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PubMedDate not supplied

Increased susceptibility of the left compared to the right ventricle to remote ischemia/reperfusion injury in human C1-inhibitor-overexpressing transgene mice.

Acute myocardial injury has been demonstrated as a remote sequela of severe lower torso ischemia-reperfusion (I/R) due to proinflammatory events. In a model of I/R injury, administration of C1 esterase inhibitor (C1-Inh) reduces myocardial necrosis. We investigated the susceptibility of the left (LV) versus right ventricle (RV) and the protective effect of transgenic C1-Inh-overexpressing mice. Two groups of mice (n = 6) underwent a 2-h lower torso ischemia followed by 3 h of reperfusion: transgenic and wild type with sham-operated controls. Animals were then injected with (125)I bovine albumin. Heart was removed and samples from right and left ventricular free wall were harvested, weighted, and radioactivity was determined. Permeability index for wild-type animals in the RV was 0.22 +/- 0.04, compared to 0.17 +/- 0.07 in controls (NS), and in the LV 0.36 +/- 0.08, compared to 0.21 +/- 0.05 in controls (p <.01). The LV showed a significantly higher value compared to the right (0.22 +/- 0.04 vs. 0.36 +/- 0.08, p <.01). No difference was seen in the RV between transgenic and wild-type mice; however, in the LV the values decreased significantly in transgenic animals (p <.015). Thus, remote myocardial injury after lower torso I/R is present in both ventricles; however, the LV seems to be more susceptible as assessed by albumin permeability. Inhibition of the classic complement cascade may be a promising therapeutic approach for myocardial protection in reperfusion injury.

Acute Disease↗
PubMed2004

Influence of lactation parameters on the N-glycosylation of recombinant human C1 inhibitor isolated from the milk of transgenic rabbits.

The large-scale production of recombinant biopharmaceutical glycoproteins in the milk of transgenic animals is becoming more widespread. However, in comparison with bacterial, plant cell, or cell culture production systems, little is known about the glycosylation machinery of the mammary gland, and hence on the glycosylation of recombinant glycoproteins produced in transgenic animals. Here the influence is presented of several lactation parameters on the N-glycosylation of recombinant C1 inhibitor (rhC1INH), a human serum glycoprotein, expressed in the milk of transgenic rabbits. Enzymatically released N-glycans of series of rhC1INH samples were fluorescently labeled and fractionated by HPLC. The major N-glycan structures on rhC1INH of pooled rabbit milk were similar to those on native human C1 inhibitor and recombinant human C1 inhibitor produced in transgenic mouse milk, with only the degree of sialylation and core fucosylation being lower. Analyses of individual animals furthermore showed slight interindividual differences; a decrease in the extent of sialylation, core fucosylation, and oligomannose-type glycosylation with the progress of lactation; and a positive correlation between expression level and oligomannose-type N-glycan content. However, when large quantities of rhC1INH were isolated for preclinical and clinical studies, highly consistent N-linked glycan profiles and monosaccharide compositions were found.

Animals↗
PubMed2001

The inhibition of TNK-t-PA by C1-inhibitor.

TNK-t-PA is a recombinant mutant of tissue plasminogen activator that has a longer half-life and higher selectivity for fibrin than normal tissue plasminogen activator (t-PA). In addition, it is reported to be serpin resistant because of reduced inhibition by plasminogen activator inhibitor-1. In this study, we have investigated the inhibition of TNK-t-PA by the serpin C1-inhibitor. TNK-t-PA is inhibited with a second-order rate constant of 7.5 per mol/l per s compared with 4.5 per mol/l per s for t-PA. In both cases, the stoichiometry was close to 20, indicating that C1-inhibitor was predominantly a substrate for both forms of t-PA. The formation of cleaved C1-inhibitor was seen on sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), and the t-PA-C1-inhibitor (or TNK-t-PA-C1-inhibitor) complex seen on SDS-PAGE and by zymography. Although the rates of inhibition are very slow in vitro, the fact that in vivo formation of the t-PA-C1-inhibitor complex after infusion of t-PA has been well documented suggests that TNK-t-PA will also be inhibited by C1-inhibitor in vivo and, perhaps more importantly, could cause a significant reduction in C1-inhibitor concentration.

Complement C1 Inactivator Proteins↗
PubMed2001

In vitro interaction of C1-inhibitor with thrombin.

Previous observations of increased generation of thrombin during acute attacks of angioedema in plasma of patients with C1-inhibitor (C1-INH) deficiency prompted us to evaluate the interaction of C1-INH with thrombin in both purified systems and human plasma. For this purpose, we used several methods: (1) sodium dodecyl sulfate-polyacrylamide gel electrophoresis and immunoblotting analysis; (2) enzyme-linked immunosorbent assays to measure complexes between C1-INH and thrombin and inactivated C1-INH; and (3) kinetic studies using a chromogenic assay. We found that the interaction of purified C1-INH with thrombin is associated with the formation of bimolecular complexes of molecular weight (Mr) 130 000 and 120 000 as well as with the appearance of a cleaved form of C1-INH of Mr 97 000. The kinetic studies of inhibition of thrombin by C1-INH showed an average second-order rate constant of 19/s per mol/l, which was significantly increased in the presence of heparin. The addition of thrombin to human plasma was not associated with detectable C1-INH-thrombin complex formation or with cleavage of C1-INH. In conclusion, our data demonstrate that C1-INH upon interaction with thrombin, in part, forms enzyme-inhibitor complexes and, in part, is cleaved. The low second-order rate constant and the lack of a significant interaction in plasma suggest that the inhibition of thrombin by C1-INH has a minor role in circulating blood; however, its role might be important at the endothelial surface, where high concentrations of glycosaminoglycans occur.

Complement C1 Inactivator Proteins↗
PubMed2002

C1-inhibitor in patients with severe sepsis and septic shock: beneficial effect on renal dysfunction.

OBJECTIVE: To investigate the efficacy and the safety of the parenteral administration of C1-inhibitor to patients with severe sepsis or septic shock. DESIGN: Double blind, randomized, and placebo-controlled trial. SETTING: Surgical and medical intensive care units of a tertiary care university hospital. PATIENTS: Forty consecutive patients (20 C1-inhibitor/20 placebo) who entered the intensive care unit with severe sepsis or septic shock. INTERVENTION: C1-inhibitor intravenously in a 1-hr infusion, starting with 6000 IU, followed by 3000 IU, 2000 IU, and 1000 IU at 12-hr intervals, compared with placebo. MEASUREMENTS AND MAIN RESULTS: C1-inhibitor administration significantly increased plasma C1-inhibitor antigen and activity levels during days 1-4 (p <.007). Patients in the C1-inhibitor group had significantly lower serum creatinine concentrations on day 3 (p =.048) and 4 (p =.01) than placebo patients. Multiple organ dysfunction assessed by logistic organ dysfunction and sepsis-related organ failure assessment scores was less pronounced in patients treated with C1-inhibitor. Mortality rate was similar in both groups. There were no C1-inhibitor-related side effects. CONCLUSIONS: C1-inhibitor administration attenuated renal impairment in patients with severe sepsis or septic shock.

Adult↗
PubMed2003

Autoantibodies and lymphoproliferative diseases in acquired C1-inhibitor deficiencies.

Angioedema due to acquired C1-inhibitor (C1-INH) deficiency (also referred to as "acquired angioedema") is a rare, life-threatening disease with poorly defined etiology, therapy, and prognosis. To define the profile of acquired C1-INH deficiency and to facilitate the clinical approach to these patients, we report on 23 patients with acquired C1-INH deficiency followed for up to 24 years (median, 8 yr), and review the literature. We measured C1-INH activity with chromogenic assay and detected autoantibodies to C1-INH by enzyme-linked immunosorbent assay (ELISA). Median age at onset of angioedema was 57 years (range, 39-75 yr). All patients had C1-INH function and C4 antigen below 50% of normal. C1q was reduced in 17 patients. Autoantibodies to C1-INH were present in 17 patients. Long-term prophylaxis of attacks with danazol was effective in 2 of 6 patients, and with tranexamic acid, in 12 of 13 patients. Therapy with C1-INH plasma concentrate was necessary in 12 patients: 9 had rapid positive response and 3 became progressively resistant. Associated diseases at the last follow-up were non-Hodgkin lymphomas (3 patients), chronic lymphocytic leukemia (1 patient), breast cancer (1 patient), monoclonal gammopathies of uncertain significance (13 patients). In 4 patients no pathologic condition could be demonstrated. Compared with the general population, patients with acquired C1-INH deficiency present higher risk for B-cell malignancies, but not for progression of monoclonal gammopathies of uncertain significance to malignancy. Antifibrinolytic agents are more effective than attenuated androgens in long-term prophylaxis. Patients with acquired C1-INH deficiency may be resistant to replacement therapy with C1-INH plasma concentrate.

Aged↗
PubMed2003

Hyperacute rejection of mouse lung by human blood: characterization of the model and the role of complement.

BACKGROUND: The pathophysiology of hyperacute lung rejection (HALR) is not fully understood. A mouse model of HALR by human blood would be valuable to efficiently dissect the molecular mechanisms underlying this complex process, but it has not been described. METHODS: We developed a xenogenic mouse lung-perfusion model. Perfusion with heparinized autologous blood (n=3) was compared with human blood unmodified (n=7) or pretreated with C1 inhibitor (n=5) or soluble complement receptor type 1 (n=6) at unchanged flow conditions. RESULTS: Perfusion with autologous blood was associated with stable physiologic parameters and no overt evidence of lung injury for up to 2 hr. Pulmonary artery perfusion pressure increased rapidly after introduction of unmodified human blood, plasma anti-Gal(alpha)1,3Gal antibodies declined (90% immunoglobulin [Ig]M, 80% IgG), and lungs reliably met survival endpoints within 11 min (median 10 min, confidence interval [CI]: 9-11). Human Ig and neutrophils were rapidly sequestered in the lung. Survival was significantly prolonged in the soluble complement receptor type 1 group (36 min, CI: 26-46) (P<0.01) and in the C1 inhibitor group (23 min, CI: 21-25) (P<0.05), and pulmonary vascular resistance elevation and complement activation were significantly attenuated but not prevented. CONCLUSIONS: Hyperacute rejection of mouse lung by human blood occurs with kinetics, physiology, and histology closely analogous to the pig-to-human model. In addition, as in that model, neither of two potent soluble-phase complement inhibitors prevented complement activation or HALR. We conclude that the mouse lung model is relevant to dissect the cellular and molecular mechanisms governing HALR.

Acute Disease↗
PubMed2005

Treatment with C1 inhibitor concentrate in abdominal pain attacks of patients with hereditary angioedema.

BACKGROUND: Abdominal edema attacks in patients with hereditary angioedema are often extremely painful, associated with vomiting and diarrhea, and have a high potential for causing recurrent disability of the patient. STUDY DESIGN AND METHODS: Intraindividual comparison of retrospective data in 75 hereditary angioedema patients comprising 4,834 abdominal attacks treated with C1 inhibitor concentrate versus 17,444 untreated abdominal attacks. RESULTS: The mean duration of abdominal attacks was 92.0 hours (SD, 40.8 hr) when untreated compared to 39.9 hours (SD, 30.0 hr) when treated. Patients reported a mean maximal pain score of 8.6 (SD, 1.7; range, 1-10) for untreated attacks compared to 4.5 (SD, 2.9) when treated. Vomiting occurred in 83.3 percent of untreated attacks and in 6.0 percent of treated attacks, respectively. Diarrhea was reported in 41.8 percent of untreated attacks and in 11.0 percent of treated attacks, whereas cardiovascular collapse due to hypovolemia was observed in 3.5 percent of untreated attacks versus 0.1 percent in treated attacks. Mean time to relief of symptoms was 53.5 minutes when treated early compared to 114 minutes when treatment was delayed. No drug-related adverse or serious adverse events were observed as far as the injections were performed correctly. CONCLUSION: C1 inhibitor concentrate is highly effective and safe in treating abdominal attacks in patients suffering from hereditary angioedema.

Abdominal Pain↗
PubMed2006

Symptoms, course, and complications of abdominal attacks in hereditary angioedema due to C1 inhibitor deficiency.

OBJECTIVES: Recurrent abdominal attacks belong to the cardinal and most distressing symptoms of hereditary angioedema (HAE) due to C1 inhibitor deficiency. They are characterized by crampy pain, but may include vomiting, diarrhea, and other features. Detailed clinical data about the symptoms and course of abdominal attacks have not been reported. METHODS: We retrospectively observed a total of 33,671 abdominal attacks in 153 patients with HAE including a prospectively examined subgroup of 23 patients. Symptoms, course, frequency of attacks, and complications were analyzed. RESULTS: The relation of mild, moderate, and severe attacks was 1:1.4:5.6 in the prospective part of the study. Extra-abdominal symptoms preceded the abdominal symptoms. The mean maximal pain score was 8.4 (range 1-10). Vomiting occurred in 73% (24,696) and diarrhea in 41% (13,682) of the attacks. Circulatory collapse accompanied 4.4% (1,468) of the attacks, with loss of consciousness (LOC) occurring in 2.2% (739). Nine patients could clearly distinguish two types of abdominal attacks: vomiting and diarrhea. Rare complications included tetany, hemorrhagic stools, and intussusception of the colon. In 28% (43) of the patients, recurrent abdominal attacks had started before the characteristic swelling of the skin had ever occurred. A model is proposed to classify the severity of the attacks and to describe the clinical course. CONCLUSIONS: Abdominal attacks in HAE constitute a more disabling and complex syndrome than previously assumed. Our results add to the understanding of symptoms and course of HAE and may aid in the early recognition of an impending attack and improve clinical management.

Abdominal Pain↗
PubMed2003

Administration of C1 inhibitor reduces neutrophil activation in patients with sepsis.

Forty patients with severe sepsis or septic shock recently received C1 inhibitor. In the present study we studied the effect of C1 inhibitor therapy on circulating elastase-alpha(1)-antitrypsin complex (EA) and lactoferrin (LF) levels in these patients to gain further insight about agonists involved in the activation of neutrophils in human sepsis. Elevated levels of EA and LF were found in 65 and 85% of the septic patients, respectively. Patients with elevated EA levels had higher organ dysfunction scores, higher levels of cytokines, and higher levels of complement activation products than patients with normal EA levels. C1 inhibitor therapy reduced EA as well as complement activation and IL-8 release in the patients with elevated EA on admission. We conclude that neutrophil activation in human sepsis correlates with the severity of organ dysfunction and involves complement and interleukin-8 as agonists. The effect of C1 inhibitor therapy on neutrophils may provide an explanation for the beneficial, although mild, effects of this treatment on organ dysfunction in sepsis.

Adult↗
PubMed2006

Serum concentrations of C reactive protein, alpha1 antitrypsin, and complement (C3, C4, C1 esterase inhibitor) before and during the Vuelta a Espańa.

OBJECTIVES: To determine serum concentrations of proinflammatory (C reactive protein, complement C3 and C4) and anti-inflammatory (alpha(1) antitrypsin, C1 esterase inhibitor (C1-INH)) acute phase proteins in elite cyclists before and during a three week cycle tour. METHODS: Seventeen professional cyclists participating in the Vuelta a Espańa volunteered for the study. Their mean (SD) physical characteristics were: age 28 (1) years; height 1.7 (0.06) m; weight 65 (7) kg; body fat 7.6 (0.8)%; Vo(2)max 75.3 (2.3) ml/kg/min. Venepuncture was performed on each subject 24 hours before the tour began (T0), on day 11 (the first rest day; T1) and day 21 (the second to last stage of the tour; T2). Samples at T1 and T2 were taken about 17 hours after the previous stage. Analysis of variance was used to determine changes over time. Where significance was found, a Tukey post hoc test was performed. RESULTS: C reactive protein concentrations were consistently within the normal range, although there was a 228%, non-significant increase at T1. C3 concentrations fell within the normal range at all times assessed. C4 concentrations before the race were within the normal range and were significantly increased 10 days (T1) into the race. C1-INH concentrations did not change significantly throughout the race. alpha(1) Antitrypsin concentration before the race was at the lower end of the normal range and was only significantly raised at T2. CONCLUSIONS: Although not as pronounced as those reported in marathon/ultramarathon runners, elite cyclists participating in a three week cycle tour experienced increases in selected proinflammatory and anti-inflammatory acute phase proteins, indicating an acute phase/inflammatory response. It is tenable that the increase in alpha(1) antitrypsin and C1-INH (anti-inflammatory mediators) at T2 served to attenuate the acute phase/inflammatory response. The lower than normal resting concentrations of the acute phase proteins supports the notion that chronic aerobic exercise induces an anti-inflammatory state.

Adult↗
PubMed2004

Normal complement C4 values do not exclude hereditary angioedema.

This report describes a patient with hereditary angioedema (HAE) in whom complement C4 values were consistently normal. There was a family history of HAE, for which the patient had previously been screened, but in view of her normal C4 values she was deemed unaffected. However, at 10 years of age she presented with an eight month history of episodes of swelling affecting her hands and recurrent episodes of abdominal pain over the previous few months. In view of the recent clinical history of swellings and the family history of HAE, C4 and C1 inhibitor (C1inh) were measured. The C4 concentration was found to be within the normal range but the C1inh value was low (0.07 g/litre; normal range, 0.18-0.37). The patient was started on tranexamic acid and at an outpatient review three months later her episodes of swelling were occurring less often and were less severe. Although recent papers have suggested that the diagnosis of HAE can be excluded if complement C4 concentrations are normal, this case highlights the fact that C4 concentrations can be normal in this condition, and it is recommended that both C4 and C1inh concentrations should be measured to exclude HAE.

Angioedema↗
PubMed2004

Casein kinase II alpha subunit and C1-inhibitor are independent predictors of outcome in patients with squamous cell carcinoma of the lung.

PURPOSE: Gene expression profiling has been shown to be a valuable tool for prognostication and identification of cancer-associated genes in human malignancies. We aimed to identify potential prognostic marker(s) in non-small cell lung cancers using global gene expression profiles. EXPERIMENTAL DESIGN: Twenty-one previously untreated patients with non-small cell lung cancer were analyzed using the Affymetrix GeneChip high-density oligonucleotide array and comparative genomic hybridization. Identified candidate genes were validated in an independent cohort of 45 patients using quantitative real-time reverse transcription-PCR and Western blot analyses. Follow-up data for these patients was collected and used to assess outcome correlations. RESULTS: Hierarchical clustering analysis yielded three distinct subgroups based on gene expression profiling. Cluster I consisted of 4 patients with adenocarcinoma and 1 with squamous cell carcinoma (squamous cell carcinoma); clusters II and III consisted of 6 and 10 patients with squamous cell carcinoma, respectively. Outcome analysis was performed on the cluster groups containing solely squamous cell carcinoma, revealing significant differences in disease-specific survival rates. Moreover, patients having a combination of advanced Tumor-Node-Metastasis stage and assigned to the poor prognosis cluster group (cluster II) had significantly poorer outcomes. Comparative genomic hybridization analysis showed recurrent chromosomal losses at 1p, 3p, 17, 19, and 22 and gains/amplifications at 3q, 5p, and 8q, which did not vary significantly between the cluster groups. We internally and externally validated a subset of 11 cluster II (poor prognosis)-specific genes having corresponding chromosomal aberrations identified by comparative genomic hybridization as prognostic markers in an independent cohort of patients with lung squamous cell carcinoma identifying CSNK2A1 and C1-Inh as independent predictors of outcome. CONCLUSION: CSNK2A1 and C1-Inh are independent predictors of survival in lung squamous cell carcinoma patients and may be useful as prognostic markers.

Aged↗
PubMed1986

Serum profiles of the regulatory complement proteins during the progression of renal damage in human glomerulonephritis.

Persistent activation of the complement system after escape from control by the regulatory proteins results in an excessive release of split products with inflammatory properties. Serum levels of the regulatory proteins of the complement system (Cl-INH, H, I and AT III) were assayed by the radial immunodiffusion technique in 521 serum samples from 124 patients with idiopathic chronic glomerulonephritis divided into two groups: 81 cases with normal renal function (NRF), and 43 cases with deteriorated renal function (DRF). Significant high mean levels of Cl-INH, H, I and AT III were found in patients with NRF, when they were compared with DRF patient groups. Positive correlations between the regulatory proteins and the corresponding complement components were found in patients with NRF, whereas they were reduced considerably in patients with DRF. Serial measurement of the control proteins showed a decay of the levels of Cl-INH, H and I in patients with progressive impairment of renal function. The presence of high levels of regulatory proteins suggest that a control mechanism may occur in patients with NRF; measurement of these proteins could, therefore, be of prognostic value, as the presence of high levels are indicative of a block of the complement system.

Antithrombin III↗