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PubMed1998

[Genetic aspects of silicosis: polymorphic gene distribution frequency].

Electrophoresis and isoelectrofocusing were used to study polymorphism by 7 genetic loci: haptoglobin (Hp), proteinase inhibitor (PI), transferrin (TF), Vitamin D-transporting protein (GC), complement 3 (C3), phosphoglucomutase 1 (PGM1) and glyoxalase (GLO1) in 60 patients with silicosis and in 70 apparently healthy workers of the Dynamo plant. Comparison of the study groups by significant differences in the summary of the genetic information obtained suggests that 5 (Hp, C3, TF, PI, PGM1) of the 7 studied systems showed the hereditary features of silicosis. The gene carriers Hp*2, C3*F, PGM1*2-, PI*M1, TF*C1, TF*C16 TF*D, GC*R due to peculiar biochemical processes appear to have less adaptive potentialities and a greater likelihood of the disease on exposure to industrial factors.

Adult↗
PubMed1983

A new simple method for determination of C1-esterase inhibitor activity in plasma.

A convenient method for the determination of C1-esterase inhibitor activity in plasma samples is described. The method is based on addition of purified C1s to plasma and measuring excess C1s with a new chromogenic tripeptide-p-nitroanilide substrate with a recording spectrophotometer. Addition of C1s to C1-esterase inhibitor-depleted plasma did not result in any appreciable inactivation of the enzyme for three hours. The concentration of C1-esterase inhibitor in 19 healthy individuals was estimated as 1.63 +/- 0.27 (SD) mumol/l. The correlation with C1-esterase inhibitor antigen in these individuals and 19 patients with varying concentrations of C1-esterase inhibitor was excellent. The correlation with an antikallikrein assay was found to be poor.

Complement Activating Enzymes↗
PubMed1983

[New preparation method of C1 esterase for the dosage of its plasma inhibitor].

A purification method for C1 esterase is described. The final product significantly improved the sensitivity and the specificity of the enzymatic measurement of its plasma inhibitor C1-INH or alpha 2-neuraminoglycoprotein (alpha 2-NGP) by esterolysis of a synthetic substrate N-acetyl-L-tyrosine ethyl ester (ALTEe). A comparative study was done between the chromatographed C1 esterase and the native serum euglobulins: qualitative and quantitative determination of the serum contaminants, enzymatic activity measurement of C1-INH in normal subjects and in patients suffering from hereditary angioneurotic oedema (OANH) as well as in therapeutical C1-inhibitor concentrates.

Angioedema↗
PubMed1997

Potentiation of C1 inhibitor by glycosaminoglycans: dextran sulfate species are effective inhibitors of in vitro complement activation in plasma.

Activation of the complement system may contribute to the pathogenesis of many diseases. Hence, an effective inhibitor of complement might be useful to reduce tissue damage. Some glycosaminoglycans (GAG), such as heparin, are known to inhibit the interaction of C1q with activators and the assembly of the classical and the alternative pathway C3 convertases. Furthermore, they may potentiate C1 inhibitor-mediated inactivation of C1s. To search for potential complement inhibitors, we systematically investigated the complement inhibitory properties of various synthetic and naturally occurring GAG (dextran sulfates 500,000 and 5,000, heparin, N-acetylheparin, heparan sulfate, dermatan sulfate, and chondroitin sulfates A and C). First, we assessed the effect of GAG on the second-order rate constant of the inactivation of C1s by C1 inhibitor. This rate constant increased 6- to 130-fold in the presence of the GAG, dextran sulfate being the most effective. Second, all tested GAG were found to reduce deposition of C4 and C3 on immobilized aggregated human IgG (AHG) and to reduce fluid phase formation of C4b/c and C3b/c in recalcified plasma upon incubation with AHG. Dextran sulfate again was found to be most effective. We conclude that GAG modulate complement activation in vitro and that the low molecular weight dextran sulfate (m.w. 5000) may be a candidate for pharmacologic manipulation of complement activation via potentiation of C1 inhibitor.

Complement Activation↗
PubMed2000

The Arthus reaction in rodents: species-specific requirement of complement.

We induced reverse passive Arthus (RPA) reactions in the skin of rodents and found that the contribution of complement to immune complex-mediated inflammation is species specific. Complement was found to be necessary in rats and guinea pigs but not in C57BL/6J mice. In rats, within 4 h after initiation of an RPA reaction, serum alternative pathway hemolytic titers decreased significantly below basal levels, whereas classical pathway titers were unchanged. Thus the dermal reaction proceeds coincident with systemic activation of complement. The serine protease inhibitor BCX 1470, which blocks the esterolytic and hemolytic activities of the complement enzymes Cls and factor D in vitro, also blocked development of RPA-induced edema in the rat. These data support the proposal that complement-mediated processes are of major importance in the Arthus reaction in rats and guinea pigs, and suggest that BCX 1470 will be useful as an anti-inflammatory agent in diseases where complement activation is known to be detrimental.

Animals↗
PubMed1987

Autoantibody-mediated acquired deficiency of C1 inhibitor.

During the past 25 years, three forms of deficiency of the inhibitor of the first component of complement (C1 inhibitor) with angioedema have been recognized; two forms are hereditary and one is acquired. As compared with hereditary angioedema, the syndrome of acquired C1-inhibitor deficiency is rare, and it is usually associated with lymphoproliferative diseases. We report another type of acquired C1-inhibitor deficiency with angioedema. Two patients with recurrent angioedema but no associated diseases were found to have IgG1 autoantibodies against C1 inhibitor. The anti-C1-inhibitor antibodies prevented binding of C1 inhibitor to activated C1s. Both patients had 60 to 70 percent of normal levels of C1 inhibitor, but it was functionally inactive, with a molecular weight of 96,000 (normal C1 inhibitor, 105,000). In vitro studies of the patients' serum revealed degradation of 125I-labeled 105,000-dalton C1 inhibitor into the inactive 96,000-dalton molecule, caused by activated C1s and not found in normal human serum. We conclude that these cases of acquired C1-inhibitor deficiency resulted from a blockade of C1-inhibitor function by the anti-C1-inhibitor antibodies and from subsequent inactivation of C1 inhibitor by the now uncontrolled enzyme, activated C1s. As in other forms of C1-inhibitor deficiency, the unopposed activation of the complement system led to angioedema.

Adult↗
PubMed2004

Proteases of the complement system.

The complement system is a group of about 35 soluble and cell-surface proteins which interact to recognize, opsonize and clear or kill invading micro-organisms or altered host cells (e.g. apoptotic or necrotic cells). Complement is a major part of the innate immune system. Recognition proteins such as C1q, MBL (mannan-binding lectin) and ficolins bind to targets via charge or sugar arrays. Binding causes activation of a series of serine protease proenzymes, such as C1r, C1s and MASP2 (MBL-associated serine protease 2), which in turn activate the atypical serine proteases factor B and C2, which then activate the major opsonin of the system, C3. Activated C3 binds covalently to targets, and is recognized by receptors on phagocytic cells. Two of the complement proteases, factors D and I, circulate not as proenzymes, but in activated form, and they have no natural inhibitors; their substrates are transient protein complexes (e.g. C3bB and C3bH) which form during complement activation. Factor B and C2 also have no natural inhibitor; they are active only when proteolytically cleaved and bound in an unstable, short-lived complex with C3b or C4b. C1r, C1s and the MASPs, in contrast, are regulated more conventionally by the natural serpin, C1-inhibitor. Complement proteases in general have very narrow specificity, and low substrate turnover with both natural and synthetic substrates. Excessive activation of complement is inflammatory, and causes tissue damage (e.g. in rheumatoid arthritis, or in ischaemia/reperfusion injury). Substances that regulate complement activation are likely to be useful in the regulation of inflammation. Complement activation might potentially be controlled at many different steps. Much attention has been focused on controlling the formation or activity of the protease complexes C3bBb and C4b2a (containing activated factor B and C2 respectively), as these generate the inflammatory peptides C3a and C5a.

Complement Activation↗
PubMed1987

Aspects of C1-inhibitor biochemistry and pathophysiology.

During the last few years, the structure and function of human C1-inhibitor have been elucidated. Chromogenic substrate assays for determination of C1-inhibitor activity in plasma are available, and have proved to be of value not only for the diagnosis of hereditary angioedema but also in acquired diseases involving C1-inhibitor, such as cold urticaria and autoimmune disorders as well as acute-phase types of disease states.

Complement C1 Inactivator Proteins↗
PubMed2000

The effect of C1-esterase inhibitor in definite and suspected streptococcal toxic shock syndrome. Report of seven patients.

OBJECTIVE: To evaluate the effect of adjunctive C1-esterase inhibitor substitution therapy on clinical characteristics and outcome of patients with streptococcal toxic shock syndrome (TSS). DESIGN: Observational. SETTING: Medizinische Poliklinik, University of Bonn, Germany. PATIENTS: Seven patients with direct or indirect evidence of streptococcal TSS. INTERVENTION: In addition to conventional and supportive therapy, all patients received 2-3 single doses of C1-esterase inhibitor totaling 6,000-10,000 U within the first 24 h after admission. MEASUREMENTS AND RESULTS: All patients developed fulminant septic shock, multiorgan failure and/or capillary leak syndrome and necrotizing fasciitis within 10-72 h following the onset of first symptoms. Between 1 and 4 days following administration of C1-esterase inhibitor, a marked shift of fluid from extravascular to intravascular compartments took place in all but one patient, accompanied by a transient intra-alveolar lung edema and rapidly decreasing need for adrenergic agents. Six of seven patients survived. CONCLUSIONS: These clinical observations in a small series of patients and the favorable outcome point towards a positive effect of early and high-dose administration of C1-esterase inhibitor as adjunctive therapy in streptococcal TSS. The possible mechanism involved may be the attenuation of capillary leak syndrome (CLS) via early inactivation of complement and contact systems. Controlled studies are needed to establish an improvement of the survival rates of patients with streptococcal TSS following administration of C1-esterase inhibitor.

Adult↗
PubMed1983

Inactivation of kallikrein in human plasma.

Human plasma kallikrein is inactivated by plasma protease inhibitors. This study was designed to determine the nature of these protease inhibitors and to assess their relative importance in the inactivation of kallikrein. Therefore, the kinetics of kallikrein inactivation and the formation of kallikrein inhibitor complexes were studied in normal plasma and in plasma depleted of either alpha 2-macroglobulin (alpha 2M), C1 inhibitor, or antithrombin (AT III). Prekallikrein was activated by incubation of plasma with dextran sulfate at 4 degrees C. After maximal activation, kallikrein was inactivated at 37 degrees C. Inhibition of kallikrein amidolytic activity in AT III-deficient plasma closely paralleled the inactivation rate of kallikrein in normal plasma. The inactivation rate of kallikrein in alpha 2M-deficient plasma was slightly decreased compared with normal plasma, but in contrast to normal, C1 inhibitor-deficient, and AT III-deficient plasma, no kallikrein amidolytic activity remained after inactivation that was resistant to inhibition by soybean trypsin inhibitor. Suppression of kallikrein activity in C1 inhibitor-deficient plasma was markedly decreased, and this was even more pronounced in plasma deficient in both C1 inhibitor and alpha 2M. The pseudo first-order rate constants for kallikrein inactivation in normal, AT III-deficient, alpha 2M-deficient, C1 inhibitor-deficient plasma, and plasma deficient in both alpha 2M and C1 inhibitor, were 0.68, 0.60, 0.43, 0.07, and 0.016 min-1, respectively. Sodium dodecyl sulfate gradient polyacrylamide slab gel electrophoresis showed that during inactivation of kallikrein in plasma, high-Mr complexes were formed with Mr at 400,000-1,000,000, 185,000, and 125,000-135,000, which were identified as complexes of 125I-kallikrein with alpha 2M, C1 inhibitor, and AT III, respectively. In addition, the presence of an unidentified kallikrein-inhibitor complex was observed in AT III-deficient plasma. 52% of the 125I-kallikrein was associated with C1-inhibitor, 35% with alpha 2M, and 13% with AT III and another protease inhibitor. A similar distribution of 125I-kallikrein was observed when the 125I-kallikrein inhibitor complexes were removed from plasma by immunoadsorption with insolubilized anti-C1 inhibitor, anti-alpha 2M, or anti-AT III antibodies. These results suggest that only covalent complexes are formed between kallikrein and its inhibitors in plasma. As a function of time, 125I-kallikrein formed complexes with C1 inhibitor at a higher rate than with alpha 2M. No difference was observed between the inactivation rate of kallikrein in high-Mr kininogen-deficient plasma and that in high-Mr kininogen-deficient plasma reconstituted with high-Mr kininogen; this suggests that high-Mr kininogen does not protect kallikrein from inactivation in the plasma milieu. These results have quantitatively demonstrated the major roles of C1 inhibitor and alpha 2M in the inactivation of kallikrein in plasma.

Complement C1 Inactivator Proteins↗
PubMed1987

Hydrolysis of human high-molecular-mass kininogen by human plasma kallikrein. Proposal of a new model concept for the course of reaction in presence and absence of C1(-)-inhibitor.

Hydrolysis of high-molecular-mass kininogen was studied by following the changes in the amounts of substrate, intermediates and products as a function of time using quantitative polyacrylamide-gel electrophoresis (silver staining). The experimental data was analysed on the basis of the concept that the overall reaction is composed of three hydrolysis reactions, two positional-change processes of intermediates at the active site, and two product-substrate exchange processes. It is proposed C1(-)-inhibitor to form two types of complexes with kallikrein, one with non-covalent and one with covalent bonds. With an adequately chosen set of reaction-partner concentrations and four different kinds of experimental conditions with respect to kininogen and inhibitor addition to kallikrein, the following results were obtained: 1) Non-covalently bound inhibitor has no effect on the first and the second hydrolysis reaction, but efficiently interferes with the third hydrolysis reaction; 2) Nicked kininogen (first intermediate; one of the two bradykinin bonds split) for the second bond to be hydrolysed undergoes a positional change during which it remains strongly bound to the enzyme, never exchanges with kininogen, and is not displaced by non-covalently bound inhibitor; 3) Intermediate kinin-free kininogen (second intermediate; both bradykinin bonds split and bradykinin released) prior to turning over into stable kinin-free kininogen (final product; histidine-rich fragment split off and released) undergoes a positional change involving dissociation and reassociation so that non-covalently bound inhibitor finds access to the active site; 4) Intermediate kinin-free kininogen to sustain multiple turnovers exchanges with kininogen via a stable complex of such structure that during this process non-covalently bound inhibitor cannot or can only slightly interfere; 5) Stable kinin-free kininogen to sustain multiple turnovers exchanges with intermediate kinin-free kininogen via free enzyme with the effect that non-covalently bound inhibitor efficiently interferes; 6) As hydrolysis proceeds more and more inhibitor becomes covalently bound, gradually leading to complete inactivation of the enzyme.

Bradykinin↗
PubMedDate not supplied

Laparoscopic splenectomy in a patient with acquired angioneurotic edema.

BACKGROUND: We report the case of a 77-year-old female with acquired angioneurotic edema, C1 esterase inhibitor level = 4mg/dL, who was scheduled to undergo laparoscopic splenectomy. METHODS: In the operating room, we administered on call 500 units (UI) of C1 esterase inhibitor concentrate intravenously. Intraoperative hemodynamic instability and generalized blood oozing improved following the administration of aprotinin 250000 UI intravenous (IV) drip. CONCLUSION: We recommend the administration of an antifibrinolytic agent in addition to C1 esterase inhibitor concentrate in patients with acquired angioneurotic edema.

Aged↗