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At least 667 records · Page 37Linked to original sources
PubMed1975

Complement inhibitor(s) released by leukocytes. I. Pretreatment of sheep erythrocytes with supernatants of mouse spleen and thymus cells inhibit whole complement activity and C2 utilization.

Sheep erythrocytes pretreated with supernatants of mouse spleen or thymus cells become resistant to lysis by guinea pig complement. The inhibitory activity (IA) reduces the utilization of C2 by EAC14. Because IA binds to the surface of sheep erythrocytes and does not inhibit C1 irreversibly, it is probably a hitherto undescribed inhibitor of complement.

Animals↗
PubMed1989

Pathogenic potentials of bacterial proteases.

Six separate molecular mechanisms for pathogenesis attributed to bacterial proteases are described. (I). Enhancements of vascular permeability and edema formation which result from the activation of kinin generating cascade such as Hageman factor by the proteases. (II). Degradation of defense oriented proteins including IgG and IgA as well as destruction of structural matrices such as fibronectin, proteoglycan and collagen. (III). Inactivation of complement system and generated chemotactic factor from C3 and C5. (IV). Degradation of regulatory plasma protease inhibitors (serpins) including alpha 1-protease inhibitor, alpha 2-macroglobulin (alpha 2M), C1-esterase inhibitor, alpha 2-antiplasmin and antithrombin-III. (V). The protease forms a transitory stable enzyme/inhibitor(alpha 2M) complex. It binds to and internalizes into the cells which possess alpha 2M-receptor such as fibroblasts via the alpha 2M-receptor, and the protease activity is regenerated in cells, and subsequently intracellular integrity is destroyed resulting in cell killing. (VI). The serratial 56 kDa (56K) protease is found to potential viral yield 100 fold more when influenza virus infected mice were subjected to administrations of this protease intranasally. This results in rapid and much elevated lethality.

Animals↗
PubMed2000

Hereditary angioneurotic edema and familial Crohn's disease.

A 29-year-old man with Crohn's disease involving the ileum and cecum was seen. He had angioneurotic edema with C1' esterase inhibitor deficiency. Later, his 50-year-old mother was evaluated because of abdominal pain. She had recurrent urticaria, C1' esterase inhibitor deficiency and radiographic studies showed Crohn's disease of the ileum. A maternal family history revealed other members affected with either Crohn's disease or angioneurotic edema. The clinical observations in this family suggest that angioneurotic edema associated with C1' esterase inhibitor deficiency may be closely linked genetically with a familial form of Crohn's disease.

Adult↗
PubMed1987

Inactivation of C-1 inhibitor by proteases: demonstration by a monoclonal antibody of a neodeterminant on inactivated, non-complexed C-1 inhibitor.

Monoclonal antibodies were raised against kallikrein-C-1 inhibitor and factor XIIa-C-1 inhibitor complexes. One of the monoclonal antibodies (KII) appeared to react predominantly with C-1 inhibitor complexes in an ELISA. However, the apparent binding of KII to C-1 inhibitor complexes was probably due to the presence of proteolytically inactivated C-1 inhibitor in the complex mixture used for the coating:KII did not bind either kallikrein-C-1 inhibitor or factor XIIa-C-1 inhibitor complexes generated in plasma by dextran sulphate. SDS-PAGE analysis of C-1 inhibitor incubated with proteases revealed that KII-reactive C-1 inhibitor has a lower molecular weight than native C-1 inhibitor. We propose that the determinant that reacts with KII is exposed after cleavage of C-1 inhibitor in its reactive site. The monoclonal antibody KII will enable us to study the inactivation of C-1 inhibitor in human inflammatory disease.

Antibodies, Monoclonal↗
PubMed1981

Inactivation of purified human alpha 2-antiplasmin and purified human C1 inhibitor by synthetic fibrinolytic agents.

3-Hydroxypropyl flufenamide (Flu-HPA) is one of a series of flufenamic acid derivatives that enhances blood clot lysis in vitro. Studies of possible mechanisms of action of Flu-HPA were undertaken. The profibrinolytic activity of Flu-HPA in clot lysis assays was found to be dependent on plasminogen. The influence of Flu-HPA on the ability of purified alpha 2-antiplasmin to inhibit purified plasmin was studied. Plasmin activity was determined using 125I-fibrin plates or the spectrophotometric tripeptide substrate, Val-Leu-Lys-paranitroanilide. At Flu-HPA concentrations greater than 1 mM, the inhibitory activity of alpha 2-antiplasmin was abolished in a time-dependent and concentration-dependent manner. The influence of Flu-HPA on the ability of purified Cl inhibitor to inhibit purified plasma kallikrein and beta-Factor XIIa was also studied. Cl inhibitor activity was abolished by Flu-HPA at concentrations greater than 2 mM. Notably, Flu-HPA up to 60 mM did not affect the amidolytic activities of plasmin, kallikrein, or beta-Factor XIIa. Flu-HPA did not release enzyme activity from preformed complexes of either alpha 2-antiplasmin and plasmin of Cl inhibitor and kallikrein. A water-soluble derivative of flufenamic acid, N-flufenamyl-glutamic acid, also inactivated alpha 2-antiplasm and Cl inhibitor. This inactivation was shown to be reversible. These results indicate that synthetic fibrinolytic compounds such as flufenamic acid derivatives may promote fibrinolysis by directly inactivating alpha 2-antiplasmin and Cl inhibitor.

Blood Coagulation↗
PubMed1980

[Hereditary angio-oedema: complement levels under treatment with danazol (author's transl)].

A mother and her son are described who both suffer from hereditary angiooedema. Both were treated with Danazol, a synthetic derivative of ethisterone. The prophylactic clinical effect seemed obvious, and also the serum concentration of the complement component C4, which had regularly been lower before treatment, became normal. However, no change of the serum concentration of the C1 esterase inhibitor could be demonstrated; this is in contrast to observations of other authors.

Adult↗
PubMed1997

Preoperative prophylaxis for C1 esterase-inhibitor deficiency in patients undergoing oral surgery: a report of three cases.

C1-inhibitor deficiency, or hereditary angioedema, is a genetic disorder characterized by recurrent circumscribed, nonpruritic, nonpitting subepithelial edema. Minor trauma to the tissue, such as tooth extraction, can trigger life-threatening laryngeal edema. The use of fresh frozen plasma and/or danazol before treatment prevents angioedema attacks. A critical review of the treatment regimen and prophylaxis for C1-inhibitor deficiency is presented, and three new cases are described.

Adult↗
PubMed1993

Chymotrypsin inhibitory activity of normal C1-inhibitor and a P1 Arg to His mutant: evidence for the presence of overlapping reactive centers.

C1-inhibitor is a serine proteinase inhibitor that is active against C1s, C1r, kallikrein, and factor XII. Recently, it has been shown that it also has inhibitory activity against chymotrypsin. We have investigated this activity of normal human C1-inhibitor, normal rabbit C1-inhibitor, and P1 Arg to His mutant human C1-inhibitors and find that all are able to inhibit chymotrypsin and form stable sodium dodecyl sulfate-resistant complexes. The Kass values show that the P1 His mutant is a slightly better inhibitor of chymotrypsin than normal human C1-inhibitor (3.4 x 10(4) compared with 7.3 x 10(3)). The carboxy-terminal peptide of normal human C1-inhibitor, derived from the dissociated protease-inhibitor complex, shows cleavage between the P2 and P1 residues. Therefore, as with alpha 2-antiplasmin, C1-inhibitor possesses two overlapping P1 residues, one for chymotrypsin and the other for Arg-specific proteinases. In contrast, with the P1 His mutant, the peptide generated from the dissociation of its complex with chymotrypsin demonstrated cleavage between the P1 and P'1 residues. Therefore, unlike alpha 2-antiplasmin, chymotrypsin utilizes the P2 residue as its reactive site in normal C1-inhibitor but utilizes the P1 residue as its reactive site in the P1 His mutant protein. This suggests that the reactive center loop allows a degree of induced fit and therefore must be relatively flexible.

Amino Acid Sequence↗
PubMed1992

Computerized immunoblot analyses (CIBA) of the distribution of prekallikrein and its activation products in vivo and in vitro.

The distribution of prekallikrein and the complexes of kallikrein with C1 inhibitor (C1INH), alpha 2-macroglobulin and approximately 58-kDa protein(s) (e.g. antithrombin III), differs in normal and C1INH-deficient human plasma, activated in vitro, due to different C1INH levels. Different distribution in the deficient plasma activated in vivo or in vitro, suggests different rates of complex clearance.

Antithrombin III↗
PubMed1982

Proteolytic cleavage and inactivation of alpha 2-plasmin inhibitor and C1 inactivator by human polymorphonuclear leukocyte elastase.

This study has examined the interaction between human leukocyte elastase and alpha 2-plasmin inhibitor, or C1 inactivator, inhibitors of proteases of the complement, kinin, coagulation, and fibrinolytic enzyme systems. Leukocyte elastase, in catalytic concentrations, progressively inactivates the plasmin inhibitory activity of both inhibitors. The C1s binding function of C1 inactivator is also destroyed by leukocyte elastase. The nature of the molecular events underlying the inactivation of these protease inhibitors was examined by acrylamide gel electrophoresis in the presence of sodium dodecyl sulfate. Loss of functional activity was accompanied by limited proteolytic cleavage of both inhibitors with the production of several characteristic derivative peptide chains. Leukocyte elastase cleaved alpha 2-plasmin inhibitor at two separate sites and generated lower molecular weight fragments similar to those produced by bovine beta-trypsin. C1 inactivator was hydrolyzed at three different regions on the molecule whereas beta-trypsin cleaved two regions in common with leukocyte elastase. These findings suggest that inactivation of alpha 2-plasmin inhibitor and C1 inactivator by leukocyte elastase released in the inflammatory reaction may potentiate pathological proteolysis. The limited digestion of these inhibitory proteins by leukocyte elastase may prove useful in studies of their primary structure.

Complement Activating Enzymes↗
PubMed1992

Fat-storing cells of the rat liver synthesize and secrete C1-esterase inhibitor; modulation by cytokines.

During liver fibrogenesis, fat-storing cells transform into myofibroblast-like cells and produce increasing amounts of extracellular matrix proteins. Because fat-storing cells produce alpha 2-macroglobulin, an important serine protease inhibitor (serpin), we investigated whether fat-storing cells also synthesize C1-esterase inhibitor, another important serpin. C1-esterase inhibitor synthesis was studied in rat fat-storing cells at day 0, 3 and 7 after isolation by biosynthetic labeling, immunoprecipitation and sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Messenger RNA was examined by Northern-blot analysis. C1-esterase inhibitor gene expression and synthesis were detectable in freshly isolated fat-storing cells and increased distinctly during the time in culture. The cellular source of C1-esterase inhibitor in fat-storing cell cultures was also identified by in situ hybridization of cells at different times after isolation. By inhibition of the N-glycosylation using tunicamycin, rat C1-esterase inhibitor was identified as a glycoprotein. The time course of C1-esterase inhibitor secretion was determined by pulse-chase experiments. C1-esterase inhibitor synthesis was increased 6-fold to 10-fold by interferon-gamma. Specific messenger RNA levels were also raised distinctly by this cytokine. In contrast, interferon-alpha and dexamethasone did not alter C1-esterase inhibitor gene expression. Because C1-esterase inhibitor synthesis is increased by advancing culture time and by the inflammatory mediator interferon-gamma, we suggest that fat-storing cells may enhance the deposition of extracellular matrix proteins by inhibiting their degradation.

Animals↗
PubMed1994

Protein S deficiency in lupus erythematosus secondary to hereditary angio-oedema.

We report a child with lupus erythematosus secondary to type 2 hereditary angio-oedema (HAE). Reduced levels of free protein S were found. Total protein S, and C4 binding protein (C4bp) were normal, and there was no evidence of anticardiolipin antibodies or lupus anticoagulant. We postulate that reduced levels of C4, secondary to C1 inhibitor deficiency, resulted in increased binding of protein S to C4bp, leading to reduced levels of free protein S and thus functional deficiency of protein S.

Angioedema↗
PubMed1989

CpG mutations in the reactive site of human C1 inhibitor.

C1 inhibitor plays an important role in the regulation of vascular permeability through its ability to inactivate enzymes which release polypeptide kinins. Dysfunctional C1 inhibitor molecules are present in the plasma of affected members of the Da and Ri hereditary angioneurotic edema kindreds. We constructed genomic libraries from Da and Ri patient DNAs which had been cleaved with BclI to generate a fragment containing 21 kilobases of the C1 inhibitor locus. C1 inhibitor gene-containing recombinants originating from mutant Da and Ri alleles were differentiated from those derived from normal alleles by linkage analysis using the intragenic HgiAI restriction fragment length polymorphism. Nucleotide sequencing of the complete protein-coding regions of the mutant alleles identified two different mutations in a CpG dinucleotide corresponding to the first two bases of arginine codon 444. These single base mutations changed the identity of the functionally critical P1 reactive site residue from arginine to cysteine (Da) or histidine (Ri). The additional cysteine residue in C1 inhibitor Da suggests how it is covalently bound to albumin in plasma. The presence of CpG dinucleotides in the codons specifying the P1 arginines of C1 inhibitor and antithrombin III explains the high incidence of histidine and cysteine substitutions observed among dysfunctional mutants of these serine protease inhibitors.

Alleles↗