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PubMed1995

Design, synthesis, and evaluation of A/C/D-ring analogs of the fungal metabolite K-76 as potential complement inhibitors.

The terpenoid 6,7-diformyl-3',4',4a',5',6',7',8',8a'-octahydro-4,6',7'-trihydrox y-2',5',5', 8a'-tetramethylspiro[1'(2'H)-naphthalene-2(3H)-benzofuran] (1a; K-76), a natural product of fungal origin, and its monocarboxylate sodium salt 1c (R = COONa; K-76COONa) inhibit the classical and alternative pathways of complement, and 1c was shown to inhibit the classical pathway at the C5 activation step. In an attempt to elucidate the essential pharmacophore of 1a,c, the natural product was used as a "topographical model" for the design of partial analogs retaining the desired complement inhibiting potency. Therefore, A/C/D-ring analogs have been synthesized, as shown in Scheme 1 using 3-methoxyphenol (3) and limonene chloride (5) as starting materials, which contain functional groups similar to those found on the natural product. The use of (4R)-(+)- and (4S)(-)-limonene chloride (5a,b, respectively) provided two series of compounds differing in the stereochemistry of the C-4 chiral center (limonene moiety numbering). The in vitro assay results of the inhibition of anaphylatoxin production and classical complement-mediated hemolysis revealed that 7-carboxy-2-(R,S)-methyl-2-(1'-methylcyclohexen-(4'R)-yl)-4-met hoxybenzofuran (13a) and 7-carboxy-2-(R,S)-methyl-2-(1'-methylcyclohexen-(4'S)-yl)-4-met hoxybenzofuran (13b) were active in the same range of concentrations as the natural product.

Animals↗
PubMed1995

Hemofiltration in human sepsis: evidence for elimination of immunomodulatory substances.

Continuous hemofiltration is widely used for renal replacement therapy in patients with acute renal failure. It has been suggested that hemofiltration may also eliminate toxic mediators thought to be important in the pathophysiology of sepsis. The present study examined whether hemofiltration can activate or eliminate inflammatory mediators in patients with sepsis, and whether ultrafiltrate can alter specific functions of peripheral blood mononuclear leukocytes (PBMC) in vitro. Veno-venous hemofiltration was performed in 16 patients and in 5 healthy volunteers. Pre-filter (afferent), post-filter (efferent) and ultrafiltrate concentrations of cytokines (IL-1 beta, IL-6, IL-8, TNF alpha) and of complement components (C3, C3adesArg, C5adesArg, terminal complement complex) were measured after the beginning of hemofiltration (t0), and 60 minutes later (t60). PBMC, and monocyte and lymphocyte subfractions were incubated with ultrafiltrate, and cytokines were determined in the supernatants. Hemofiltration did not induce significant mediator activation. There was no evidence for significant cytokine elimination. However, pre-filter C3adesArg concentration showed a significant decline during hemofiltration (patients: t0 = 676.9 +/- 99.7 ng/ml, t60 = 545.4 +/- 83.2, P < 0.001; volunteers: t0 = 54.8 +/- 13.3 ng/ml, t60 = 33.9 +/- 10.7, P < 0.001). Ultrafiltrate from septic patients significantly stimulated PBMC and monocyte TNF alpha release, but suppressed lymphocyte IL-2 and IL-6 production. Ultrafiltrate from volunteers was without effect. Hemofiltration effectively eliminates certain mediators such as C3adesArg. Ultrafiltrate contains compounds with significant immunomodulatory qualities. Therefore, hemofiltration may represent a new modality for removal of immunomodulatory mediators.

Adjuvants, Immunologic↗
PubMed1990

Generation of the membrane attack complex during haemodialysis: impact of classical and alternative pathway components.

1. The generation of the plasma SC5b-9 complex (the soluble form of the membrane attack complex) during haemodialysis was studied in 29 patients together with markers of the classical (C4d fragment) and alternative (Bb fragment) pathways and the common iC3b fragment. 2. In the patients dialysed with Hemophan and Cuprophan membranes, a rapid increase in the plasma levels of SC5b-9 complex, Bb fragment and iC3b fragment occurred within 15 min of the initiation of the haemodialysis procedure. The SC5b-9 complex and the Bb fragment concentrations remained at a plateau until 120 min thereafter. The iC3b fragment level showed a continual decline. 3. The C4d fragment concentrations remained unchanged, indicating that generation of the membrane attack complex is most likely due only to activation of the alternative pathway. 4. The generation of the membrane attack complex occurred throughout the full haemodialysis period. In patients treated with Polysulfon membranes no statistically significant variation in these components was noted. 5. The study shows that the membrane attack complex may be generated during the full period of the haemodialysis session and is a stable index of biocompatibility. 6. Moreover, it seems be involved directly in haemodialysis-associated phenomena.

Complement Activation↗
PubMed1997

Comparative study of the complement-activating and specific IgE-binding properties of ragweed pollen allergen.

Previous reports have defined the capacity of ragweed pollen extract (RWA) to activate human complement (C) in fluid phase through the classical pathway and have ascertained a strong correlation between the extent of complement activation and the severity of symptoms of allergic rhinoconjunctivitis during the ragweed blooming season. In the present study the complement-activating and specific IgE-binding capacities of various ragweed allergen preparations were compared. Elimination of physically adsorbed (flavonoid) pigments from the allergenic proteins had no significant effect on their complement-consuming capacity, although the process strongly diminished specific IgE binding. Removal of an IgE-binding trypsin inhibitor from RWA significantly enhanced RWA-induced complement activation, whereas it did not change IgE binding. These findings indicate that neither the physically adsorbed pigments nor the trypsin inhibitor are involved in complement activation by ragweed pollen allergens, and suggest that complement activation and specific IgE binding are distinct molecular properties of ragweed pollen allergen.

Allergens↗
PubMed1997

Complement and complement deficiencies.

The complement system provides a first line of defense and mediates a large variety of cellular and humoral interactions within the immune response, including chemotaxis, phagocytosis, cell adhesion, and B-cell differentiation. The system involves more than 30 serum components and numerous cell surface regulators and receptors. Similar to the blood clotting system, complement activation is initiated through a series of complex activation cascades involving enzymatic cleavage. Three independent complement activation cascades, the classical, the alternative, and the lectin pathway, have been described. The liver is the main site of biosynthesis for most of the serum components of complement and diseases of the liver can lead to alterations of the normally stable plasma levels of complement. Deficiencies of single components can lead to a broad variety of secondary diseases, caused by either imbalanced activation or defects in the humoral or cellular response to microbial infections.

Complement C3a↗
PubMed1998

Effects of complement depletion on the pharmacokinetics and gene delivery mediated by cationic lipid-DNA complexes.

We show that lipoplexes activate complement in human serum in vitro and deplete complement when administered intravenously (i.v.) to mice. This raised the possibility that complement proteins might alter gene expression mediated by lipoplex in animals. To investigate this phenomenon, complement levels were depleted to less than 5% in ICR mice by intraperitoneal (i.p.) injection of cobra venom factor and anti-C3 antibodies. The pharmacokinetics and distribution of radio labeled DOTAP-cholesterol (1.0:0.9 molar ratio)-DNA (5:1 positive charge ratio) complexes containing 131I-labeled p-hydroxybenzamidine phosphatidylethanolamine and 125I-labeled DNA were measured in mice after i.v. administration. Greater than 75% of the injected lipoplex appeared in the lungs 5 min following injection. The lipid and DNA were eliminated from the lungs at a constant ratio. Distribution in various organs was not affected by complement depletion. Expression of luciferase was highest in the lungs and showed a dose-dependent increase as the amount of DNA injected increased from 3 to 60 microg. Reporter gene expression was not affected by complement depletion. In addition, complement depletion had no effect on either the distribution or gene expression in the heart, spleen, or liver. We conclude that cationic lipid-DNA complexes interact with serum complement proteins upon i.v. injection in mice, but this interaction does not influence the lipofection efficiency or systemic distribution of the lipoplex.

Animals↗
PubMed1987

Complement and anaphylatoxin responses to cross-clamping of the aorta. Studies during general anaesthesia with or without extradural blockade.

Complement activation and anaphylatoxin formation were studied in 28 patients undergoing aortic reconstructive surgery under general anaesthesia. In 12 of the patients an extradural catheter was placed in the L1-2 space and 2% mepivacaine was injected until blockade reached the T4 level. The remaining 16 patients were operated upon under general anaesthesia alone. Complement activation was not obvious until aortic cross-clamping. The release of anaphylatoxin was less pronounced during cross-clamping in the extradural group.

Aged↗
PubMed1993

Behaviour of white blood cells and the complement system.

Seven different types of dialysers were investigated in five dialysis centres in four countries with respect to behaviour of white blood cells and the complement system. The results of this controlled crossover study demonstrated significant differences in the dialysers. Those containing cuprammonium cellulose (G10-3N and G120 M) showed the greatest changes in white blood cell count, including monocytes and neutrophils, as well as the greatest complement activation. With regard to lymphocytes the subpopulation of low-mobility cells, which were predominantly the B-cells, showed the greatest mobility with dialysers containing cuprammonium cellulose. The PAN copolymer- and PMMA-containing dialysers Filtral and T 150 clearly caused the least changes in white blood cells and complement factors. Dialysers containing cellulose acetate and polysulphone membranes (Duo-Flux Artificial Kidney, CD 4000, and F 60) produced only a moderate decrease of WBC, monocyte, neutrophil, and lymphocyte counts, and this result corresponded to a relatively small change in complement factors.

Acrylic Resins↗
PubMed1987

C5a and thromboxane generation associated with pulmonary vaso- and broncho-constriction during protamine reversal of heparin.

The authors conducted a study in humans to determine the mediators associated with acute pulmonary vaso- and broncho-constriction occurring episodically with protamine reversal of heparin anticoagulation. Of 48 adult patients investigated prospectively after termination of cardiopulmonary bypass, two presented a sudden increase of airway pressure, acute pulmonary hypertension, and systemic hypotension 1-3 min after right atrial protamine injection. In these two subjects, plasma levels of C5a increased from 0.7 and 2.2 to 9.8 and 9.9 ng/ml, respectively, and thromboxane B2 increased from 0.26 and 0.34 to 7.5 and 16.2 ng/ml 1 minute after drug injection. A third subject not identified prospectively had an identical reaction and mediator profile (C5a, 10.2 ng/ml; TxB2, 18.6 ng/ml at 1 min). The plasma levels of these mediators were unchanged in the remaining patients (C5a, 0.7 +/- 1.1 [x +/- S.D.] to 0.6 +/- 0.9 ng/ml; TxB2, 0.16 +/- 0.12 to 0.15 +/- 0.07 ng/ml). Plasma histamine was not involved in this type of reaction, but increased from 0.7-10.4 ng/ml in a fourth patient who became hypotensive without acute pulmonary hypertension, bronchoconstriction, or elevation of C5a or TxB2. The authors' data indicate that the generation of high plasma levels of C5a anaphylatoxins and thromboxane is associated with pulmonary vaso- and broncho-constriction induced by protamine reversal of heparin in humans.

Adult↗
PubMedDate not supplied

In vitro activation of human complement by polyacrilonitrile dialyzer membrane assayed by complement binding to bystander red cells.

Quantitation of complement activation by polyacrilonitrile (PAN) dialyzer membrane is complicated by the high adsorptive capacity of the membrane for fluid phase anaphylotoxins. Assays for these anaphylotoxins, therefore, underestimate the degree of complement activation produced by this membrane. Alternative methods of measuring in vitro complement activation by the PAN and Cuprophan membranes were explored by incubating normal human erythrocytes with the membranes in the presence of serum. This led to deposition of C3d on these "innocent bystander" red cells, and provided an independent parameter for measuring complement activation. The PAN membrane caused significantly more C3d deposition on red cells, and thus more complement activation than Cuprophan. The possible significance of complement activation by PAN membrane, in consideration of its property of binding the resultant anaphylotoxins, is discussed.

Acrylic Resins↗
PubMedDate not supplied

Clinical trials of a cryoglobulin filter.

The authors report the results of clinical trials of a high capacity cryoglobulin filter (Cryofilter) in seven patients with cryoglobulinemia unresponsive to high doses of prednisone or immunosuppressive drugs who required plasmapheresis. The objective of this study was to test the safety and efficacy of the cryofilter in a limited patient population according to the investigational Device Exemption guidelines of the FDA. The cryoglobulins were selectively filtered from plasma at 4 degrees C by a cryofilter characterized by a membrane surface area of 0.135 m2 and an average pore size of 4.3 microns. Safety was evaluated by patients vital signs, complement activation, and clinical score of symptoms in the course of 10 treatments. Efficacy of cryofiltration was evaluated by comparing sieving of the cryoglobulins to that of albumin; immunoglobulins G, A, and M; and fibrinogen. All seven patients completed the series of 10 treatments without notable complement activation or any signs of discomfort. The cryofilter was particularly selective in patients with high cryoglobulin concentrations. Improvement in clinical symptoms was observed in all patients.

Adult↗
PubMed1987

Psoriasis and leukocyte chemotaxis.

Transepidermal migration of leukocytes, with resultant formation of microscopic or macroscopic sterile subcorneal pustules is a phenomenon characteristically noted in psoriasis and related sterile pustular dermatoses. It is natural to assume the presence of potent neutrophil chemotactic substances in the subcorneal portion of the lesional epidermis, because this location is the target of the in vivo leukocyte chemotaxis. In fact, crude psoriasis scale extracts show remarkably high neutrophil chemotactic and activating properties as compared with those of other non-psoriatic inflammatory dermatoses. We isolated a psoriatic leukotactic factor (PLF) having a molecular mass of around 12 kD, distinct from those common to other inflammatory changes involving the skin or those released by bacteria. Further analysis of PLF identified C5 cleavage fragments, together with other chemotactic peptides, such as those derived from monocytes. Likewise, potent low-molecular-mass chemotactic factors, including cell membrane lipid derived chemotactic factor, e.g. leukotriene B4, are also increased in psoriatic lesions, as in other nonpsoriatic inflammatory dermatoses. However, their activity to stimulate the generation of oxygen radicals in neutrophils was found to be much weaker than that of PLF. The peripheral blood leukocytes from active psoriatic patients show enhanced function in chemotaxis, phagocytosis, active oxygen production, and enzyme release; patients' sera contain substances such as anaphylatoxins that activate leukocyte function. Further research is required for clearer understanding of the series of events resulting in the leukocyte chemotaxis, as well as for the elucidation of the background immunoregulatory mechanisms.

Cell Movement↗
PubMed1995

Differentiation-induced production of ASP in human adipocytes.

Acylation Stimulating Protein (ASP) is a human plasma protein that stimulates both triacylglycerol synthesis and glucose transport. ASP is identical to C3adesArg and is generated by the interaction of factor B, complement C3 and adipsin. We have demonstrated that mature fat cells express messages for factors B, complement C3 and adipsin; that human pre-adipocytes, when cultured under differentiating conditions to produce adipocytes, generate ASP in the culture medium; and that human adipocytes also become more responsive to ASP as they differentiate. The aim of this study, therefore, was to examine the temporal production of ASP during adipocyte differentiation in relation to other adipose specific factors involved in lipogenesis. The results demonstrate that (i) there was little ASP production by differentiating adipocytes over the first 7 days, with a marked increase in ASP thereafter (up to sixfold); (ii) this increase was paralleled by large increases in the message level of factor B and complement C3 and moderate increases in adipsin message; (iii) increases in lipoprotein lipase (LPL) message and glycerol-3-phosphate dehydrogenase (GPDH) activity (both key enzymes for substrate supply for triacylglycerol synthesis) occurred earlier than the increase in ASP; and (iv) in spite of the increase in LPL and GPDH, triacylglycerol synthetic capacity only markedly increases following the increase in ASP production in adipocytes. Although the present study cannot be interpreted as showing causality with respect to triacylglycerol synthesis, it does point to an important role for ASP in human adipose tissue physiology.

Adipocytes↗
PubMed1987

Is contact activation of the coagulation system involved in the genesis of the first-use syndrome?

A number of mechanisms have been thought to be involved in the pathogenesis of the first-use syndrome. These include IgE antibody-mediated response to ethylene oxide-related antigens, membrane activation of the alternative complement pathway, activation of tissue mast cells and basophils by materials released from the dialyzer into the circulation, and transfer of bacterial products through high flux dialyzer. However, the possible role of the activation of blood coagulation system and platelets during dialysis has not been considered. The present communication reviews the theoretical basis for a possible connection between dialysis-induced activation of platelets and coagulation system with the first-use syndrome. Although the available data concerning the activation of intrinsic coagulation pathway during dialysis are conflicting, there is no controversy as to the occurrence of platelet activation. It is suggested that biochemical events triggered by activation of these systems may in part contribute to the genesis of first-use syndrome.

Anaphylaxis↗
PubMed1993

Granulocyte superoxide anion and elastase release during cardiopulmonary bypass.

Cardiopulmonary bypass (CPB) is known to induce several pathogenic responses in cardiovascular surgery. To explore leukocyte activation during PCB, we investigated superoxide anion (O2-) production by granulocytes in 6 patients undergoing aortocoronary bypass surgery. O2- production was determined with chemiluminescence amplified by a cypridina luciferin analogue. Granulocytes collected from the blood in the arterial site of the CPB circuit were stimulated by phorbol myristate acetate, n-formyl-methionyl-leucyl-phenylalanine, and opsonized zymosan. All the stimulators failed to disclose a significant difference between the magnitude of chemiluminescence during and after CPB. However, significant complement activation was detected, and the plasma level of granulocyte elastase increased gradually during and after CPB. This discrepancy between the unchanged O2- production by stimulated granulocytes and the increase in inflammatory mediators including granulocyte elastase may be due to sequestration of activated granulocytes in extravascular tissues. Namely, it was highly likely that activated granulocytes responsible for the increased plasma elastase level were sequestered and remained outside the blood circulation.

Aged↗
PubMed1993

Lipid apheresis by hemoperfusion: in vitro efficacy and ex vivo biocompatibility of a new low-density lipoprotein adsorber compatible with human whole blood.

To date, selective extracorporeal low-density lipoprotein (LDL) removal can only be performed from plasma; that is, a plasma-cell separation step using a centrifuge or a plasma membrane separator is necessary initially. This article characterizes a new polyacrylate-based LDL adsorber directly applicable to whole blood. In vitro single-pass hemoperfusion tests using pooled donor blood showed quantitative adsorption of atherogenic LDL-cholesterol (LDL-C) and complete recovery of protective high-density lipoprotein C. Fibrinogen, another independent risk factor of atherosclerosis, was also adsorbed to a lesser extent. Single-pass ex vivo biocompatibility using fresh donor blood on-line was excellent and resulted in minimal cell loss. Neither signs of hemolysis nor activation of monocytes (interleukin-1 production) were detected. Only slight activation of leukocytes (elastase release) and thrombocytes (platelet factor 4 secretion) as well as of coagulation (thrombin-antithrombin complex formation) and complement (C3a, C5a generation) was observed. Under the experimental conditions used, the optimal anticoagulation regimen was 0.5 IU heparin plus 0.375 mg citrate/ml blood. Priming the column with a buffer of pH 7.4 containing heparin, citrate, and Ca2+ is recommended. In conclusion, this new adsorber exhibited selective LDL-C adsorption in vitro combined with excellent ex vivo biocompatibility and thus holds great promise for a successful clinical application in a closed-loop system in patients.

Acrylic Resins↗