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PubMed2001

C1-esterase-inhibitor treatment at early reperfusion of hemorrhagic shock reduces mesentry leukocyte adhesion and rolling.

OBJECTIVE: Complement activation probably plays a pathogenic role in multiple organ failure in shock. This study evaluates the effects of C1-esterase-inhibitor treatment on leukocyte-endothelial interaction in the mesenteric microcirculation in hemorrhagic shock. METHODS: Rats underwent median laparotomy and exteriorization of an ileal loop for intravital microscopy of the mesenteric microcirculation. Volume controlled hemorrhagic shock was provoked by arterial blood withdrawal (2.5 mL/100 g body wt. for 60 minutes) followed by a 4-hour reperfusion period. C1-INH (100 IU/kg body wt. i.v.) or 0.9% NaCl i.v. were administered as a bolus at the beginning of reperfusion. Reperfusion time mimicked a "pre-hospital" phase of 30 minutes followed by a quasi "in-hospital" phase of 3.5 hours. The "in-hospital" phase was initiated by substitution of blood followed by fluid resuscitation with normal saline. RESULTS: Application of C1-INH markedly reduced rolling and adherent leukocytes to numbers approaching baseline values. Vmax and shear rate of the mesenteric microcirculation improved in both groups after reperfusion with a trend to higher values in the C1-INH group (n.s. p = 0.08). CONCLUSION: C1-INH applied in a bolus dose of 100 IU/kg body wt. i.v. abrogated enhanced leukocyte adhesion and rolling in the mesenteric microcirculation after hemorrhagic shock. Single bolus treatment with a complement inhibitor may provide clinical benefit when applied at an early stage of reperfusion during hemorrhagic shock.

Animals↗
PubMed1991

[Hereditary angioedema type II with predominantly abdominal symptoms].

For two years a 19-year-old patient had been complaining of recurrent abdominal symptoms consisting of severe colicky pain, nausea, vomiting and diarrhoea. Occasionally he noticed concomitant subcutaneous swellings in the limbs. There were no swellings in the face or the region of the upper airway. The symptoms occurred once or twice a month, spontaneously receding within 3-4 days. These signs and symptoms indicated hereditary angio-oedema. Serum concentration of C1-esterase inhibitor was normal (13 mg/dl), but its serum activity was reduced to 16% (normal range 80-125%). This is thus a case of type II C1-esterase inhibitor deficiency. Since starting low-dosage treatment with Danazol (initially, for two months, 200 mg daily, then 200 mg five times per week) the patient has been symptom-free.

Adult↗
PubMed1976

Treatment of hereditary angioedema with danazol. Reversal of clinical and biochemical abnormalities.

Danazol, an androgen derivative, was evaluated for its effectiveness in preventing attacks of hereditary angioedema in a double-blind study with nine patients. Of 47 placebo courses, 44 ended with attacks, but during 46 danazol courses only one attack occurred. Side effects were minimal, and virilization was not observed in the women studied. C1 esterase inhibitor levels increased three to four times, and levels of the fourth component of complement (C4) increased 15 times. These changes began during the first day of therapy and were maximal by one to two weeks. After therapy was stopped, C1 esterase inhibitor and C4 levels rapidly decreased. Danazol effectively prevents attacks in hereditary angioedema and acts to correct the underlying biochemical abnormality.

Adult↗
PubMed1986

Acquired C1 esterase inhibitor deficiency.

A case of acquired C1 esterase inhibitor deficiency and its anaesthetic implications is presented. Prophylaxis against angioneurotic oedema using danazol and tranexamic acid is described and the resultant complication of mesenteric venous thrombosis reported.

Angioedema↗
PubMed1993

Acquired C1 inhibitor deficiency revealing systemic lupus erythematosus.

We report the case of a previously healthy 54-year-old woman, without any family history, who developed an angioneurotic edema with acquired C1 inhibitor deficiency and systemic lupus erythematosus. The search for a lymphoproliferative disorder was negative. Hydroxychloroquine therapy induced simultaneous resolution of lupus and angioedema. The pathophysiology of this association is discussed.

Angioedema↗
PubMed1984

Kinin activation as a predictive assay for adverse reactions to radiographic contrast medium.

The rate of conversion in vitro, of prekallikrein to kallikrein has been measured in 74 reactors to contrast medium and 70 controls. The conversion rate is significantly more rapid in reactors than controls. There was no difference in C1-esterase inhibitor and factor XII levels between reactors and controls. This retrospective investigation suggests that prekallikrein/kallikrein conversion rate may form the basis of a test for differentiating between reactors and non-reactors.

Adolescent↗
PubMed2000

Acquired C1 esterase inhibitor deficiency.

Acquired C1 esterase inhibitor deficiency is a rare condition associated with autoimmune or low-grade lymphoproliferative disorders. Adults or elderly patients are most commonly affected. The diagnosis is suspected when patients present with recurrent angioedema and low serum levels of C4 with normal levels of C3. Low levels of C1q and low C1 esterase inhibitor activity confirm the diagnosis. In this paper, we summarize experience with 22 cases of acquired C1 esterase inhibitor deficiency in the context of a review of the published literature on diagnosis and treatment of this condition.

Adrenal Cortex Hormones↗
PubMed1989

Familial occurrence of C1-inhibitor deficiency and the effect of treatment.

Seventy one persons (67 children and 4 of their mothers) who came to the out-patient department of our hospital because of recurrent edemas of subcutaneous tissue and mucous membranes were the subjects of study. Serum haemolytic activity of complement and concentration of C1-esterase inhibitor, C1q, C4 and C3 were measured. Twenty six persons were related: altogether 12 families were studied, mostly sisters and brothers. In six patients (k 8.5% of the group studied) inherited type I defect of C1-inhibitor was detected and the diagnosis of angioneurotic edema confirmed. The results of complement determination in these patients (5 girls and 1 mother) were compared to the rest of the group and to healthy blood donors and showed clear differences in concentrations of C1-inhibitor, C1q, C4 and in haemolytic activity. Treatment consisted of fibrinolysis inhibitor, epsilon-aminocaproic acid and of antihistamine drugs. The value of this kind of therapy in the treatment of a very well responding child is discussed.

Adolescent↗
PubMed1996

[Hereditary angioneurotic edema in gynecology-obstetrics. Management].

Hereditary angioneurotic edema is a rare disease (250 cases currently identified in France). It is the most frequent among hereditary deficiencies of the complement system. This severe disease is fatal in 15-20% of the patients before 40 years of age. Death can be prevented if correct steps are taken in case of even minor trauma, which often trigger acute, potentially fatal, episodes. Danazol is used as preventive therapy before surgery and C1-esterase inhibitor or fresh frozen plasma is given for acute episodes. In case of obstetrical trauma, C1-esterase inhibitors should be used either as prophylaxy or as treatment. Fresh frozen plasma is used if C1-esterase inhibitors are not available. We report here our experience with three patients with known hereditary angioneurotic edema. Gynecology surgery was required in two.

Adult↗
PubMed2000

Therapeutic inhibition of the complement system. Y2K update.

Activation of complement is an essential part of the mechanism of pathogenesis of a large number of human diseases; its inhibition by pharmacological means is likely to suppress disease processes in complement mediated diseases. From this point of view low molecular weight synthetic inhibitors of complement are being developed and high molecular weight natural inhibitors of human origin present in plasma or embedded in cell membrane are being purified or produced in their recombinant forms. This review is concerned with high molecular weight inhibitors, some of which are already in clinical use but may be efficacious in many other diseases in which they have not yet been tried. C1-esterase inhibitor (C1-INH) concentrate prepared from human plasma is being successfully used for the treatment of hereditary angioneurotic edema. Recently, C1-INH has been found to be consumed in severe inflammation and has been shown to exert beneficial effects in several inflammatory conditions such as human sepsis, post-operative myocardial dysfunction due to reperfusion injury, severe capillary leakage syndrome after bone marrow transplantation, reperfusion injury after lung transplantation, burn, and cytotoxicity caused by IL-2 therapy in cancer. Factor I has been used for the treatment of factor I deficiency. Recombinant soluble forms of membrane cofactor protein (MCP), and decay accelerating factor (DAF) have not yet been tried in humans but have been shown to be effective in immune complex mediate inflammation in animals. Organs of pigs transgenic for one or more of human membrane regulators of complement namely membrane cofactor protein (MCP), decay accelerating factor (DAF) or CD59, are being produced for transplantation into humans. They have been shown to be resistant to hyperacute rejection in non-human primates; acute vascular rejection is still a problem in their clinical use. It is hoped that these observations together with future developments will make xeno-transplantation in clinical practice a reality. Several recombinant variants of complement receptor 1 (CR1) have been produced. The most effective of these appears to be sCR1-SLe x, sCR1 part of which inhibits complement and carbohydrate Sle x moiety inhibits selectin mediated interactions of neutrophils and lymphocytes with endothelium. Although clinical trials of sCR1 in humans is eagerly awaited, several of the recombinant versions of sCR1 have been shown to suppress ischemia/reperfusion injury, thermal trauma, and immune complex mediated inflammation. They have also been shown to be effective in experimental models of systemic sclerosis, arthritis, myasthenia gravis, Guillain Barré syndrome and glomerulonephritis. Intravenous immunoglobulin, three of the most prominent properties of which are neutralization of autoantibody activity, suppression of autoantibody production and inhibition of complement activity, is being used in several diseases. These include autoimmune thrombocyopenic purpura, Kawasaki disease and several neurological diseases such as myasthenia gravis and Guillain Barre syndrome. In many uncontrolled small scale studies intravenous immunoglobulin has been shown to be effective in many immunological including dermatological diseases; controlled clinical trials in a large number of patients with these diseases is needed to establish the efficacy. It is hoped that in future therapeutic inhibition of complement will be one of the major approaches to combat many human diseases.

Animals↗
PubMed1979

Complement abnormalities in diffuse plane xanthomatosis with paraproteinaemia.

Paraproteinaemia may be associated with xanthomatous skin deposits and these can arise in the absence of elevated lipid levels. Two cases of benign monoclonal gammopathy with diffuse plane xanthomatosis are reported. Case 1 exhibited hypolipidaemia and a functional deficiency of C1 esterase inhibitor. Case 2 showed a normal lipoprotein profile, abnormal platelet aggregation, and a cutaneous vasculitis with evidence of complement consumption via the classical pathway. The significance of these abnormalities is discussed.

Aged↗
PubMed1988

A common neoepitope is created when the reactive center of C1-inhibitor is cleaved by plasma kallikrein, activated factor XII fragment, C1 esterase, or neutrophil elastase.

The reactive center of C1-inhibitor, a plasma protease inhibitor that belongs to the serpin superfamily, is located on a peptide loop which is highly susceptible to proteolytic cleavage. With plasma kallikrein, C1s and beta-Factor XIIa, this cleavage occurs at the reactive site residue P1 (Arg444); with neutrophil elastase, it takes place near P1, probably at residue P3 (Val442). After these cleavages, C1-inhibitor is inactivated and its conformation is modified. Moreover, in vivo, cleaved C1-inhibitor is removed from the blood stream more rapidly than the intact serpin, which suggests that proteolysis unmasks sites responsible for cellular recognition and the uptake of the cleaved inhibitor. In the study reported here, we show, using an MAb, that an identical neoepitope is created on C1-inhibitor after the cleavage of its exposed loop by plasma kallikrein, C1s, beta-Factor XIIa, and by neutrophil elastase.

Animals↗
PubMed1996

Protection of porcine endothelial cells from complement-mediated cytotoxicity by the human complement regulators CD59, C1 inhibitor, and soluble complement receptor type 1. Analysis in a pig-to-human in vitro model relevant to hyperacute xenograft rejection.

Inhibition of complement activation is considered a prerequisite to overcome hyperacute xenograft rejection. In the present study, we investigated the efficacy of C1 inhibitor (C1 inh) and recombinant soluble complement receptor type 1 (rsCR1) to protect xenogeneic cells against complement-mediated cytotoxicity in an in vitro xenotransplantation model. The addition of the soluble complement regulators to human serum led to a dose-dependent inhibition of complement-mediated destruction of aortic porcine endothelial cells (PEC). On a molar base, rsCR1 was more efficient than C1 inh. Transfection of PEC with cDNA of human CD59 resulted in several clones where protection against complement-mediated cell destruction correlated with the expression level of the inhibitor. Addition of low concentrations of C1 inh and rsCR1 to a CD59 (human)-positive PEC clone, expressing a suboptimal level of the membrane-bound regulator, resulted in a significant improvement of protection against complement-mediated cell destruction.

Animals↗
PubMed1990

Studies on components of the contact phase system in patients with advanced gastrointestinal cancer.

The authors have studied components of the contact system in plasma obtained from patients with advanced gastrointestinal cancer. Plasma samples from 118 healthy blood donors served as controls. Plasma prekallikrein (PKK) values, evaluated by chromogenic peptide substrate technique, were significantly decreased in patients with cancer compared with healthy blood donors. High molecular weight kininogen (HMwK) and Hageman factor (FXII) values, assayed by immunochemical techniques, were also decreased in the patients with cancer. The changes of contact factors were most pronounced in patients with liver metastasis. The most striking observation in our study, however, was the elevated inhibitor values in patients with cancer. Alpha-2-macroglobulin (alpha 2-M) and C1 inhibitor (C1INH) values, determined both by functional and immunochemical techniques, were markedly increased in patients with cancer. In conclusion, this study shows that patients with intestinal cancer have reduced values of contact factors and markedly elevated inhibitor values which indicate that development of malignant tumors in the gastrointestinal tract is associated with changes in the contact system of plasma.

Aged↗
PubMed1995

Infusion of C1-inhibitor plasma concentrate prevents hyperamylasemia induced by endoscopic sphincterotomy.

Hyperamylasemia after endoscopic sphincterotomy is a common event, occurring in about 70% of cases. Clinical acute pancreatitis may also develop in 1% to 6% of cases. Previous attempts to prevent this reaction with inhibitors of exocrine pancreatic secretion (somatostatin and octreotide) provided conflicting and often disappointing results. Kallikrein is one of the proteases that sustain the inflammatory process in acute pancreatitis; the C1 inhibitor is the only physiologic inhibitor of the first component of the human complement cascade and is a major inactivator of kallikrein and Factor XII. Therefore, we tested the C1 inhibitor in the prevention of hyperamylasemia in 40 consecutive patients undergoing endoscopic sphincterotomy for common bile duct stones or benign papillary stenosis. They were given either C1 inhibitor (20 cases) or placebo (20 cases) before the procedure. Serum amylase levels were determined at baseline and 2, 4, 8, and 24 hours thereafter. Significant differences in serum amylase levels between groups were observed at 2 hours (p < .01), 4 hours (p < .0005), and 8 hours (p < .005) after sphincterotomy. The differences in amylase levels were also significant among the 24 subjects with pancreatic ductal filling (2 hours, p < .05; 4 hours, p < .005; 8 hours, p < .01) and the 9 patients with previous episodes of acute pancreatitis (4 hours, p < .05; 8 hours, p < .05; 24 hours, p < .05). The infusion of C1-inhibitor plasma concentrate resulted in a 50% increase in functional levels of C1 inhibitor (in the 8 cases for whom they were assayed), which persisted throughout the observation period.

Acute Disease↗
PubMed1996

Clearance of human factor XIa-inhibitor complexes in rats.

The serpins C1 esterase inhibitor (C1Inh), antithrombin (AT), alpha 1-antitrypsin (alpha 1AT) and alpha 2-antiplasmin (alpha 2AP) are known inhibitors of coagulation factor XIa (FXIa). Although initial studies suggested alpha 1AT to be the main inhibitor of FXIa, we recently demonstrated C1Inh to be a predominant inhibitor of FXIa in vitro in human plasma. The present study was performed to investigate the plasma elimination kinetics of preformed human FXIa-FXIa inhibitor complexes injected in rats. The amounts of complexes remaining in circulation were measured using enzyme-linked immunosorbent assays. The plasma half-life time of clearance (t1/2) was 98 min for FXIa-alpha 1AT complexes, whereas it was considerably shorter, i.e. 19, 18 and 15 min for FXIa-C1Inh, FXIa-alpha 2AP and FXIa-AT complexes, respectively. Thus, due to this different plasma t1/2, preferentially FXIa-alpha 1AT complexes may be detected in clinical samples. Furthermore, measuring FXIa-FXIa inhibitor complexes in patient samples may not help to clarify the relative contribution of the individual serpins to inactivation of FXIa in vivo.

Animals↗
PubMedDate not supplied

[The mechanism of inhibition of the activation of the complement first component by polyanions and polycations ].

Polyethyleneimine (PEI, 50 kDa) and polymethacrylic acid (PMA, 200 kDa) were shown to inhibit the lysis of sheep erythrocytes induced by the guinea pig complement. They twofold suppress the hemolysis at the concentrations of 0.47 and 0.89 microgram/ml, respectively. The inhibitory effect on the binding of the C1q subunit of human complement to the sensitized sheep erythrocytes (EA) was found to depend on the component of the reaction with which the inhibitors were preliminarily incubated. When an inhibitor, C1q, and EA were simultaneously incubated, the inhibition constants for PEI and PMA were 17 +/- 6 and 8.1 +/- 0.1 micrograms/ml, respectively. The preincubation of EA with PEI and the subsequent washing out of the inhibitor resulted in the inhibition constant of 22 +/- 3 micrograms/ml. No inhibitory effect was observed after a similar preincubation of EA with PMA. No inhibition was also detected when the inhibitors were added after the formation of the C1q complex with antibodies. These observations suggest that the binding of antibodies to cationic PEI prevents the C1q-antibody complex formation, while the binding of anionic PMA to the active site of C1q impedes the interaction of this subunit with immunoglobulins. Moreover, within the range of concentrations studied, the studied inhibitors did not affect the subsequent C1q binding to the C1r and C1s enzymes.

Animals↗
PubMed1996

Improvements on the purification of mannan-binding lectin and demonstration of its Ca(2+)-independent association with a C1s-like serine protease.

Mannan-binding lectin (MBL), previously called 'mannan-binding protein' or MBP, is a plasma C-type lectin which, upon binding to carbohydrate structures on micro-organisms, activates the classical pathway of complement. Purification of MBL relies on its Ca(2+)-dependent affinity for carbohydrate, but existing methods are susceptible to contamination by anti-carbohydrate antibodies. In the present study a sequential-sugar-elution method has been developed which can achieve a preparation of virtually pure MBL and its associated serine protease (MBL-associated serine protease, MASP) by two steps of affinity chromatography. In further separation of MASP from MBL, it was found that activated MASP was associated with MBL independent of Ca2+. Since MBL was found to bind to underivatized Sepharose 4B, the MBL-MASP complex was purified using Sepharose 4B and protease inhibitors were included to purify the complex with MASP in its proenzyme form. Analysis of thus-purified MBL-MASP complex by gel filtration on a Sephacryl S-300 column at pH 7.8 showed that the proenzyme MASP was also associated with MBL independently of Ca2+, but that the complex could be disrupted at a low pH (5.0). Therefore the mechanism of MBL-MASP-mediated complement activation appears to be significantly different from the C1-mediated classical pathway.

Calcium↗