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PubMed1987

Relation between complement activation and susceptibility to decompression sickness.

The consequences of complement activation and the symptoms of decompression sickness are similar. Consequently, the relation between the sensitivity of individuals to complement activation by air bubbles and their susceptibility to decompression sickness has been examined. Plasma samples from 34 individuals were incubated with air bubbles, and the concentration of the fluid phase metabolites of complement activation C3a, C4a, and C5a were measured with radioimmunoassays. It was found that both the anaphylatoxins C3a and C5a were produced by the presence of air bubbles but that the anaphylatoxin C4a was not. This finding indicates that air bubbles activate the complement system by the alternate pathway. One group of individuals was found to be particularly sensitive to complement activation by this pathway. They produced 3.3 times more C3a and 5.3 times more C5a in their plasma samples incubated with air bubbles as did the other group. Sixteen individuals were subjected to a series of pressure profiles that were severe enough to produce bubbles in their circulatory system that could be detected by Doppler ultrasonic monitoring. The group of individuals that had been identified as being more sensitive to complement activation by the alternate pathway was also found to be more susceptible to decompression sickness.

Adult↗
PubMed1990

Comparison of hollow fibre membrane oxygenators during cardiopulmonary bypass in children: Dideco Masterflo versus Terumo Capiox II.

This prospective study was planned to compare two different (reversed blood and gaseous compartments) hollow fibre membrane oxygenators, Dideco Masterflo and Terumo Capiox II, in order to find out which of these oxygenators was less injurious during cardiopulmonary bypass (CPB) surgery in small children. Twenty children underwent CPB surgery for complex congenital cardiac malformations. Ten patients were selected for each study group by matching age and weight. Oxygenators were the only variables in the CPB circuit, and special attention was focused on the kinetics of white blood cell count (WBC), complement C3, anaphylatoxin C3a, total haemolytic complement (CH100), C-reactive protein (CRP) and haptoglobin. There were no significant differences between the parameters studied at any sample time. However, there was less intense C3a (peak C3a levels 2506 +/- 1187 SD versus 4302 +/- 3958 SD; p = 0.19) generation, and also less intense CH100 consumption (percentual drop of initial CH100 values was 30% versus 55.2%) in the Dideco Masterflo group of patients. Moreover, postoperative respiratory treatment was somewhat shorter when using Masterflo oxygenators (2.4 +/- 2.41 SD versus 4.0 +/- 2.49 SD days; p = 0.16), although statistical significance was not obtained. These findings may be important in high-risk paediatric patients undergoing open-heart surgery.

Cardiopulmonary Bypass↗
PubMedDate not supplied

Mechanism of injection pain with long and long-medium chain triglyceride emulsive propofol.

PURPOSE: t has been suggested that long-medium chain triglyceride (LCT/MCT) emulsive propofol causes less injection pain than long chain triglyceride (LCT) emulsive propofol because of the decreased propofol concentration in the aqueous phase. Alternatively, LCT propofol generates bradykinin causing the injection pain and activates complement, but these effects when using LCT/MCT propofol have not been examined. To identify the mechanism for reduced pain with LCT/MCT propofol, injection pain, bradykinin generation and complement activation with use of both propofol products were compared. METHODS: Two hundred adult patients randomly allocated to two groups were given 1.5 mg x kg(-1) iv of either LCT propofol or LCT/MCT propofol at a rate of 200 mg x min(-1) in a double-blind manner and were asked to grade pain scores. In another study, bradykinin and activated complement 3 (C3a) concentrations were measured using blood obtained from 13 healthy volunteers mixed with saline, LCT propofol or LCT/MCT propofol. RESULTS: There was a significant difference in pain scores between groups, showing a lower incidence of injection pain in the LCT/MCT propofol group. The bradykinin concentrations in blood mixed with LCT and LCT/MCT propofol were significantly higher than in blood mixed with saline. The C3a concentrations showed similar results. CONCLUSIONS: LCT/MCT propofol causes less pain on injection compared with LCT propofol. Bradykinin generation and complement activation are similar with both LCT and LCT/MCT propofol. Thus, the reason for less pain on injection with LCT/MCT propofol may be attributed to a decreased concentration of propofol in the aqueous phase.

Adolescent↗
PubMed1993

Biocompatibility of leukocyte removal filters during leukocyte filtration of cardiopulmonary bypass perfusate.

To evaluate the biocompatibility and the efficacy of leukocyte removal filters, we performed a prospective study by using the cardiopulmonary bypass perfusate taken from the heart-lung machine for 20 patients who underwent cardiac surgery and were randomly divided into four groups according to the filters used. A leukocyte removal filter was installed in the transfusion line while the perfusate was transfused to the patients. No increases of C3a, C5a, elastase, and thromboxane were found during leukocyte filtration by polyester filters (Optima, Sepacell R500, and Pall RC100). Activation of the complement cascade was observed during filtration by the cellulose acetate filter (Cellselect) although the efficacy of the Cellselect filter was evidently higher than that of the polyester filter. These results imply that polyester leukocyte filters are superior to cellulose acetate filters in terms of biocompatibility but have a reduced efficacy. An optimal leukocyte filter providing both high efficacy and biocompatibility has yet to be developed.

Biocompatible Materials↗
PubMed2004

C3a and C3b activation products of the third component of complement (C3) are critical for normal liver recovery after toxic injury.

Although the complement system has been implicated in liver regeneration after toxic injury and partial hepatectomy, the mechanism or mechanisms through which it participates in these processes remains ill-defined. In this study, we demonstrate that complement activation products (C3a, C3b/iC3b) are generated in the serum of experimental mice after CCl(4) injection and that complement activation is required for normal liver regeneration. Decomplementation by cobra venom factor resulted in impaired entry of hepatocytes into S phase of the cell cycle. In addition, livers from C3-deficient (C3(-/-)) mice showed similarly impaired proliferation of hepatocytes, along with delayed kinetics of both hepatocyte hyperplasia and removal of injured liver parenchyma. Restoration of hepatocyte proliferative capabilities of C3(-/-) mice through C3a reconstitution, as well as the impaired regeneration of C3a receptor-deficient mice, demonstrated that C3a promotes liver cell proliferation via the C3a receptor. These findings, together with data showing two waves of complement activation, indicate that C3 activation is a pivotal mechanism for liver regeneration after CCl(4) injury, which fulfills multiple roles; C3a generated early after toxin injection is relevant during the priming of hepatocytes, whereas C3 activation at later times after CCl(4) treatment contributes to the clearance of injured tissue.

Animals↗
PubMed1999

Complement activation by propofol and its effect during propofol anaesthesia.

We have examined whether propofol activates complement. In the first study, blood was mixed with saline, propofol or the lipid solvent for propofol, and the activated complement 3 (C3a) and 4 (C4a) concentrations in the supernatant were assayed. In the second study, blood and propofol were mixed with various levels of nafamostat mesilate (anti-complement agent) up to 0.3 mmol/l and the C3a was assayed. In the third study, the time course of plasma C3a concentration in patients during propofol anaesthesia was examined. The results showed that the lipid solvent activated complement and produced similar levels of C3a to propofol, probably via both the classical and alternative pathways. This activation was not inhibited by any of the nafamostat concentrations used. There was no significant change in plasma C3a concentration during propofol anaesthesia. These results suggest that C3a is generated by the lipid solvent, but its accumulation during propofol anaesthesia is minimal.

Adult↗
PubMed1997

Biomaterial-dependent blood activation during simulated extracorporeal circulation: a study of heparin-coated and uncoated circuits.

OBJECTIVE: Blood activation during extracorporeal circulation is associated with morbidity and mortality in cardiac surgery. This activation can be diminished by usage of heparin-coated circuits. Nitric oxide has also been reported to influence humoral and cellular components of blood. This study was performed to determine biomaterial-dependent part of blood activation. DESIGN: Fresh, whole human blood mixed with Ringer's solution was circulated through a heart-lung machine for two and half hours. Five circuits were heparin-coated (group HC), whilst five other circuits were uncoated (group NC). During the last half hour NO was added to the oxygen/air mixture. METHODS: Blood activation was estimated by measuring following parameters: interluekin 6, complement activation products C3a and terminal complement complex, and oxygen free radicals (OFR) production capacity, which was determined using chemiluminescence enhanced by serum opsonized zymosan (SOZ) and phorbol myristate acetate (PMA). Granulocyte activation was measured as release of myeloperoxidase (MPO) and human neutrophil lipocalin (HNL). RESULTS: OFR in granulocyte suspension stimulated by SOZ and PMA were significantly lower in the NC group, mostly later during ECC. Similarly, lower neutrophil and monocyte counts were observed in this group. NO increased superoxide production in the whole blood in heparin-coated circuits, but did not change OFR in isolated granulocytes. MPO was also affected by heparin-coating. NO supply seemed to increase release of MPO and HNL. It is concluded that heparin-coating contributed to reduction of biomaterial-dependent blood activation. An addition of NO at late stage of ECC tended to influence this activation.

Adult↗
PubMed1997

Is subclinical ovarian failure an autoimmune disease?

Young women with unexplained infertility who exhibit elevated basal serum follicle stimulating hormone (FSH) concentrations (>10 IU/l) have poor outcomes in in-vitro fertilization. A subgroup of these women has regular menses, representing 'subclinical' ovarian failure, which may have an autoimmune basis and could potentially be treated by immunosuppression. To investigate this further, a range of immunological markers was used to assess autoimmune activity in 14 women aged <40 years with elevated FSH compared with 15 infertile women with normal FSH and 10 pre-menopausal, healthy controls. All samples were taken during natural menstrual cycles. Organ-specific antibodies against ovary, endometrium and thyroid, and non-organ-specific antibodies against histones and cardiolipin, were not significantly increased in elevated FSH patients compared with other control groups. Soluble CD23 and soluble intercellular adhesion molecule concentrations were not elevated in the sera of the women tested, and circulating T cell subsets remained unaltered. Significantly, increased concentrations of the complement breakdown product C3a and terminal complement complexes were detected in the elevated FSH group compared with the normal FSH group, although the latter also had significant complement activation compared with laboratory controls. Autoimmunity appears as an infrequent cause of 'subclinical' ovarian failure, but there is evidence of activation of complement in the sera of infertile women.

Adult↗
PubMed1986

Determination of anaphylatoxin concentrations in suction blisters in patients with psoriasis.

Concentrations of C3a and C4a anaphylatoxins in suction blister fluids were determined by radioimmunoassay in patients with psoriasis and normal controls. Comparison of anaphylatoxin levels between serum samples and blister contents in the same subjects revealed that the levels of both C3a and C4a anaphylatoxins were significantly higher in the former than the latter even in those raised on normal skin, suggesting that the classic complement pathway is activated during suction procedure. Therefore we cannot regard suction blister fluid to be simply representative of undisturbed interstitial tissue fluid as far as the complement system is concerned. There was no difference in anaphylatoxin levels between those from uninvolved skin of psoriatic patients and those from normal controls. However, significantly high anaphylatoxin levels were noted in fluids of suction blisters raised on lesional skin as compared with those produced on uninvolved skin in psoriatic patients.

Adolescent↗
PubMed1996

A comparison of three brands of polysulfone membranes.

A prospective clinical crossover study comparing the functional performance and biocompatibility of three brands of polysulfone membranes (Fresenius Polysultone (Fresenius Ag, Bad Homburg, Germany), Polyphen (Minntech Corp., Minneapolis, MN), and Biosulfane (WR Grace Inc., Danvers, MA)) incorporated in ethylene oxide-sterilized dialyzers of comparable surface area (1.3 to 1.35 m2) was undertaken. The clearance of small molecules by each membrane was comparable. Plasma levels of beta 2 microglobulin fell to 49.9% of pretreatment values by 210 min when using the Fresenius Polysulfone membrane, 60.2% with the Polyphen membrane, and 63.1% with the Biosulfane membrane. The reduction achieved by the Fresenius Polysulfone membrane was superior (P = 0.003). The plasma reductions were associated with the recovery of 195 mg beta 2 microglobulin from the dialysate for the Fresenius Polysulfone membrane and 158 mg for the Polyphen membrane, but no beta 2 microglobulin was recovered from the dialysate with the Biosulfane membrane. The dialysate collected with the Fresenius Polysulfone membrane also contained a mean of 6853 mg of total protein, compared with 5490 mg with the Polyphen membrane and 8422 mg with the Biosulfane (P = 0.04) membrane. The neutropenia was slight and independent of membrane brand, as were the changes in C3a des arg and SC5b-9 complement components. The reduction in platelet counts was higher for the Biosulfane membrane than for the other brands (P = 0.003). This study indicates that whereas the polymer base of the membrane is the same, its production and subsequent handling during dialyzer production induce changes that attain statistical significance, most notably in the way that the membrane removes beta 2 microglobulin and interacts with proteins. The differences observed are a consequence of the different alloying polymers used during manufacture and, consequently, the membranes cannot be considered equivalent.

Adult↗
PubMed1994

C3a activates the respiratory burst in human polymorphonuclear neutrophilic leukocytes via pertussis toxin-sensitive G-proteins.

In contrast to C5a, which represents a well-established potent activator of the respiratory burst in polymorphonuclear neutrophilic granulocytes (PMN), the functional role of C3a in the activation of PMN is, so far, poorly understood. Herein, the potential role of human C3a in the activation of the respiratory burst in human PMN was investigated. The release of reactive oxygen species (ROS) of PMN from healthy donors was measured by lucigenin-dependent chemiluminescence. C3a dose-dependently induced the production of ROS in human PMN in the range between 10 ng/mL and 1,000 ng/mL, whereas C3a-desArg was inactive. Flow cytometric measurement of H2O2 by dihydrorhodamine-123 labeling of anti-CD16-stained PMN showed that predominantly neutrophilic PMN are responsible for the C3a-induced activation of the respiratory burst. To exclude that C3a stimulation was caused by contamination with C5a, the specificity of C3a-induced activation of PMN was shown using monoclonal antibodies (MoAbs). Accordingly, the effect of C3a was completely abolished in the presence of Fab fragments of a blocking anti-C3a MoAb. In addition, blockade of the C5a receptor by the anti-C5a receptor (anti-C5aR) MoAb, S5/1, totally inhibited the C5a-induced production of ROS, whereas the C3a response in the presence of the anti-C5aR MoAb was unaffected. The specificity of the response was further confirmed by homologous desensitization after restimulation with C3a. In contrast, no cross-desensitization was observed upon stimulation with C5a. The C3a-induced ROS production by PMN was inhibited by pertussis toxin, indicating the involvement of guanine nucleotide-binding proteins (Gi proteins) in the signal transduction process initiated by C3a. In addition, stimulation of PMN by C3a resulted in a transient increase in the cytosolic free calcium concentration ([Ca2+]i) in a dose-dependent manner. In contrast to C3a-induced ROS production, C3a did not induce a chemotactic response in PMN, indicating functional qualitative differences as compared with C5a. In summary, these results show that C3a is a potent activator of the respiratory burst in human PMN. Therefore, these findings point to a novel role of C3a in the pathogenesis of inflammatory diseases associated with increased C3a levels and PMN activation.

Calcium↗
PubMed2000

In vitro investigation of the blood response to medical grade PVC and the effect of heparin on the blood response.

This paper reports the results of an investigation into the blood response of polymers in vitro, using non-anticoagulated and heparinised blood and plasma. The materials studied were regenerated cellulose, (Cuprophan), an acrylonitrile-allyl sulphonate copolymer (AN69S), and medical grade polyvinyl chloride plasticised with di-2-ethyl-hexyl-phthalate (PVC/DEHP). Blood-material or plasma-material contact was achieved using a parallel plate flow cell, and C3a generation and FXII-like activity measured. The results of the study with non-anticoagulated human blood show that PVC/DEHP is a high complement activator. C3a concentration in the blood was higher after contact with PVC/DEHP than after contact with regenerated cellulose. The introduction of heparin in the blood induced complex alterations in the blood response. C3a generation could be elevated, decreased, or remain the same, depending on the material. The FXII-like activity on the surface of the PVC/DEHP after contact with plasma was also higher than the other two polymers. The introduction of heparin could increase or decrease FXII-like activity, depending on material. The patterns of response obtained with non-anticoagulated blood in vitro for AN69S and Cuprophan bore a strong resemblance with patterns of response obtained in the clinic, whereas those obtained with heparinised blood in vitro did not.

Acrylic Resins↗
PubMed1997

Evaluation of haemodialysis membrane biocompatibility by parallel assessment in an ex vivo model in healthy volunteers.

BACKGROUND: Precise evaluation of the haemocompatibility of prototype membranes, flow configurations and anticoagulant regimens is an essential step in the development of dialysis systems minimizing blood activation. An ex vivo model in humans currently employed in our laboratory has recently been adapted to allow the parallel evaluation of two minimodule dialysers with blood from a single donor, thus eliminating differences due to donor variability in the comparison of test and control dialysis modules. METHODS: The ex vivo flow system is designed to reproduce the haemodynamic conditions of clinical dialysis on a 1/50 scale. A blood line from the forearm vein of the volunteer donor is divided at a Y-shaped junction, two roller pumps assure equivalent blood flow (5 ml/min) in the branches leading to two minimodule dialysers and heparin (0.1 IU/ml final concentration) is injected into each branch immediately after the Y junction. Samples for analysis of blood activation markers are collected at the exits of the two minimodules over a test period of 27 min. In the present series of tests, a new polyacrylonitrile membrane (PAN) was evaluated relative to standard commercial polysulphone (PS), acrylonitrile copolymer (AN 69) and cuprophan (CUP) membranes. RESULTS: A steady minimal level of anticoagulation corresponding to a slightly less than two-fold prolongation of APTT (activated partial thromboplastin time) was maintained throughout testing in both branches of the ex vivo flow system. Time curves for the accumulation of activation markers (thrombin-antithrombin III complexes, prothrombin fragment 1 + 2, platelet beta-thromboglobulin, and complement fragment C3a) showed all four types of minimodule dialyser to induce comparable low levels of activation of coagulation parameters and platelets, together with similar mild activation of complement for AN 69, PAN, and PS dialysers as compared to stronger activation for CUP modules. Overall results thus confirmed the acceptable haemocompatibility of the prototype polyacrylonitrile (PAN) membrane. CONCLUSIONS: Among current methods for evaluation of the biocompatibility of haemodialysis systems, ex vivo flow models in humans avoid problems arising from species differences and may be designed to closely reproduce the conditions of clinical dialysis. A parallel configuration eliminates artefacts due to individual variations in donor response. This not only facilitates the direct comparison of test and control membranes under close to identical experimental conditions, but also provides a model particularly well adapted to studies of the effects of different anticoagulation regimens, flow configurations, and dialysates, or alternative methods of sterilization, rinsing, and priming of the dialysers.

Adolescent↗
PubMed1993

Cellular responses of guinea-pig macrophages to C4a; inhibition of C3a-induced O2- generation by C4a.

We have investigated the cellular responses of guinea-pig macrophages to human C4a. C4a induced a biphasic Ca2+ mobilization; a rapid temporary Ca2+ mobilization from intracellular Ca2+ pool followed by a weak Ca2+ influx of extracellular Ca2+. Although the C4a-treated macrophages did not respond again to C4a, that is, desensitization to C4a, the C4a-desensitized macrophages still responded to C3a to induce a Ca2+ mobilization. Furthermore, C4a failed to inhibit [125I]-C3a binding to macrophages, suggesting that C4a receptors are different from C3a receptors. In contrast to C3a, C4a-induced Ca2+ mobilization didn't link to O2- generation but inhibited the C3a-induced O2- generation. These results suggest that C4a binds to a specific C4a receptor on guinea-pig macrophages to down-regulate the C3a receptor-mediated O2- generation in macrophages.

Animals↗