. Our study shows that in vitro endotoxin-induced activation of the contact system is a slow process that is both time and dose dependent.

Chromogenic Compounds↗
PubMed1996

The influence of C1-esterase inhibitor substitution on coagulation and cardiorespiratory parameters in an endotoxin-induced rabbit model of hypercoagulability.

In a short-time model of endotoxin-induced (lipopolysaccharide from Escherichia coli, 120 micrograms kg-1 i.v.) hypercoagulability in rabbits, the therapeutic effects of C1-esterase inhibitor (C1I) substitution (bolus 400 U kg-1 i.v. followed by continuous infusion of 400 U kg-1 4 h-1 i.v.) were studied. When compared to endotoxin-challenged untreated animals, C1I substitution significantly stabilized mean arterial pressure (p < 0.01), increased central venous oxygen saturation (p < 0.05), prevented the decrease of antithrombin III (p < 0.05), and reduced fibrin deposition in the microcirculation of the liver and the lungs to approximately 30% of that observed in the untreated animals (p < 0.01). Although C1I substitution did not reduce systemic procoagulant turnover, the improvement of blood pressure and blood flow and local inhibitory actions in the coagulation and complement cascade prevented fibrin deposition in the microcirculation of vital organs. This study supports the beneficial role of C1I substitution during early disseminated intravascular coagulation.

Animals↗
PubMed1997

Intracoronary application of C1 esterase inhibitor improves cardiac function and reduces myocardial necrosis in an experimental model of ischemia and reperfusion.

BACKGROUND: Myocardial injury from ischemia can be aggravated by reperfusion of the jeopardized area. The precise underlying mechanisms have not been clearly defined, but proinflammatory events, including complement activation, leukocyte adhesion, and infiltration and release of diverse mediators, probably play important roles. The present study addresses the possibility of reducing reperfusion damage by the application of C1 esterase inhibitor (C1-INH). METHODS AND RESULTS: Cardioprotection by C1-INH 20 IU/kg IC was examined in a pig model with 60 minutes of coronary occlusion, followed by 120 minutes of reperfusion. C1-INH was administered during the first 5 minutes of coronary reperfusion Compared with the NaCl controls, C1-INH reduced myocardial injury (48.8 +/- 7.8% versus 73.4 +/- 4.0% necrosis of area at risk, P < or = .018). C1-INH treatment significantly reduced circulating C3a and slightly attenuated C5a plasma concentrations. Myocardial protection was accompanied by reduced plasma concentration of creatine kinase and troponin-T. C1-INH had no effect on global hemodynamic parameters, but local myocardial contractility was markedly improved in the ischemic zone. In the short-axis view, 137 degrees of the anteroseptal region showed significantly improved wall motion at early and 29 degrees at late reperfusion with C1-INH treatment. CONCLUSIONS: C1-INH significantly protects ischemic tissue from reperfusion damage, reduces myocardial necrosis, and improves local cardiac function.

Anaphylatoxins↗
PubMed1985

C1-inhibitor--biochemical properties and clinical applications.

C1-inhibitor (C1-INH) is an alpha-2-neuraminoglycoprotein with a molecular weight of 105,000 daltons. It has a broad spectrum control of the many blood cascades including the complement system. Inherited deficiency of this molecule has been associated with the development of hereditary angioneurotic edema (HANE), a dominant genetic disorder. The liver and monocytes are the primary sites of C1-INH synthesis. The genetic basis of dysfunctional C1-INH is a defect at the structural locus for one C1-INH gene; both the dysfunctional C1-INH gene and the normal C1-INH gene products are present in the plasma of the affected person. The absence of C1-INH permits spontaneous activation of the first component of the complement system (C1); this, in turn, activates C4 and C2. A kinin derived from C2 may be elaborated, which then increases vascular permeability. However, recent investigations have indicated that kinin activity generated from C1-INH-depleted plasma is not derived from C2 but implicates kallikrein, an enzyme which is also controlled by C1-INH, in the formation of a kinin which is most probably bradykinin. A number of therapeutic approaches have been used to treat HANE patients, including antifribrinolytic drugs such as tranexamic acid, plasma infusion, and steroids. The anabolic steroids such as danazol and stanazolol have been used widely to treat HANE patients. We discuss in this review the potential mechanisms by which danazol promotes selective synthesis of C1-INH and several other proteins in the liver.

Angioedema↗
PubMed1997

Autoimmune C1 inhibitor deficiency and angioedema.

C1 inhibitor (C1-INH) deficiency results in bouts of mucocutaneous edema and may be inherited (hereditary angioedema) or acquired (acquired angioedema). The syndrome of acquired angioedema, characterized by the adult onset of angioedema and by the lack of evidence of inheritance of the disease, may be associated with lymphoproliferative or other malignant diseases (type I) or with the presence of autoantibodies to C1-INH (type II); this is a rare variant form of C1-INH deficiency with angioedema. We report here a case of acquired C1-INH deficiency with angioedema, hypotension and abdominal discomfort observed in a 71-year-old man in whom complement abnormalities and autoantibodies against C1-INH have been observed and who was classified as having an autoimmune C1-INH deficiency. From the therapeutic point of view after resolution of the acute attacks, high doses of tranexamic acid have been able, at first, to decrease the frequency and the severity of the symptoms, and subsequently to provide a long symptom-free time.

Aged↗
PubMed1976

Evidence for immune complexes involving anti-lymphocyte antibodies associated with hypocomplementaemia in chronic lymphocytic leukaemia (CLL).

Unmeasurable total haemolytic complement (C) was observed in serum of a patient with untreated chronic lymphocytic leukaemia and recurrent non-hereditary angioedema. Analysis of C components immunochemically demonstrated a marked reduction of C1q and C1s inhibitor, undetectable C1r, C1s and an elevated B. Haemolytic C1, C4 and C2 were less than 5 percent of normal, functional C1s inhibitor was absent. Cryoglobulin and C1q precipitins were present in the serum. Of special interest was the presence of high levels of cold-reactive antilymphocyte antibody, determined by both C-dependent cytotoxicity and indirect immunofluorescence. The antibody exhibited specificities for both autologous lymphocytes and lymphocytes from normal donors; cytotoxic activity for autologous leukaemia cells was removed by absorption with normal isologous tonsil lymphocytes. Specific enrichment of this antibody relative to the serum level was demonstrated in the cryoglobulin and its isolated 19S fractions. Free lymphocyte surface antigen was also demonstrated by gel diffusion using specific rabbit antilymphocyte antiserum. These data strongly suggest the presence of pathogenetically significant circulating complexes of lymphocyte surface antigen and specific antibody in certain patients with CLL.

Angioedema↗
PubMed1995

Development of a novel recombinant serpin with potential antithrombotic properties.

Recombinant alpha 1-antitrypsin with a P1 arginine residue (Arg-alpha 1-antitrypsin) is a rapid inhibitor of both thrombin and activated protein C (APC). A series of mutants were made in an attempt to increase the specificity of this serpin for thrombin over APC. Initially, P2 and P'1 residues of Arg-alpha 1-antitrypsin were replaced in single and double mutations by the corresponding residues in antithrombin and C1 inhibitor which are very poor inhibitors of APC. No improvement in selectivity was achieved by these mutations. In fact, all P2/P'1 substitutions led to a decrease in selectivity for thrombin over APC. For example, replacement of the P2 proline of Arg-alpha 1-antitrypsin by glycine decreased the association rate constant (kass) with thrombin by 37-fold while the kass value with APC was reduced by only 16-fold. Cooperative effects were observed with the double P2 and P'1 substitutions; the mutational effects were not additive. The decrease in the kass for thrombin caused by the mutation of the P2 proline to alanine or glycine was 3-fold greater when threonine was present in the P'1 position instead of the normal serine. In contrast to the disappointing results with the P2/P'1 mutations, replacement of the P7 to P'3 residues of alpha 1-antitrypsin by those of antithrombin led to a dramatic increase in selectivity. Although this substitution only affected the kass value with thrombin by 10-fold, a 12,500-fold decrease in this value with APC was observed. Substitution of proline for the P2 glycine of this chimeric serpin increased the kass values with thrombin and APC by 7- and 90-fold, respectively. The effect of the P2 substitution was again found to depend on the sequence surrounding the residue; the change in the kass for APC caused by the P2 Pro-->Gly replacement was 6-fold larger in the chimeric serpin. Evaluation of the kass values of the chimeric serpin with a P2 proline in light of the likely rates of inhibition of thrombin and APC during antithrombotic therapy with heparin suggested that this serpin may have kinetic parameters suitable for an antithrombotic agent.

Amino Acid Sequence↗