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PubMed1999

Effect of C1-inhibitor in a rat model of necrotizing enterocolitis.

Our aim was to investigate the effect of C1-inhibitor (C1-INH) in a rat model of necrotizing enterocolitis (NEC). Twenty-four anesthetized and artificially ventilated rats received 0.1 mg/kg endotoxin. Fifteen minutes later, the animals in the study group (n = 12) were treated with 200 IU/kg C1-INH whereas the control animals (n = 12) received normal saline. In all animals, FiO(2) was reduced after 90 min from 0.21 to 0.05 and ventilation continued until 180 min or death. All animals developed shock symptoms. Drop in mean arterial blood pressure was more pronounced and survival time was shorter in the control group. Whereas the C1-INH activity increased in the study group, it decreased in the control group. The extent of macroscopic intestinal lesions did not differ between the groups. In conclusion, C1-INH did not prevent shock, but mitigated and delayed its course.

Animals↗
PubMed1985

Characterization of C1q, C1s and C-1 Inh synthesized by stimulated human monocytes in vitro.

C1q, C1s and C1 Inh synthesized and secreted by human monocytes were characterized by SDS-PAGE. C1q is formed of three chains A (Mr approximately 35 000), B (Mr approximately 33 000) and C (Mr approximately 25 000) which are associated in two subunits A-B and C-C. It appears identical to C1q purified from plasma. C1s is secreted as a non-activated, monocatenar protein of Mr approximately 87 000 identical to proenzymic C1s from plasma. Secreted C1 Inh (Mr approximately 100 000) has a slightly higher Mr than purified plasmatic C1 Inh. Monensin treatment of the cells favours the intracytoplasmic accumulation of products at various glycosylation stages.

Cells, Cultured↗
PubMed1993

Endotoxin-induced pulmonary dysfunction is prevented by C1-esterase inhibitor.

In septic shock, hypotension, disseminated intravascular coagulation, and neutrophil activation are related to the activation of the blood coagulation contact system. This study evaluates in dogs the effect of the C1-esterase inhibitor (C1-INH), a main inhibitor of the blood coagulation contact system, on the cardiovascular and respiratory dysfunction associated with endotoxic shock. Two groups were included: controls, which received Escherichia coli endotoxin, and a C1-INH group in which C1-INH was infused before E. coli endotoxin administration. In both groups, endotoxin produced hypodynamic shock; however, the decrease in the systolic index and the ventricular systolic work indexes were greater in controls than the C1-INH group. In controls, the arterial O2 partial pressure decreased by 30% and the alveolo-arterial O2 difference increased by 625%, these parameters remained unchanged in the C1-INH group. Hypoxemia was associated with increased intrapulmonary shunt, decreased blood coagulation contact factors, and decreased C3c. In contrast, C1-INH administration prevented endotoxin-induced hypoxemia, the increase in intrapulmonary shunt, and the decrease in blood coagulation contact factors. This study shows that, in dogs with endotoxic shock, pulmonary dysfunction is associated with an activation of the blood coagulation contact phase system. An inhibition of this system by C1-INH prevented the hypoxemia induced by endotoxic shock.

Animals↗
PubMed2004

Phosphorylation by cAMP-dependent protein kinase is essential for synapsin-induced enhancement of neurotransmitter release in invertebrate neurons.

Synapsins are synaptic vesicle-associated phosphoproteins involved in the regulation of neurotransmitter release and synapse formation; they are substrates for multiple protein kinases that phosphorylate them on distinct sites. We have previously found that injection of synapsin into Helix snail neurons cultured under low-release conditions increases the efficiency of neurotransmitter release. In order to investigate the role of phosphorylation in this modulatory action of synapsins, we examined the substrate properties of the snail synapsin orthologue recently cloned in Aplysia (apSyn) for various protein kinases and compared the effects of the intracellular injection of wild-type apSyn with those of its phosphorylation site mutants. ApSyn was found to be an excellent in vitro substrate for cAMP-dependent protein kinase, which phosphorylated it at high stoichiometry on a single site (Ser-9) in the highly conserved domain A, unlike the other kinases reported to phosphorylate mammalian synapsins, which phosphorylated apSyn to a much lesser extent. The functional effect of apSyn phosphorylation by cAMP-dependent protein kinase on neurotransmitter release was studied by injecting wild-type or Ser-9 mutated apSyn into the soma of Helix serotonergic C1 neurons cultured under low-release conditions, i.e. in contact with the non-physiological target neuron C3. In this model of impaired neurotransmitter release, the injection of wild-type apSyn induced a significant enhancement of release. This enhancement was virtually absent after injection of the non-phosphorylatable mutant (Ser-9-->Ala), but it was maintained after injection of the pseudophosphorylated mutant (Ser-9-->Asp). These functional effects of apSyn injection were paralleled by marked ultrastructural changes in the C1 neuron, with the formation of extensive interdigitations of neurite-like processes containing an increased complement of C1 dense core vesicles at the sites of cell-to-cell contact. This structural rearrangement was virtually absent in mock-injected C1 neurons or after injection of the non-phosphorylatable apSyn mutant. These data indicate that phosphorylation of synapsin domain A is essential for the synapsin-induced enhancement of neurotransmitter release and suggest that endogenous kinases phosphorylating this domain play a central role in the regulation of the efficiency of the exocytotic machinery.

Animals↗
PubMed1984

The role of immune complexes in the activation of the first component of human complement.

Immune complex-induced C1 activation and fluid phase C1 autoactivation have been compared in order to elucidate the immune complex role in the C1 activation process. Kinetic analyses revealed that immune complex-bound C1 activates seven times faster than fluid phase C1 spontaneously activates. The rate of spontaneous C1 activation increased after decreasing the solution ionic strength. In fact at one-half physiologic ionic strength (i.e., 0.08 M), the kinetics of spontaneous C1 activation were indistinguishable from the kinetics of activation of immune complex-bound C1 at physiologic ionic strength. The enhanced fluid phase C1 activation at low ionic strength resulted neither from C1 nor C1q aggregation, nor from selective effects on the C1r2S2 subunit; however, at the reduced ionic strength, the C1 association constant (defined for C1q + C1r2S2 in equilibrium C1qr2S2) did increase to 2.3 X 10(8) M-1, which is equal to that for C1 bound to an immune complex at physiologic ionic strength. Therefore, C1 can spontaneously activate in the fluid phase as rapidly as C1 on an immune complex when the strength of interaction between C1q and C1r2S2 is the same in both systems. In conclusion, under physiologic conditions, C1q and C1r2S2 are two weakly interacting proteins. Immune complexes provide a site for the assembly of a stable C1 complex, in which C1q and C1r2S2 remain associated long enough for C1q to activate C1r2S2. Thus, immune complexes enhance the intrinsic C1 autoactivation process by strengthening the association of C1q with C1r2S2.

Antigen-Antibody Complex↗
PubMed1992

[Hereditary angioedema. Control and treatment in 7 cases].

Hereditary angioedema (HAE) is due to a deficit of the C1 inhibitor (C1 INH) of a dominant autosomic inheritance. Seven patients are presented from a family with HAE, four of whom with poor prognosis due to the frequency and site of the angioedema. Prophylaxis was obtained with long-term danazol since antifibrinolytic drugs are not efficient in the prevention of outbreaks of angioedema. In three cases a concentrate of C1 INH was administered and in another as short term prophylaxis prior to surgery. C1 INH was more efficient under these indications than fresh plasma or antifibrinolytic drugs.

Adult↗
PubMed1989

Monocyte C1-inhibitor synthesis in patients with C1-inhibitor deficiency.

Monocytes of seven out of eight patients with type 1 C1-inhibitor (C1-inh) deficiency (HAE) produced 40% as much C1-inh as monocytes from normal donors (controls). In contrast, monocytes from three patients with type 2 and three patients with acquired C1-inh deficiency produced similar amounts of C1-inh as controls. Recombinant gamma-interferon (gamma-interferon 10 ng/ml) stimulated C1-inh production of C1-inh (eight-10-fold) by control and patients' monocytes. Monocytes from patients with type 1 HAE contained 40% the level of C1-inh messenger ribonucleic acid (mRNA) found in control monocytes. Gamma-interferon increased the abundance of C1-inh mRNA by the same extent in both control and patients' monocytes. C1-inh protein and mRNA were undetectable in the monocytes of one patient, unless stimulated by gamma-interferon. Under these conditions, his monocytes produced comparable amounts of C1-inh (protein and mRNA) as gamma-interferon-stimulated monocytes of the other type 1 HAE patients. The data suggest that in most type 2 HAE patients there is a lesion in the C1-inh gene such that mRNA is transcribed by a single allele.

Angioedema↗
PubMed2004

[Hereditary angioedema of delayed onset].

Hereditary angioedema is a disorder characterized by episodes of angioedema of the skin, respiratory and gastrointestinal tract resulting from a defect in the C1 esterase inhibitor. The disease is hereditary. Inheritance is autosomal dominant with incomplete penetration. We report a 56-year-old man with edema in different locations as forearm, testicles and palms. It started recently. The study showed low levels of C4, and C1 inhibitor. He was diagnosed of hereditary angioedema and it was necessary the family study.

Age of Onset↗
PubMed1992

Dynamic equilibria between subcomponents of C1, the first component of human complement.

C1r and C1s, the serine protease components of activated C1, form a tetramer in the presence of Ca2+. The stability of this tetramer is sufficient that its association with the third component, C1q, has been successfully treated as a reversible bimolecular equilibrium reaction [Siegel and Schumaker, Molec. Immun. 20, 53-66 (1983)]. We have used the fluorescence anisotropy (A) of fluorescein-labeled C1s (s*) to monitor assembly and subcomponent exchange in 0.15 mol/l NaCl, 0.001 mol/l Ca2+ 0.02 mol/l Tris, pH 7.4. Addition of q to r2s*2 causes a small but measurable delta A of 0.01-0.02. The response is too fast to measure at 37 degrees but can be readily followed at 4 degrees where t 1/2 = 0.6 min when [q] = [r2s*2] = 0.5 mumol/l. The increase in A can be readily reversed by dilution or by addition of unlabeled C1s. Slow incremental addition of q to a solution of r2s*2 produces a dose-dependent delta A from which stoichiometry and dissociation constants can be derived. Measurements of Kd as a function of temperature establish an inverse temperature dependence with delta H = -15 kcal/mol and a value of Kd = 0.031 mumol/l at 37 degrees (delta G = + 11, T delta S = -26 kcal/mol). Thus, the assembly process appears to be entropy-driven presumably due to the exclusion of structured water from protein-protein interfaces in the complex.

Complement C1r↗
PubMed1998

A randomized, controlled trial to study the efficacy and safety of C1 inhibitor concentrate in treating hereditary angioedema.

BACKGROUND: No effective treatment exists in the United States for acute attacks of hereditary angioedema (HAE). STUDY DESIGN AND METHODS: To evaluate the efficacy and safety of C1 inhibitor concentrate in treating HAE, a large primary care and referral center hospital conducted a randomized, placebo-controlled, double-blind trial with intent-to-treat analysis. Of the 36 patients enrolled in the study, 23 received treatment, and 22 completed the trial. C1 inhibitor concentrate or albumin (placebo) infusions were administered in a blind fashion to HAE patients who came to the hospital for treatment no later than 5 hours after an attack began. RESULTS: Relief was almost twice as fast in persons receiving C1 inhibitor concentrate than in the controls: 7.62 hours (mean; SD 7.08) versus 15.35 hours (mean; SD 8.31), respectively. The difference for time-to-relief was highly significant (p = 0.007, Mann-Whitney U test). The median time-to-relief was 6.17 hours (interquartile range 0.33-15.35) in the treatment group and 15.35 hours (interquartile range 14.00-22.83) in the control group. Resolution of symptoms was one-third faster in the C1 inhibitor concentrate group than in the placebo group: 23.98 hours (mean; SD 14.81) and 34.58 hours (mean; SD 13.56), respectively (p = 0.09, Mann-Whitney U test). Recovery of functional C1 inhibitor was 119.65 percent (mean; SD 50.80), and half-life was 37.87 hours (mean; SD 19.75). Recovery of antigenic C1 inhibitor was 147.75 percent (mean; SD 97.68), and half-life was 24.01 hours (mean; SD 9.70). There were no viral infections or serious adverse effects from the drug after 70 attacks in the treatment group and 96 attacks in the control group. CONCLUSIONS: C1 inhibitor concentrate is a safe, effective treatment for acute attacks of HAE.

Acute Disease↗
PubMed2002

A multicentre evaluation of the diagnostic efficiency of serological investigations for C1 inhibitor deficiency.

AIM: To determine the diagnostic efficiency of assays routinely used in the investigation of hereditary angio-oedema. METHODS: Over a four year period, 1144 samples were received for analysis from 907 patients suspected of C1 inhibitor deficiency. Analyses were performed for C4 and C1 inhibitor (functional and immunochemical). Notes were reviewed retrospectively on patients with low serological indicators to determine diagnosis. RESULTS: These are the first data to indicate the sensitivity, specificity, and predictive values of the assays most frequently used to screen for C1 inhibitor deficiency. A combination of low C4 and low C1 inhibitor function has 98% specificity for C1 inhibitor deficiency in this population and a 96% negative predictive value, and is thus a very effective screen. All patients with untreated C1 inhibitor deficiency had a low C4 value. CONCLUSIONS: All patients considered for a diagnosis of C1 inhibitor deficiency should have serum examined to measure both C4 and functional C1 inhibitor. If either is normal at presentation this essentially excludes a diagnosis of C1 inhibitor deficiency. These tests can be performed sequentially. If C4 is normal it is not necessary to proceed to C1 inhibitor analysis. If C1 inhibitor function and C4 are both low then a repeat sample should be obtained to confirm the findings.

Angioedema↗
PubMed1989

Inherited C1 inhibitor deficiency.

The paper reports our experience of a 15-year follow-up of 179 patients with hereditary angioedema (HAE). The disease is transmitted as an autosomal dominant trait and two variants have been described: type I characterized by functional and antigenic C1-inhibitor (C1-INH) deficiency and type II with normal or upper normal C1-INH antigenic levels but no functional activity. The clinical picture is characterized by self-limiting bouts of swelling in the subcutaneous and/or mucous tissues. Data about frequency, localization and possible triggering factors of HAE attacks are reported. Analysis of genomic DNA from our patients using a C1-INH cDNA probe demonstrated the presence of restriction fragment length polymorphisms tightly linked with the disease in a minority of them. Data concerning prophylaxis and treatment of HAE attacks are also shown.

Angioedema↗
PubMed1979

Diagnosis and management of hereditary angioedema (HAE).

In summary, HAE is a dominantly inherited form of angioedema which is manifested by nonpainful, nonerythematous, nonpruritic and nonpitting swelling of the extremities, face, gastrointestinal and respiratory tracts unaccompanied by urticaria. These patients have deficient activity of the C1 INH and the laboratory diagnosis can be easily made by finding low C4 and C1 inh levels during an attack. Effective and specific therapy is now available that prevents the clinical syndrome and corrects the serologic hallmarks of the disease.

Airway Obstruction↗
PubMed1990

Hormonal regulation of complement biosynthesis in human cell lines--II. Upregulation of the biosynthesis of complement components C3, factor B and C1 inhibitor by interleukin-6 and interleukin-1 in human hepatoma cell line.

The effect of interleukin (IL)-6 and IL-1 on the biosynthesis of complement components C3, factor B, C2, C4 and C1 inhibitor (C1 inh), as well as that of albumin, was studied in vitro in human hepatoma-derived cell line, HepG2. Measuring the amounts of secreted complement proteins we detected a significant upregulation of C3 by both hormones. The enhancement of the factor B and especially that of C1 inh production was predominant by IL-6. In our experimental system neither IL-1 nor IL-6 affected the biosynthesis of C2 and C4. Albumin secretion was significantly decreased only in the simultaneous presence of IL-1 and IL-6. Detection of the changes in the amounts of C3- and factor B-specific mRNA of HepG2 cells suggests a pretranslational regulation by these cytokines. The secretion of C3 and factor B was markedly potentiated when IL-1 and IL-6 were added together. However only the gene expression of factor B, but not of C3, was found to reveal synergism. IL-6 enhanced the in vitro production of C3 in mouse hepatocytes as well. This effect was greatly potentiated in the presence of histamine.

Carcinoma, Hepatocellular↗
PubMed1980

treatment of hereditary angio-oedema by low dose attenuated androgens: disassociation of clinical response from levels of C1 esterase inhibitor and C4.

Nine patients with hereditary angio-oedema (H.A.E.) with a deficiency of C1 esterase inhibitor (C1 INH), have been treated with low dose attenuated androgenic drugs, with complete control of their disease. The C1 esterase inhibitor and C4 levels became normal in only one patient. It is concluded that H.A.E. can be controlled in the absence of correction of the reduced levels of C1 INH and C4. The mode of action of these drugs appears to be more complex than is generally realized.

Adult↗
PubMed1990

Acquired C1 inhibitor deficiency: postmortem diagnosis.

Acquired C1 esterase inhibitor deficiency is a clinical syndrome closely resembling hereditary angioedema in which most patients have an associated malignancy of B cell lineage. Sera from 33 patients with B cell neoplasms were assayed for C1 esterase inhibitor level by rocket immunoelectrophoresis. The clinical summary of a patient who met the biochemical criteria for acquired C1 esterase inhibitor deficiency (low C1 esterase inhibitor, low C4) is presented. We hypothesize that this syndrome represents an autoimmune reaction involving tumor cell rejections and of potential benefit to the patient.

Adult↗