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PubMed1990

Regulation of the hepatic synthesis of C1 inhibitor by the hepatocyte stimulating factors interleukin 6 and interferon gamma.

C1 inhibitor (C1INH), the major plasma inhibitor of activated C1, kallikrein, and activated Hageman factor, may be an important factor in limiting inflammatory injury mediated by the complement and contact systems. C1INH is thought to be synthesized primarily in the liver; however, the regulators of hepatic C1 inhibitor synthesis are completely unknown. In this report, we analyze the regulation of C1INH synthesis by hepatocyte stimulating factors in human hepatoma cell lines and primary hepatocytes. Interleukin-6 and interferon gamma increase C1INH production in both hepatoma cells and hepatocytes. These cytokines stimulate de novo synthesis of functional C1INH, acting at a pretranslational level as assessed by Northern blotting. The stimulatory effects of interleukin-6 and interferon gamma on C1INH synthesis are separate and are differentially modulated by interleukin-1. These results establish that hepatic C1INH synthesis is regulated by hepatocyte stimulating factors and reveal novel interactions between these factors.

Acute-Phase Proteins↗
PubMed1986

Kinetics of interaction of C1 inhibitor with complement C1s.

The kinetics of inhibition of the complement serine protease, C1s, by its only known inhibitor, C1 inhibitor, have been measured by a variety of methods. One method continuously monitors the loss of esterolytic activity with a synthetic substrate coupled to a chromogen while another monitors the formation of a stable (covalent) complex by high-pressure size-exclusion chromatography under dissociating conditions. Additional methods employ fluorescence probes to follow the formation of bimolecular complexes but are not expected to distinguish between covalent product and noncovalent (reversible) intermediates. There was good agreement between rate constants obtained by the various methods over a broad range of inhibitor concentrations, suggesting that noncovalent intermediates do not accumulate to a significant extent. The reaction appears to be pure second order with a bimolecular rate constant of 6.0 X 10(4) M-1 s-1 at 30 degrees C, independent of Ca2+, and an activation energy of 11.0 kcal/mol. The rate increases up to 35-fold in the presence of heparin which was shown to bind to all three components (enzyme, inhibitor, and complex) with similar affinity (Kd = 2.0-3.3 microM). The fluorescent probe 1,1'-bis(anilino)-4-,4'-bi(naphthalene)-8,8'-disulfonate [bis(ANS)] bound to the complex with Kd = 0.26 microM under conditions where the individual components had little affinity for the dye, consistent with the generation of one or more hydrophobic binding sites on the protein surface during complex formation.

Complement Activating Enzymes↗
PubMed1995

Galactosylation of N- and O-linked carbohydrate moieties of IgA1 and IgG in IgA nephropathy.

The mechanism of IgA deposition in the kidneys in IgA nephropathy is unknown. Mesangial IgA is of the IgA1 subclass, and since no consistent antigenic target for the IgA1 has been described, we have investigated the glycosylation of the molecule, as a potential non-immunological abnormality which may contribute to its deposition. IgA1 is rich in carbohydrate, carrying N-linked moieties in common with IgG, but also O-linked sugars, which are rare in serum proteins, and not expressed by IgG or IgA2. Lectin binding assays were designed to examine the expression of terminal galactose on the N-linked carbohydrate chains of purified serum IgG and IgA1, and the O-linked sugars of IgA1 and C1 inhibitor (one of the very few other serum proteins with O-linked glycosylation). No evidence was found for abnormalities of N-linked glycosylation of either isotype in IgA nephropathy compared with matched controls. However, in IgA nephropathy, reduced terminal galactosylation of the hinge region O-linked moieties was demonstrated; this was not seen in C1 inhibitor, which showed normal or increased galactosylation of the O-linked sugars. This abnormality of IgA1 has considerable implications for the pathogenesis of IgA nephropathy, since the O-linked sugars lie in an important functional location within the IgA1 molecule, close to the ligand of Fc receptors. Changes in the carbohydrates in this site may therefore affect interactions with receptors and extracellular proteins, leading to anomalous handling of the IgA1 protein in this condition, including failure of normal clearance mechanisms, and mesangial deposition.

Adult↗
PubMed1988

The functional role of acute phase plasma proteinase inhibitors.

Human plasma contains an array of proteinase inhibitors which are utilized in the regulation of a host of biological activities, including coagulation, fibrinolysis, connective tissue turnover, and complement activation. The concentration of several of these inhibitors increase at varying rates in the acute phase state while others remain constant or actually decrease. Increases are presumably an attempt to retain rigid control over certain critical reactions, while decreases are probably due to inhibitor turnover either through consumption during complex formation or inactivation by other endogenous proteinases. Virtually all of these latter reactions take place in a reactive site loop which is an exposed region present in at least eight related serine proteinase inhibitors (Serpins) in plasma. Complex formation and inhibitor inactivation presumably act as signals for inhibitor production and turnover in the acute phase state. However, exactly how this initial stimulus for increased protein synthesis is manifested at the protein level remains to be established.

Acute-Phase Reaction↗
PubMed2003

DX-88 and HAE: a developmental perspective.

An example of an approach to the developmental philosophy of novel recombinant products is explored by using the exemplar of Hereditary Angioedema (HAE). Plasma kallikrein is believed to be an important mediator of angioedema in patients with genetic deficiency of C1 esterase inhibitor (HAE patients). DX-88, a novel Kunitz domain produced by phage display (a powerful method of generating novel binders to potentially therapeutic targets), is a potent and selective inhibitor of plasma kallikrein which in early clinical studies demonstrates a useful efficacy/safety ratio in the treatment of acute attacks of HAE.

Acute Disease↗
PubMed1993

Postoperative multiple organ dysfunction syndrome associated with gut mucosal hypoperfusion, increased neutrophil degranulation and C1-esterase inhibitor depletion.

We have examined the relationship between gut mucosal perfusion, as determined by gastric intramucosal pH (pHi), changes in plasma neutrophil elastase concentrations and components of the contact system during elective major surgery and related these findings to patient outcome. Of the 26 patients studied, 16 developed gut mucosal hypoperfusion (pHi < 7.32) by the end of surgery; four of these developed multiple organ dysfunction syndrome; three of these died. In this group there was a significant increase in neutrophil elastase (P < 0.005) and significant reductions in plasma components of the contact system from immediately before surgery to 24 h later. Ten patients maintained gut mucosal perfusion (pHi > or = 7.32); none of these developed life threatening complications. In this group there was no significant increase in neutrophil elastase and, although there were significant reductions in some plasma components of the contact system, concentrations of C1-esterase inhibitor (the main inhibitor of the contact system) were not significantly reduced. We conclude that gut mucosal hypoperfusion, neutrophil degranulation and activation of the contact system to the extent that C1-esterase inhibitor becomes depleted are associated with a poor outcome after major surgery.

Adult↗
PubMed2002

Kallikrein-kinin system activation in Crohn's disease: differences in intestinal and systemic markers.

OBJECTIVES: Observations in experimental models and in human ulcerative colitis suggest that activation of the kallikrein-kinin system plays a role in the pathogenesis of inflammatory bowel disease. The aim of this study was to assess activation of the plasma and tissue kallikrein-kinin system in Crohn's disease. METHODS: We studied plasma inflammatory and contact system parameters in 36 patients with Crohn's disease and in 36 control subjects with noninflammatory GI diseases. We also obtained tissue samples from the involved intestine of 12 patients with Crohn's disease, and from normal peritumoral tissue (12 patients) and diverticulitis tissue (seven patients) as controls. Full-thickness sections were tested for intestinal tissue kallikrein reactivity with a specific antibody. RESULTS: In Crohn's disease patients and controls, plasma levels of prekallikrein, factor XI, high molecular weight kininogen and its cleaved form were normal. Crohn's disease patients had significantly higher levels of antigen and functional Cl-inhibitor (+22%, +12%) than did controls (p = 0.005, p = 0.004). After surgical resection, antigen and functional Cl-inhibitor significantly decreased in Crohn's disease patients (-22%, -15%; p = 0.035, p = 0.006). Intestinal tissue kallikrein immunoreactivity was absent (75%) or weak (25%) in the goblet cells from Crohn's disease tissue sections but was normal in controls, with a highly significant difference in the staining score (p = 0.0001). Intestinal tissue kallikrein immunoreactivity in the interstitium was higher in Crohn's disease than in normal and diverticulitis samples (p = 0.0001 and p = 0.001, respectively). CONCLUSIONS: Our observations suggest that intestinal tissue kallikrein is involved in the inflammatory process in Crohn's disease. The lack of contact system activation in peripheral blood might be related to the high plasma levels of Cl-inhibitor, the most important inhibitor of the contact system in the circulation.

Adult↗
PubMed1999

Angioedema: frightening and frustrating.

Angioedema can have a variety of causes, including drug reactions, food allergies, and C1 esterase inhibitor deficiency, but many cases are idiopathic. Swelling usually subsides in days if the offending agent can be removed. The throat is often involved, but few patients actually require intubation.

Angioedema↗
PubMed2004

[Hereditary angioedema of delayed onset].

Hereditary angioedema is a disorder characterized by episodes of angioedema of the skin, respiratory and gastrointestinal tract resulting from a defect in the C1 esterase inhibitor. The disease is hereditary. Inheritance is autosomal dominant with incomplete penetration. We report a 56-year-old man with edema in different locations as forearm, testicles and palms. It started recently. The study showed low levels of C4, and C1 inhibitor. He was diagnosed of hereditary angioedema and it was necessary the family study.

Age of Onset↗
PubMed2000

Impaired human ovarian follicular fluid complement function in hereditary angioedema.

We sought and detected functionally active complement in human ovarian follicular fluid obtained during the peri-ovulatory period. All the functional complement activities tested, including total haemolytic complement, classical pathway activity, alternative pathway activity and C1 inhibitor function were present with values within the normal serum range. Active complement in follicular fluid is relevant for the function of the enzymatic multifactorial mechanism of ovulation. The presence in hereditary angioedema patients of both complement (C1 inhibitor deficiency and chronically consumed complement) and ovarian abnormalities (cystic ovaries), led us to study complement function in the follicular fluid of women of reproductive age affected with hereditary angioedema. In contrast to healthy women, hereditary angioedema patients showed dramatically reduced classical pathway activity and undetectable functional and antigenic C1 inhibitor. C4 was very low, while C3 and B were slightly reduced or within the normal serum range. This complement profile was also detected in patients' sera. Since hereditary angioedema patients often show cystic ovaries (polycystic or multifollicular), the presence of multifollicular ovaries in the two patients studied, along with complement dysfunction, may be relevant. These findings, as well as the normalisation of the ovaries found by us in hereditary angioedema patients and in the patients reported here who were undergoing danazol treatment, and the increase in C1 inhibitor and the improvement of clinical symptoms, suggest a further link between complement and ovarian function.

Adult↗
PubMed1979

Complement and coagulation: causative considerations in contrast catastrophies.

Earlier studies suggest that adverse reactions to injected radiographic contrast media are idiosyncratic. In an attempt to gain a better understanding of pathophysiologic events underlying these reactions, rabbit models injected with lethal dose ranges of a cholangiographic contrast material were studied. These animals showed activation of both the complement and coagulation systems. Externally applied heat potentiated complement consumption and increased mortality. Depleting complement components C3-C9 by cobra venom factor did not prevent activation of coagulation or diminish mortality. However, depleting fibrinogen diminished complement activation and markedly diminished mortality. Heparin, administered at several hourly intervals after contrast challenge, also diminished mortality. These studies suggest that the adverse effects of contrast media in this model system are mediated chiefly by the coagulation system, and that complement, if it participates deleteriously, must involve components up to, but not including, C3. A logical role for the inhibitor of C1 esterase in adverse contrast reactions is considered.

Ancrod↗
PubMed1991

Spontaneous activation of serum C1 in vitro. Role of C1 inhibitor.

The temperature and ionic strength dependence of the spontaneous activation of C1 were determined for normal human serum, and the free energy, enthalpy, and entropy of spontaneous activation were calculated. The half-life of C1 in human serum was approximately 15 h at 37 degrees C. This half-life was markedly extended by dilution with C1-depleted serum, and an extrapolated upper limit of 40 to 50 h was reached at infinite dilution. Thus, the spontaneous activation of C1 in serum appeared to involve a dilution-sensitive reaction as well as a dilution-insensitive, first order reaction. A reaction mechanism was developed combining: 1) first order spontaneous activation of C1; 2) second order, C1-catalyzed activation of C1; and 3) second order inactivation of C1 by C1-inhibitor. A steady state equation was derived from this reaction mechanism, which provided a reasonable fit to the experimental data. The equation predicts that when the C1-inhibitor concentration decreases so that the steady state condition is lost, the concentration of C1 builds up quickly, and activation of most of the C1 occurs rapidly.

Complement Activation↗
PubMed1991

Modulation of complement gene expression by glucocorticoids.

The addition of dexamethasone, prednisolone or cortisol (in order of efficacy) to human monocytes in culture produced dose-related increases in the synthesis rates of the complement components C1 inhibitor (C1-inh), factor B (B) and C2. In contrast, concentrations of C3 and lysozyme in the culture supernatants were decreased. Indomethacin stimulated synthesis of C1-inh, C2 and B, but had little effect on synthesis of C3 or lysozyme. The simultaneous addition of cycloheximide (2.5 micrograms/ml) abrogated the effects of dexamethasone on synthesis of C2, B and C1-inh, but the effect of indomethacin on the synthesis of these components was unchanged. These data suggest that protein synthesis is required for the effects of glucocorticoids on the synthesis of C2, B and C1-inh to occur. Dexamethasone and indomethacin increased the abundances of C1-inh mRNA, B mRNA and C2 mRNA in parallel with changes in the synthesis rates of these proteins. The changes in mRNA abundance were not transcriptional, but were shown to be due to increased mRNA stability. In contrast, dexamethasone decreased the expression of C3 and lysozyme by decreasing the rate of transcription of these genes. Indomethacin had no effect on transcription of the C3 and lysozyme genes. The half-lives of C3 mRNA, lysozyme mRNA and actin mRNA were not altered by dexamethasone or indomethacin. It is concluded that the effects of glucocorticoids on monocyte synthesis of C2, B and C1-inh are due to increased mRNA stability and may be related to inhibition of prostaglandin synthesis, as these effects are similar to those produced by indomethacin. The effects of dexamethasone on the synthesis of C3 and lysozyme differ from those on C2, B and C1-inh as they depend upon a decrease in gene transcription, which is not affected by indomethacin.

Cells, Cultured↗
PubMed1996

Nafamostat mesilate, a broad spectrum protease inhibitor, modulates platelet, neutrophil and contact activation in simulated extracorporeal circulation.

Activation of humoral and cellular participants in inflammation enhances the risk of postoperative bleeding and multiple organ damage in cardiopulmonary bypass (CPB). We now compare the effects of heparin alone in combination with nafamostat mesilate (NM), a protease inhibitor with specificity of trypsin-like enzymes, in an extracorporeal circuit which simulates CPB. NM significantly inhibits the release of platelet beta-thromboglobulin (beta TG) at 60 and 120 min. Platelet counts do not differ. ADP-induced aggregation decreases in circuits with NM, which is due to a direct effect of NM on platelet function. NM prevents any significant release of neutrophil elastase; at 120 min, plasma elastase-alpha 1-antitrypsin complex is 0.16 micrograms/ml in the NM group and 1.24 micrograms/ml in the control group. NM completely inhibits formation of complexes of C1 inhibitor with kallikrein and FXIIa. NM does not alter markers of complement activation (C1-C1-inhibitor complex and C5b-9), or indicators of thrombin formation (F1.2). However, at 120 min, thrombin activity as measured by release of fibrinopeptide A is significantly decreased. The data indicate that complement activation during CPB correlates poorly with neutrophil activation and that either kallikrein or FXIIa or both may be more important agonists. The ability of NM to inhibit two important contact system proteins and platelet and neutrophil release raises the possibility of suppressing the inflammatory response during clinical CPB.

Anticoagulants↗
PubMed1988

Plaque-lift testing of expression vector lambda gt11 with gold-labeled immunoglobulins.

Colloidal gold particles were coated with affinity-purified antibodies against the human plasma protein, C1 inhibitor, and used to probe for fusion proteins of C1 inhibitor with beta-galactosidase encoded by recombinant bacteriophage lambda gt11 DNA. Plaque-lift tests were done with recombinant proteins immobilized on nitrocellulose applying anti-C1 inhibitor gold particles followed by the silver enhancement treatment. This procedure resulted in a sensitive and specific staining of the recombinant proteins and allowed the selective detection of relevant clones in a complex cDNA expression library. Under optimized conditions, plaque-lift testing was completed within 2.5 h after removal of nitrocellulose filters from the plate. Hence, the immunogold detection method provides an alternative to conventional enzyme- or radionuclide-based screening procedures for cDNA expression libraries.

Animals↗
PubMed1998

Transmission of hepatitis G virus in patients with angioedema treated with steam-heated plasma concentrates of C1 inhibitor.

BACKGROUND: Hepatitis G virus (HGV) is a blood-borne flavivirus that may cause acute and chronic transfusion-transmitted infections. Patients with complement component 1 (C1) inhibitor (C1-INH) deficiency may acquire blood-borne infections through infusion of plasma concentrates. STUDY DESIGN AND METHODS: Serum samples from 84 patients with C1-INH deficiency (19 who received unmodified C1-INH concentrates, 23 who received steam-heated concentrates, and 42 untreated patients) were tested for HGV RNA and hepatitis C virus (HCV) RNA by a nested polymerase chain reaction (PCR). The samples were also tested for antibodies to the E2 envelope protein of HGV (anti-HGV) and to HCV with enzyme-linked immunosorbent assays. RESULTS: Nine (11%) patients had serum HGV RNA; that is, 7 (17%) of 42 patients previously treated with C1-INH concentrates and 2 of 42 previously untreated patients. HGV RNA was as common in the 19 patients treated with unmodified concentrates as in the 23 given steam-heated concentrates (16 vs. 17%, p = 0.60). Anti-HGV was more common among the recipients of unmodified concentrates than among those given steam-heated concentrates (26 vs. 0%, p = 0.014). HCV RNA was more frequently detected in treated patients than in untreated patients (33 vs. 7%, p = 0.005) and in the 19 recipients of unmodified concentrates than in the 23 treated with steam-heated concentrates (58 vs. 16%, p = 0.003). Only one HGV RNA-seropositive patient had elevated serum aminotransferase activity, compared to 11 with HCV RNA. CONCLUSION: HGV was transmitted by both unmodified and steam-heated concentrates, but it caused persistent viremia in a minority of the cases and was rarely associated with liver disease.

Adult↗
PubMed1996

Characterization of C1 inhibitor-Ta. A dysfunctional C1INH with deletion of lysine 251.

Dysfunctional C1 inhibitor (C1INH)-Ta is a naturally occurring mutant from a patient with type II hereditary angioedema. This mutant has a deletion of the codon for Lys-251, which is located in the connecting strand between helix F and strand 3A, overlying beta sheet A. Deletion of this Lys modifies the amino acid sequence at this position from Asn-Lys-Ile-Ser to Asn-Ile-Ser and creates a new glycosylation site. To further characterize the mechanism of dysfunction, we have analyzed the recombinant normal and Ta proteins expressed by COS cells in addition to the proteins in serum and isolated from serum. Recombinant C1INH-Ta revealed an intermediate thermal stability in comparison with the intact and reactive center cleaved normal proteins. Analysis of the reactivity of this recombinant protein with target proteases demonstrated no complex formation with C1s, C1r, or kallikrein. Inefficient complex formation was, however, clearly detectable with beta-factor XIIa. Each protease produced partial cleavage of the recombinant mutant inhibitor. Recombinant C1INH-Ta, on 7.5% SDS-polyacrylamide gel electrophoresis and by size fractionation on Superose 12, showed a higher molecular weight fraction that was compatible in size with dimer formation. However, no multimerization of C1INH-Ta isolated from serum or of C1INH-Ta in serum, was observed. The C1INH-Ta dimer expressed the epitopes that normally are expressed only on the protease complexed or the cleaved inhibitor. These epitopes were not expressed on the monomeric inhibitor. The data suggest that the mutation in C1INH-Ta results in a folding abnormality that behaves as if it consists of two populations of molecules, one of which is susceptible to multimerization and one of which is converted to a substrate, but which retains residual inhibitory activity.

Animals↗