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Results for “Complement C1 Inhibitor Protein”

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PubMed1981

New synthetic inhibitors of C1r, C1 esterase, thrombin, plasmin, kallikrein and trypsin.

p-Guanidinobenzoate derivates were prepared and their inhibitory effects on trypsin, plasmin, pancreatic kallikrein, plasma kallikrein, thrombin, C1r and C1 esterase were examined. Among the various inhibitors tested, 6'-amidino-2-naphthyl-4-guanidinobenzoate dihydrochloride, 4-(beta-amidinoethenyl)phenyl-4-guanidinobenzoate dimethanesulfonate and 4-amidino-2-benzoylphenyl-4-guanidinobenzoate dimethanesulfonate were the most effective inhibitors of trypsin, plasmin, pancreatic kallikrein. plasma kallikrein and thrombin and they strongly inhibited the esterolytic activities of C1r and C1 esterase, and then strongly inhibited complement-mediated hemolysis.

Benzamidines↗
PubMed1982

Inactivation of factor XIa by plasma protease inhibitors: predominant role of alpha 1-protease inhibitor and protective effect of high molecular weight kininogen.

Factor XIa is a plasma protease that, by activating Factor IX, plays an important role in the early phase of the intrinsic pathway of blood coagulation. Four plasma protease inhibitors, alpha(1)-protease inhibitor, antithrombin III, C1-inhibitor, and alpha(2)-plasmin inhibitor, have been reported to inactivate human Factor XIa, but their quantitative contribution to the inactivation of Factor XIa in plasma has not been fully assessed. Using purified systems, we observed that the second-order rate constants for the reaction of Factor XIa with alpha(1)-protease inhibitor, antithrombin III, and CI-inhibitor were 4.08, 10, and 14.6 M(-1) min(-1) x 10(3), respectively. The pseudo-first-order rate constants, at plasma concentration of the inhibitors, were 1.86 x 10(-1), 4.68 x 10(-2), and 2.4 x 10(-2) min(-1), respectively. These kinetic data predict that alpha(1)-protease inhibitor should account for 68%, antithrombin III for 16%, and C1-inhibitor and the equipotent alpha(2)-plasmin inhibitor each for 8% of the total inhibitory activity of plasma against Factor XIa. The rate of inactivation of Factor XIa in various plasma samples specifically deficient in inhibitors was consistent with these predictions. Factor XI, the zymogen form of Factor XIa, circulates in plasma associated with the contact system cofactor, high molecular weight kininogen (HMW kininogen). Kinetic analysis indicated the existence of a reversible bimolecular Factor XIa-HMW kininogen complex with a dissociation constant (K(d)) = 0.17 muM. The light chain derived from HMW kininogen decreased the inactivation rate of Factor XIa by C1-inhibitor with a K(d) of 0.08 muM for a complex of Factor XIa and the light chain derived from HMW kininogen. The protective effect of HMW kininogen was confirmed by the finding that the inactivation rate of Factor XIa in kininogen-deficient plasma was increased over normal plasma. The present study confirms that alpha(1)-protease inhibitor is the major inhibitor of Factor XIa in plasma, and that the formation of a reversible complex between Factor XIa and HMW kininogen decreases the rate of inactivation of the enzyme by its inhibitors.

Antithrombin III↗
PubMed1984

[Hereditary angioneurotic edema: a molecular disease caused by a defect in the O-glycosylation of C1 esterase inhibitor (C1-INH)].

A quantitative and qualitative study of neutral and aminosaccharides in C 1-esterase inhibitor (C 1-INH), protein of the complement system, was performed. We observe a mixed glycosylation of the molecule with an N-glycosylated: O-glycosylated chain ratio of 1: 4. The loss of the inhibitory activity of the molecule in hereditary angioedema (O ANH) is associated with an O-glycosylation deficiency which differs according to the two molecular variants: C 1-INH (1 A) and C 1-INH (II) previously described.

Angioedema↗
PubMed1993

Differential diagnosis of human ascites: inhibitors of the contact system and total proteins.

To assess their accuracies as markers for malignancy, we assayed alpha 2-macroglobulin, C1-inhibitor, alpha 1-protease inhibitor, and total proteins in ascites and plasma from patients with gastrointestinal cancer (n = 15) and non-malignant liver disease (n = 13), using functional and immunologic assays. For all inhibitors and total proteins determined in ascites, the values in the cancer group were significantly higher than the corresponding values in the group with non-malignant liver disease. The diagnostic accuracy for differentiating malignancy-related from non-malignant ascites was 93% for a alpha 1-protease inhibitor value > or = 50% of the pool plasma value and 90% for alpha 2-macroglobulin > or = 16%, C1-inhibitor > or = 40% (all functional assays), and total proteins > or = 20 g/l (biuret). In conclusion, functional assays for alpha 2-macroglobulin, C1-inhibitor, and alpha 1-protease inhibitor and determination of total proteins in ascites appeared to be very informative tests for the differential diagnosis of ascites. The test for alpha 1-protease inhibitor gave higher specificity (92% versus 77%) and likelihood ratio for a positive test (12 versus 4) compared with the other tests.

Adult↗
PubMedDate not supplied

Cheilitis granulomatosa of Melkersson-Rosenthal syndrome: treatment with intralesional corticosteroid injections.

BACKGROUND: Melkersson-Rosenthal syndrome may manifest as the classical triad (orofacial edema, facial nerve palsy and stable lingua plicata) but monosymptomatic manifestations or combinations of typical symptoms are not infrequent. The available therapeutic options provide only limited success or temporary benefit. CASE REPORT: A 20-year-old man presented with a 7-month history of recurrent episodes of swelling of the upper lip without pain, burning or local pruritus. No causative factors, such as food, drugs or latex, or physical, chemical or emotional conditions could be identified. The patient had been treated with oral antihistamines and corticosteroids with no clinical improvement. Physical examination showed firm edema without fovea, limited to the central area of the upper lip without epidermal changes or symptoms on palpation. The patient had a previous history of facial palsy 6 years previously and recurrent episodes of herpes simplex labialis. Skin prick tests with inhalant aeroallergens, food, latex and Anisakis allergens were negative. Laboratory investigation revealed normal complete blood count, erythrocyte sedimentation rate, thyroid hormones, biochemistry, complement components (C3, C4 and C1-esterase inhibitor) and CH50, rheumatoid factor, antinuclear antibodies, immune complexes, protein electrophoresis and immunoglobulins. Thorax and paranasal sinus radiographs were clear. Biopsy of the involved area of the lip showed edema with lymphocytic and plasma cell infiltration and mononuclear perivascular infiltrates without granulomas, suggesting initial granulomatous cheilitis. Because the patient showed lack of response and/or poor tolerance to prior treatments (deflazacort, clofazimine and metronidazole), intralesional triamcinolone injections were administered with satisfactory response from the first session. CONCLUSIONS: Response to available treatments for Melkersson-Rosenthal syndrome is highly variable. In the present case, intralesional triamcinolone injections were effective.

Adult↗
PubMed1987

Kallikrein inhibition and C1-esterase inhibitor levels in patients with the lupus inhibitor.

It has been suggested that kallikrein inhibition may predispose patients with the lupus inhibitor to thrombosis by interfering with the Factor XII-mediated activation of plasminogen. To further investigate this suggestion, the authors measured kallikrein inhibition in 19 patients with the lupus inhibitor. They found that kallikrein inhibition was greater than 100% of that of a normal plasma pool in all patients and greater than 125% in 11 of 19. Kallikrein inhibition was significantly correlated with C1-esterase inhibitor (C1S-INH) concentration, which they measured by rocket immunoelectrophoresis (r = +0.55, P less than 0.05). In three patients the C1S-INH was more than 30% greater than the kallikrein inhibition. Crossed immunoelectrophoresis for C1S-INH in these patients' plasma revealed an electrophoretic mobility identical with that of the normal plasma pool. The authors suggest that C1S-INH-mediated kallikrein inhibition, in conjunction with other coagulation abnormalities, predisposes patients with the lupus inhibitor to thrombosis.

Adolescent↗
PubMed1993

Activation of the complement system in baboons challenged with live Escherichia coli: correlation with mortality and evidence for a biphasic activation pattern.

Activation of the complement system was studied in baboons that were challenged with live Escherichia coli. In the group challenged with a lethal dose (n = 4), the complement activation parameters C3b/c, C4b/c, and C5b-9 increased 13, 5, and 12 times the baseline value, respectively, during the first 6 h after the E. coli infusion, whereas in the group challenged with a sublethal dose (n = 10), they increased only moderately, by 2 to 3 times the baseline value. However, in this latter group, a more pronounced activation occurred at 24 h. Subsequent experiments showed that this second phase in complement activation started at 6 h after the challenge, at which time infused microorganisms had been cleared from the circulation. The simultaneous increase in C-reactive protein with this second phase suggested an endogenous activation mechanism involving this acute-phase protein. Levels of inactivated (modified) C1 inhibitor also increased in both groups, with peak levels of 2.5 times the baseline value at 24 h in the sublethal group and of 4 times at 6 h after the challenge in the lethal group. Thus, activation of complement in this animal model for sepsis occurs in a biphasic pattern, the initial phase mediated by the bacteria and the later phase mediated by an endogenous mechanism possibly involving C-reactive protein. The differences in complement activation between animals with lethal or sublethal sepsis support the hypothesis that complement activation contributes to the lethal complications of sepsis.

Animals↗
PubMedDate not supplied

Antiproteasic activity of C1 inhibitor. Therapeutic perspectives.

Kallikrein is a protease involved in the inflammatory process causing acute pancreatitis. Attempts to prevent this process with antiprotease agents have been successful in experimental animal models but disappointing in humans. We studied 40 consecutive patients undergoing endoscopic papillosphincterotomy. This procedure can induce a transient, moderate pancreatic inflammatory reaction, characterized by hyperamylasemia, which in 1-6% of the patients may evolve to acute pancreatitis. To assess the capacity of C1 inhibitor, the main physiological inhibitor of kallikrein, to prevent such complications, we pretreated 20 patients with 3000 U of C1 inhibitor plasma concentrate i.v.; 20 patients served as controls. Serum levels of amylase and functional C1 inhibitor were determined before the procedure and after 2, 4, 8 and 24 hours. Serum levels of amylase in the control group (146 +/- 21 IU) and in the group treated with C1 inhibitor (158 +/- 25 IU) were similar before treatment. Four and 8 hours after the end of the procedure, amylase levels were significantly lower (p < 0.001) in the treated group (231 +/- 46 and 355 +/- 104 IU) than in the control subjects (969 +/- 229 and 923 +/- 207 IU). After 24 hours both groups had normal amylase levels. In treated patients, functional levels of C1 inhibitor increased from 104 +/- 30 to 175 +/- 30% and remained elevated throughout the observation period. These data indicate that C1 inhibitor plasma concentrate can prevent hyperamylasemia following pancreas injury, probably, by inhibiting the kallikrein-mediated inflammatory process. C1 inhibitor might benefit patients at high risk of pancreatitis who undergo endoscopic papillosphincterotomy.

Acute Disease↗
PubMed1988

Synthetic peptide inhibitors of complement serine proteases--I. Identification of functionally equivalent protease inhibitor sequences in serpins and inhibition of C1s and D.

Sequence homology comparisons between serum serine protease inhibitors led to the prediction that the C-terminal sequences are functionally equivalent and represent an essential protease binding domain. Inhibition of complement serine protease D cleavage of factor B and of C1s cleavage of C4 by synthetic peptides containing sequences from the C-termini of three serum serine protease inhibitors supports this prediction. These functionally equivalent peptides represent a new class of inhibitors of D and C1s as well as other serum serine proteases.

Amino Acid Sequence↗
PubMed2000

Proteolytic activities of two types of mannose-binding lectin-associated serine protease.

Mannose (or mannan)-binding lectin (MBL) is an oligomeric serum lectin that plays a role in innate immunity by activating the complement system. In human, two types of MBL-associated serine protease (MASP-1 and MASP-2) and a truncated protein of MASP-2 (small MBL-associated protein; sMAP or MAp19) are complexed with MBL. To clarify the proteolytic activities of MASP-1 and MASP-2 against C4, C2, and C3, we isolated these two types of MASP in activated forms from human serum by sequential affinity chromatography. On an anti-MASP-1 column, MASP-2 passed through the column in the presence of EDTA and high salt concentration, whereas MASP-1 was retained. Isolated MASP-1 and MASP-2 exhibited proteolytic activities against C3 and C4, respectively. C2 was activated by both MASPs. C1 inhibitor (C1 INH), an inhibitor for C1r and C1s, formed equimolar complexes with MASP-1 and MASP-2 and inhibited their proteolytic activities.

Binding, Competitive↗
PubMed1998

Screening of concentrations of C-reactive protein and various plasma protease inhibitors preoperatively for the prediction of postoperative complications.

OBJECTIVE: To find out whether concentrations of albumin (reflecting nutritional state), C-reactive protein (reflecting an acute phase reaction) or plasma protease inhibitors (reflecting ongoing proteolysis) are good predictors of postoperative complications, and whether other biochemical tests may improve diagnostic accuracy. DESIGN: Retrospective study. SETTING: University hospital, Sweden. SUBJECTS: 260 patients undergoing elective surgery for malignant (n = 149) or benign (n = 111) disease. MAIN OUTCOME MEASURES: Preoperative biochemical plasma measurements and postoperative complications. RESULTS: 192 patients recovered uneventfully and 35 had minor and 33 major postoperative complications. An increased plasma C-reactive protein concentration preoperatively, as well as a reduced albumin concentration, predicted the risk of developing major postoperative complications. Measurement of plasma protease inhibitors (C1-esterase inhibitor, alpha-2-macroglobulin and antithrombin III), specific biochemical studies of microheterogeneity, or comparison of quantitative and functional concentrations of the inhibitors gave no additional information. CONCLUSION: One measurement of the C-reactive protein and albumin concentrations preoperatively will identify patients at risk of developing severe postoperative complications.

Adult↗
PubMed1991

[Hereditary angioedema].

Hereditary angioedema is a rare disease, transmitted as an autosomal dominant trait. The disease usually manifests as acute subcutaneous or submucosal swellings and abdominal pain of two to five days duration. When localised to head or throat life-threatening edema of the larynx may occur. The disease is caused by reduced amount of active C1 inhibitor. The edema is not due to an allergic reaction and medication for such is of little or no value. Profylactic medication may be given when the attacks are frequent and ought to be given before dental extractions, intubation of the larynx, major surgery especially of the oropharynx, and births. The acute attack is best treated by intravenous injection of C1 inhibitor concentrate.

Angioedema↗
PubMed1997

Reactivation of C1-inhibitor polymers by denaturation and gel-filtration chromatography.

C1-inhibitor is a proteinase inhibitor in the serpin family. It is an important inhibitor of complement C1, plasma kallikrein, and factor XIIa, and as such is involved in regulating inflammatory pathways. Studies on the plasma-derived protein are hampered by the relative ease with which the protein converts to an inactive state on storage, under mild denaturing conditions, or by incubating in some unfavorable buffers. This inactivation is caused by formation of soluble polymers which can be visualized on native electrophoresis. In order to facilitate studies on both the plasma-derived protein and recombinant variants planned for the future, it was necessary to devise a method for the rapid reactivation of the polymers in high yield. It was found that nonionic detergents did not dissociate the polymers, but they were readily dissociated in 0.1% SDS. Treatment with 0.1% SDS followed by rapid removal of the SDS and refolding on an FPLC Superose 6 column allowed for recovery of about 15% of the protein in the active monomeric form. Eighty-five percent eluted as a range of higher order polymers. Using 8 M urea as the denaturant a 25% yield of active monomer was recovered. However, with 6 M guanidine hydrochloride as the denaturant, the yield of active monomer was almost 50%. The remaining material was not present as a range of polymeric species but was probably a dimer. Therefore this method is a useful technique to facilitate studies on C1-inhibitor. Moreover, the ability to produce monomer, dimer, and polymer forms of C1-inhibitor is useful for studies investigating the conformational changes which have occurred in the different forms.

Chromatography, Gel↗
PubMed1983

Analysis of the effects of snake venom proteinases on the activity of human plasma C1 esterase inhibitor, alpha 1-antichymotrypsin and alpha 2-antiplasmin.

Incubation of C1 esterase inhibitor with Crotalid, Viperid and Colubrid snake venoms resulted in enzymatic inactivation of the inhibitor. Intact inhibitor (104 kDa) was converted into an active intermediate species of 89 kDa and then a further cleavage resulted in formation of an 86-kDa inactive inhibitor. In contrast, C1 esterase inhibitor did not lose activity during incubation with Elapid venoms; however, the intact inhibitor was gradually converted to an active species of 89 kDa during the incubation. Human alpha 1-antichymotrypsin was inactivated by all venoms tested, including those from the Elapid family. The 67-kDa intact inhibitor was converted by the venom proteinases to an inactive 63-kDa form. The results suggest that this acute-phase plasma protein is readily susceptible to inactivation by venom proteinases. Human alpha 2-antiplasmin (68 kDa) was cleaved to form a 61-kDa active intermediate, which then underwent a second cleavage to produce an inactive 53-kDa product. Elapid venoms had no effect on alpha 2-antiplasmin activity and did not cleave this inhibitor. All inhibitors were inactivated with catalytic amounts of venom proteinases. No stable proteinase-proteinase inhibitor complexes were detected, and no random proteolysis of the inhibitors occurred.

Animals↗