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Results for “Complement C1 Inhibitor Protein”

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PubMed1977

Purification and some properties of rabbit C1 inactivator.

C1 inactivator (C1 INA) was highly purified from rabbit serum. C1 INA thus purified was a single polypeptide chain with a molecular weight of 105,000 or 140,000, as estimated by SDS-polyacrylamide gel electrophoresis or gel filtration on Sephadex G-200, respectively. It inhibited rabbit and also human C1, when the C1 activities were measured in terms of hydrolyses of acetylglycyl-L-lysine methylester, N-alpha-acetyl-L-arginine methylester and N-alpha-acetyl-L-tyrosine ethylester. These properties showed that rabbit C1 INA bears a marked structural similarity to human C1 INA. Furthermore, rabbit C1 INA was capable of inhibiting similarly both rabbit C1s and its active fragment lacking a half of the H chain of C1s, indicating that deletion of a half of the H chain did not affect the susceptibility of C1s to the inhibitory activity of C1 INA.

Animals↗
PubMed1999

Complement and contact activation related to surfactant response in respiratory distress syndrome.

The activation of inflammation and coagulation cascades is part of the pathogenesis of adult respiratory distress syndrome (RDS). Previous studies have demonstrated contact activation in preterm infants with RDS, whereas no concordant results have been found with complement activation. In this study, both systems were investigated in preterm infants with severe RDS and related to surfactant response. Thirty preterm newborns with severe respiratory distress (FiO2 > 0.5), but with no evidence of infection or fetal acidosis, were studied. Eighteen healthy preterm newborns of similar gestational age and birth weight served as controls. The study group was divided into two subgroups, according to their response to a porcine natural surfactant 6 h after administration: responders (FiO2 reduction > 50%) and poor responders (FiO2 reduction < or = 50%). C1q, C4, factor B, C3a, C5a, complement, and C1-inhibitor activity, as well as factor XIIa, were determined in blood samples, drawn 24 h after birth. Except for C1-inhibitor concentration and C1-inhibitor activity, all parameters for infants with severe RDS were different from controls. Complement precursor proteins were lower, and activated split products of the complement and contact system were higher. Infants with a poor response after application of surfactant showed higher amounts of C3a, C5a, and factor XIIa but lower C1q and C4 levels compared with infants with a good response to surfactant. Activation of the complement and the contact system was demonstrated in all respiratory distress patients. This activation was more pronounced in poor responders to exogenous surfactant.

Complement Activation↗
PubMed1995

Complement C1 inhibitor is produced by brain tissue and is cleaved in Alzheimer disease.

C1 inhibitor was identified in human brain tissue by Western blotting and by immunohistochemistry using multiple antibodies to the native protein. The presence of C1 inhibitor mRNA was identified by reverse transcriptase-polymerase chain reaction analysis of brain mRNA extracts. The mRNA was also detected in cultured postmortem human microglia and in the IMR-32 human neuroblastoma cell line. Immunohistochemically, the native protein was detected in residual serum of capillaries and pyramidal neurons of both control and Alzheimer disease cases, as well as in occasional senile plaques of Alzheimer tissue. The reacted protein was detected on dystrophic neurites and neuropil threads in Alzheimer tissue by 4C3 monoclonal antibody, which recognizes a neoepitope following suicide inhibition. These data indicate that C1 inhibitor, a regulatory molecule controlling multiple inflammatory proteolytic cascades, is produced in normal brain. In Alzheimer disease, C1 inhibitor undergoes a prominent reaction in abnormal neuronal processes, such as dystrophic neurites and neuropil threads.

Alzheimer Disease↗
PubMed1999

Proteases and protease inhibitors in taurocholate-induced acute pancreatitis in rats.

CONCLUSION: Taurocholate-induced acute pancreatitis (AP) in the rat mimics early necrotizing human pancreatitis. Protease activation and protease inhibitor consumption occur consistent with a two-stage development, and contact-phase activation is a possible primary event in this model. BACKGROUND: Proteases and protease inhibitors have been indicated to play an important role in both human and experimental acute pancreatitis, although little is known about them in rats. METHODS: Three percent sodium taurocholate was infused into the bilio-pancreatic duct to induce AP, and over 0-72 h we measured lipase, amylase, albumin, prekallikrein, factor X, alpha-1-macroglobulin, alpha-2-antiplasmin, antithrombin III, alpha-1-protease inhibitor, and C1-esterase inhibitor (all in plasma) and histologic and macroscopic findings. RESULTS: A severe necrotizing, nonlethal, AP was induced with an early increase in plasma lipase and alpha-amylase activity levels and peritoneal exudate followed by a return to near control levels after 72 h. Histologic score and pancreatic wet weight ratio increased initially and remained high during the observation period. The protease inhibitors C1-esterase inhibitor, alpha-2-antiplasmin, and antithrombin III decreased early, within 0-6 h, whereafter levels normalized. The protease inhibitors alpha-1-macroglobulin and alpha-1-protease inhibitor later gradually decreased over the 72 h.

Animals↗
PubMed2006

Complement activity and pharmacological inhibition in cardiovascular disease.

While complement is the most important component of humoral autoimmunity, and inflammation plays a key role in atherosclerosis, relatively few studies have looked at complement implications in atherosclerosis and its complications. C-reactive protein is a marker of inflammation and is also involved in atherosclerosis; it activates complement and colocalizes with activated complement proteins within the infarcting myocardium and the active atherosclerotic plaques. As new agents capable of modulating complement activity are being developed, new targets for the management of atherosclerosis are emerging that are related to autoimmunity and inflammation. The present paper reviews the putative roles of the various complement activation pathways in the development of atherosclerosis, in ST segment elevation and non-ST segment elevation acute coronary syndromes, and in coronary artery bypass graft surgery. It also provides a perspective on new therapeutic interventions being developed to modulate complement activity. These interventions include the C1 esterase inhibitor, which may be consumed in some inflammatory states resulting in the loss of one of the mechanisms inhibiting activation of the classical and lectin pathways; TP10, a recombinant protein of the soluble complement receptor type 1 (sCR1) which inhibits the C3 and C5 convertases of the common pathway by binding C3b and C4b; a truncated version of the soluble complement receptor type 1 CRI lacking the C4b binding site which selectively inhibits the alternative pathway; and pexelizumab, a monoclonal antibody selectively blocking C5 to prevent the activation of the terminal pathway that is involved in excessive inflammation and autoimmune responses.

Angina, Unstable↗
PubMed1994

Synthetic polysulfated hyaluronic acid is a potent inhibitor for tumor necrosis factor production.

Based on the premise that naturally occurring glycosaminoglycans could serve as building blocks for synthesizing nontoxic drugs for suppression of tumor necrosis factor (TNF) production by inflammatory cells, we have chemically modified hyaluronic acid (HA) and tested its effects in blocking TNF-alpha and TNF-beta production in vitro. HA was chosen mainly for its structural simplicity, nonimmunogenicity, and readiness for chemical modifications. When HA was chemically polysulfated to a sulfate/hexosamine molar ratio of 3.9, the sulfated HAs was shown to be a potent inhibitor of TNF-alpha production in lipopolysaccharide (LPS)- or interferon-gamma-activated THP-1 cells. For example, a concentration of HAs as low as 10 ng/ml reduced TNF-alpha production in LPS-activated THP-1 cells more than 50%, whereas achieving a similar extent of reduction required 50 micrograms/ml native HA. By decreasing the extent of polysulfation, the inhibitory effect of HAs on TNF-alpha production was diminished. Other chemical modifications, including deacetylation, thiolation, or reduction of the carboxylic groups, could not increase the efficacy of HA in suppression of TNF-alpha production. Naturally polysulfated glycosaminoglycans, such as chondroitin sulfates, keratan sulfate, heparan sulfate, and heparin, failed to inhibit TNF-alpha production. HAs also restricted TNF-beta (lymphotoxin) secretion in an Epstein-Barr virus-transformed B cell line, Roha-9, which constitutively produces TNF-beta. HAs had no inhibitory effect on the proliferation of THP-1 or Roha-9 cells, which would account for the reduced TNF-alpha or TNF-beta production. Furthermore, time-course metabolic labeling studies revealed that HAs could not restrict overall protein synthesis and secretion in THP-1 cells. However, HAs increased complement C1q secretion in THP-1 in a dose-dependent manner, but it had no effect on biosynthesis of complement C1 inhibitor, factor D, and Fc gamma receptor type II (Fc gamma RII). These results indicate that HA, selectively restricts the production of TNF-alpha, TNF-beta, and probably several other protein species.

Cell Division↗
PubMed1989

Studies on contact activation: effects of surface and inhibitors.

Contact activation is initiated when the plasma proteins, Hageman factor (factor XII), prekallikrein and high molecular weight kininogen interact with negatively charged materials. The activation of the intrinsic pathway of blood coagulation and the production of bradykinin are among the sequelae of contact activation. The kinetics of the activation of the contact system are modified by plasma inhibitors, C1 inhibitor being quantitatively the most important. We propose that the activation of the system requires that the stimulus provided by the surface must be greater than a threshold value to overcome the effects of the inhibitors. We show in this paper that the amount of surface required for activation is much reduced in the absence of C1 inhibitor (Hereditary Angioedema) or in the cold where the inhibitor loses much of its effectiveness. Antithrombin III inhibition of activated Hageman factor is augmented by heparin which is also an activator of Hageman factor. The rate constants for inhibition remain much lower than for C1 inhibitor, however.

Antithrombin III↗
PubMed1987

Purification of a proteinase inhibitor from bovine serum with C1-inhibitor activity.

This report describes the purification of a novel proteinase inhibitor from bovine serum. This protein was purified to apparent homogeneity employing affinity binding to sulfated dextran and precipitation by ammonium sulfate, followed by sequential chromatography on DEAE-cellulose, heparin-Sepharose and Sephacryl S-200. Quantitative enzyme-linked immunosorbent assays revealed that the concentration of this inhibitor is approximately 3 microM in bovine serum. The inhibitor is a single polypeptide chain with an estimated Mr of 83,000 as determined by SDS-polyacrylamide gel electrophoresis. An aspartic acid was found at the amino terminus of the protein; N-terminal amino acid sequence data indicated that there was no significant homology with other reported amino acid sequences. This bovine inhibitor covalently complexed the human proteinases C1-r, C1-s, factor XIIa and plasma kallikrein, which are also complexed and inactivated by human C1-inhibitor. In addition, the bovine inhibitor complexed and inactivated bovine chymotrypsin, a feature which functionally distinguishes it from human C1-inhibitor. Although the bovine inhibitor appears functionally very similar to C1-inhibitor, we found no evidence for structural homology with the human counterpart.

Amino Acid Sequence↗