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PubMed1997

Anaphylatoxins in fresh-frozen plasma.

BACKGROUND: Fresh-frozen plasma (FFP) is widely used in patients with coagulation disorders and simultaneous complement activation. Complement activation in FFP itself is poorly investigated. STUDY DESIGN AND METHODS: The concentration of anaphylatoxins C3a and C5a, the complement precursors C1q and factor B, and complement function were measured in 40 consecutively administered FFP units in two pediatric neonatal intensive care units. In 12 samples, the measurements were also performed after incubation with inulin. RESULTS: In 15 of 40 FFP units, both anaphylatoxin concentrations were below the upper cutoff levels reported for healthy humans (C3a, 500 microg/L; C5a, 5 microg/L). Anaphylatoxin levels were higher in FFP units produced by apheresis than in those from blood donation. Complement activation of FFP by inulin increased anaphylatoxin concentration, whereas C1q and factor B levels, and complement function remained unchanged. CONCLUSION: Elevated concentrations of anaphylatoxin are frequently found in FFP units produced by apheresis. Studies are necessary to investigate the reasons for complement activation and the possibilities of prevention during apheresis. As the concentrations of complement precursors and complement function did not change with activation in FFP, these studies should include measurement of the anaphylatoxins C3a and C5a.

Anaphylatoxins↗

PubMed2002

M(+) group a streptococci are phagocytized and killed in whole blood by C5a-activated polymorphonuclear leukocytes.

Historically, resistance to phagocytosis has been determined by incubating group A streptococci in human blood and comparing the numbers of CFU before and after incubation. Utilizing a flow cytometry-based technique, we have investigated the phagocytosis of M(+) group A streptococci by polymorphonuclear leukocytes (PMNs) in heparinized human peripheral whole blood. Intracellular labeling of streptococci with a nontoxic fluorescent dye allowed us to quantify the association and phagocytosis of M(+) streptococci by PMNs in whole blood in the presence or absence of C5a, a physiologically important chemotactic activator of PMNs. We found that wild-type strains of group A streptococci that are resistant to phagocytosis (determined by the classical Lancefield method) readily associate with C5a-activated whole-blood PMNs. In the absence of opsonizing M-type-specific antibodies, the M(+) streptococci associated with PMNs are phagocytized and killed. In addition, blockade of the beta(2) integrin, CD11b/CD18, with anti-human CD11b monoclonal antibody inhibited association between M(+) streptococci and C5a-activated PMNs. These findings establish a new relationship between M(+) streptococci and PMNs, in which C5a-activated PMNs have the capacity to kill M(+) streptococci in whole blood through a receptor-mediated phagocytic mechanism.

Antibodies, Monoclonal↗

PubMed1993

Complement 5a induces in vivo synthesis of cysteinyl leukotrienes in rats.

The complement derived anaphylatoxin complement 5a (C5a) is suggested to be involved in the pathogenesis of various types of diseases including endotoxic or anaphylactic shock. Studies in our laboratory demonstrated a marked and sustained reduction in renal blood flow and glomerular filtration rate after infusion of a low dose of recombinant C5a (rC5a). Renal rC5a effects were inhibited by leukotriene (LT) and thromboxane antagonists suggesting that the effects were mediated by LT. To elucidate the mechanisms of C5a effects, we monitored the biliary excretion rate of the stable metabolite, N-acetyl-LTE4, by reversed phase high performance liquid chromatography (HPLC). Rats in the experimental group were administered rC5a intravenously at 0.5 micrograms/min for 10 min. Biliary N-acetyl-LTE4 excretion was significantly increased following rC5a infusion, 0.03 ng/microliters bile to 0.129 ng/microliters. The bile flow in the experimental group was reduced about 39% by rC5a, while bile flow of the control group increased by 20% during the observation period. Infusion of rC5a resulted in an increase of arterial hematocrit from 44.7% to 48.7%, whereas blood pressure was not significantly altered in experimental and control groups. Our results suggest the in vivo effects of C5a to be mediated by cysteinyl leukotrienes, which may be important in the pathogenesis of septic, anaphylactic or traumatic shock.

Animals↗

PubMed1989

Histamine and sulfidoleukotriene release from human basophils: different effects of antigen, anti-IgE, C5a, f-Met-Leu-Phe and the novel neutrophil-activating peptide NAF.

Human blood leukocytes were challenged by IgE-dependent stimuli (antigens or anti-IgE antibodies) and the chemotactic agonists C5a, N-formyl-Met-Leu-Phe (fMLP) or NAF, a novel neutrophil-activating peptide produced by stimulated human monocytes. IgE-dependent stimuli induced abundant release of histamine and sulfidoleukotrienes (LTC, LTD and LTE). The effects of the chemotactic peptides differed considerably: C5a induced high percentages of histamine release already at concentrations as low as 10(-9) M, but no leukotriene formation: NAF was completely inactive up to 10(-6)M, and fMLP induced moderate release of both products at relatively high concentration only (1-2.5 x 10(-6) M). All three chemotactic peptides, however, induced a concentration-dependent release of elastase from cytochalasin-B-treated human neutrophils. The EC50 was approximately 0.3, 2 and 5 x 10(-9) M for C5a, NAF and fMLP, respectively. NAF showed activity over a wider concentration range and its dose-response curve was less steep than that of the two other agonists. Our results suggest that NAF, that may be generated at the sites of hypersensitivity reactions, is likely to induced the immigration of neutrophils, but not the direct activation of basophils and mast cells. In this respect, NAF differs from less selective chemotactic peptides like the complement product C5a or the N-formyl-methionyl peptides.

Antibodies, Anti-Idiotypic↗

PubMed1998

Eosinophil leukocyte degranulation in response to serum-opsonized beads: C5a and platelet-activating factor enhance ECP release, with roles for protein kinases A and C.

BACKGROUND: Eosinophils have a typical content of granule-bound, cytotoxic, cationic proteins which may, when released to the external milieu, play roles in diseases such as asthma and parasitic infestation. Therefore, we have investigated possible mechanisms by which their release is regulated in eosinophils. METHODS: The enzyme-linked immunosorbent assay (ELISA) was used to detect released eosinophil cationic protein (ECP). Release of ECP was induced by serum-opsonized, nonphagocytosable Sephadex beads (SOS). RESULTS: The complement fragment C5a and platelet-activating factor (PAF) were found to enhance ECP release in response to SOS in a dose-dependent fashion, and, contrary to previous reports, they were not found to act as secretagogues themselves on eosinophils in suspension. The role of protein kinase C (PKC) in eosinophil degranulation has been controversial. We found that ECP release induced by SOS was inhibited by the PKC inhibitors staurosporine and calphostin C. Activation of protein kinase A (PKA), by raising cAMP, also inhibited ECP release. Furthermore, pertussis toxin decreased ECP release on opsonized beads, indicating the involvement of pertussis-toxin-sensitive G proteins. CONCLUSIONS: C5a, and PAF enhance granule release, rather than acting as secretagogues themselves. PKC and PKA have opposing roles in the regulation of ECP release in response to SOS.

Blood Proteins↗

PubMed1989

Complement activation by the alternative pathway is modified in renal failure: the role of factor D.

Factor D, an essential enzyme of the alternative pathway (AP) of complement, is eliminated by the kidney, and its plasma concentration increases 10-fold in end-stage renal disease (ESRD). The purpose of this study was to analyze the consequences of factor D accumulation. A number of in vitro assays were used to analyze AP activation in normal human serum (NHS), in normal serum supplemented with purified factor D to 10-fold its normal concentration (10 x D), and in sera of patients with ESRD. When compared with NHS, in 10 x D: 1) Spontaneous fluid-phase activation of complement at 37 degrees C was greatly increased as measured by C3 cleavage, 2) The lysis of rabbit erythrocytes, a function of the AP, was accelerated, 3) More C3 fragments bound to cuprophane membranes and to immune precipitates; both reactions were accompanied by the formation of more C5a, 4) Complement mediated solubilization of antigen-antibody precipitates was enhanced. Sera of patients with ESRD behaved similarly to 10 x D in all assays used, i.e., enhanced AP function, although complement activation measured in these assays varied widely from one individual to another. Thus, the elevated factor D concentration observed in renal failure might have important pathophysiological consequences, some of which could be detrimental (e.g., C5a produced during hemodialysis), while others might be beneficial, e.g., solubilization of immune precipitates.

Aged↗

PubMed1986

Inhibition of immunological and non-immunological histamine release from human basophils and lung mast cells by formoterol.

3-Formylamino-4-hydroxy-alpha(N-1-methyl-2-p-methoxyphenethyl-a min omethyl)benzylalcohol hemifumarate (formoterol fumarate, BD40 A, CGP 25 827 A-E) inhibited both allergic (anti-IgE) and non-allergic histamine release (calcium ionophore and human complement component C5a) from human basophils. The degree and efficacy of inhibition was comparable to that of ketotifen, equal to or better than fenoterol and ten times more potent than isoprenaline (beta 2-stimulator). Salbutamol, another beta 2-stimulator was practically ineffective in these models. Similarly the anti-IgE, calcium ionophore and complement component C5a induced release of histamine from human lung mast cells could be blocked by formoterol, its potency being again comparable to that of ketotifen. The above degranulation inhibition effect taken together with the pronounced bronchodilator property would confirm formoterol as a drug of choice in asthma with more efficient action than the other beta 2-stimulators such as fenoterol, salbutamol or isoprenaline.

Albuterol↗

PubMed2006

The role of the N-terminal domain of the complement fragment receptor C5L2 in ligand binding.

C5L2 is a new cellular receptor found to interact with the human anaphylatoxins complement factor C5a and its C-terminal cleavage product C5a des Arg. The classical human C5a receptor (C5aR) preferentially binds C5a, with a 10-100-fold lower affinity for C5a des Arg. In contrast, C5L2 binds both ligands with nearly equal affinity. C5aR presents acidic and tyrosine residues in its N terminus that interact with the core of C5a while a hydrophobic pocket formed by the transmembrane helices interacts with residues in the C terminus of C5a. Here, we have investigated the molecular basis for the increased affinity of C5L2 for C5a des Arg. Rat and mouse C5L2 preferentially bound C5a des Arg, whereas rodent C5aR showed much higher affinity for intact C5a. Effective peptidic and non-peptidic ligands for the transmembrane hydrophobic pocket of C5aR were poor inhibitors of ligand binding to C5L2. An antibody raised against the N terminus of human C5L2 did not affect the binding of C5a to C5L2 but did inhibit C5a des Arg binding. A chimeric C5L2, containing the N terminus of C5aR, had little effect on the affinity for C5a des Arg. Mutation of acidic and tyrosine residues in the N terminus of human C5L2 revealed that 3 residues were critical for C5a des Arg binding but had little involvement in C5a binding. C5L2 thus appears to bind C5a and C5a des Arg by different mechanisms, and, unlike C5aR, C5L2 uses critical residues in its N-terminal domain for binding only to C5a des Arg.

Amino Acid Substitution↗

PubMed2001

Trimeresurus flavoviridis (habu snake) venom induces human erythrocyte lysis through enzymatic lipolysis, complement activation and decreased membrane expression of CD55 and CD59.

Trimeresurus flavoviridis (habu snake) bites can be fatal to man because of its virulent venom, which is clinicopathologically classified as haemorrhagic, necrotic, and haemolytic toxins. Trimeresurus flavoviridis venom causes lysis of human erythrocytes in conditions where plasma is present as well as in plasma-free conditions in a dose-dependent manner. The haemolytic process requires Ca2+ and Mg2+ ions in the solution. Additionally, the venom initiates activation of the human complement cascade as evidenced by C3a and C5a releases, complement consumption indicated by CH50 and formation of soluble membrane attack complex. The insertion of membrane attack complex into the erythrocyte membranes is morphologically identified by electronmicroscopy. Immunofluorescence analysis reveals that incubation of erythrocytes with the venom decreased cell-surface expression of CD55 (decay accelerating factor) and CD59 (protectin), which renders erythrocyte more vulnerable to adherent C3 and C5 convertases and to polymerization of C9 into membranes, and may enhance autologous complement-mediated haemolysis triggered by the venom. Our data demonstrate that Trimeresurus flavoviridis venom induces haemolysis in the presence of plasma by three distinct mechanisms, direct lipolysis through PLA2 activity, activation of the human complement system, and cleavages of CD55 and CD59 from erythrocyte membranes.

Animals↗

PubMed1979

Immune complex injury of the lung.

Abundant evidence currently exists to suggest that immune complexes play an important role in inflammatory diseases of the lung. Clinically, idiopathic pulmonary fibrosis, eosinophilic granuloma of lung, and systemic lupus erythematosus have been shown to be associated with the presence of immune complexes both in lung and in the serum. Experimentally, there is compelling evidence that acute lung injury can be triggered by the deposition of complexes in vascular walls or by the presence of performed immune complexes instilled into the airways. The observed reactions are, as expected, complement- and neutrophil-dependent. The morphologic changes in lung caused by products of complement activation (C5a and related peptides) depend on whether complement activation occurs within the vasculature or within the airways. Airway activation is associated with intraalveolar accumulations of neutrophils, while intravascular activation leads to intracapillary sequestration of neutrophils. The chronic formation of immune complexes within the vasculature (in the model of "chronic serum sickness") leads to an interstitial fibrotic reaction and a thickening of basement membranes. Recent studies of intravascularly infused preformed immune complexes indicate a proclivity for certain types of complexes to localize within lung. These "lung-seeking" complexes differ from non-lung-seeking complexes only in the ratio of antigen to antibody. Complement does not seem to alter the tendancy for certain complexes to localize within lung. These studies emphasize the potential importance of immune complexes in lung injury and point out the variety of mechanisms involved in both the localization process and the injury process.

Animals↗

PubMed1996

Neutrophils and myocardial reperfusion injury.

Ischaemia induces an acute inflammatory response in myocardial tissue with an early phase of neutrophil accumulation, which is accelerated by reperfusion. In experimental models, interventions that deplete neutrophils or inhibit their function cause a significant reduction in myocardial infarct size. These cells, therefore, may exacerbate tissue injury through the release of free radicals and proteolytic enzymes. Neutrophil recruitment depends on the presence of inflammatory mediators. Leukotriene B4, interleukin 8 and the complement fragment C5a have been implicated in this process. Studies using antibodies to the selectin, integrin and immunoglobulin superfamily adhesion molecules indicate that they also have a crucial role in myocardial neutrophil recruitment.

Animals↗

PubMed1993

Induction of interleukin-8 expression during cardiopulmonary bypass.

BACKGROUND: Patients undergoing cardiopulmonary bypass (CPB) are known to suffer from a postsurgical systemic inflammatory response, the nature of which remains to be fully elucidated. Interleukin-8 (IL-8) is a newly described, powerful leukocyte chemotactic factor known to be generated after stimulation of interleukin-1 (IL-1). As we have previously documented the generation of IL-1 beta after CPB, it followed that IL-8 generation should be measured in a comparable group of patients. METHODS AND RESULTS: Twenty-two adult patients aged 41 to 81 years undergoing coronary revascularization were studied for measurements of C3a, C5a, IL-1, IL-8, and OH(.). Blood was collected before surgery, after CPB, and at 24, 48, and 72 hours. A significant increase in IL-1 beta and IL-8 was detected in circulating leukocytes with peak levels at 24 hours after bypass. No IL-1 beta or IL-8 antigen was detected at any time in patient plasma. Comparable to interleukin generation, human complement-derived C5a also peaked after 24 hours, whereas C3a was increased dramatically immediately after CPB, followed by a decline at 24 hours and a progressive increase over the next 48 hours. CONCLUSIONS: The results demonstrated for the first time the presence of cell-associated IL-8 in CPB patients. This suggests that this powerful polymorphonuclear and T-lymphocyte chemotactic factor may be an important element in leukocyte activation and recruitment after CPB.

Adult↗

PubMed1995

C5a-induced migration of human monocytes is primed by dexamethasone.

Allergic inflammation in the lung is characteristic of allergic asthma. This inflammatory process is inhibited by treatment with glucocorticoids. One of the cell types involved in the inflammatory process, the monocyte, is found in enhanced numbers in mucosal lung biopsies of asthmatic patients. Little is known about the mechanisms that lead to increased numbers of monocytes in lung tissue. We studied one of the processes involved, chemotaxis, in a modified Boyden Chamber assay. The effect of the antiinflammatory drug dexamethasone was tested on monocyte chemotactic responses to complement fragment C5a. Human monocytes from peripheral blood of normal human volunteers were purified by centrifugal elutriation. The monocytes showed a reproducible chemotactic response toward C5a with an optimum at a concentration of 10(-9) M. After culture of the monocytes overnight, the monocyte responses were clearly impaired. It is interesting that upon culture, dexamethasone increased monocyte chemotaxis in a dose-dependent manner. Analysis of the filters with an image analyzer showed that the effect was not through modulation of a subpopulation of monocytes. This steroid effect was specific and modulated via steroid receptors, because the introduction of RU 38486, a steroid receptor antagonist, completely inhibited the effect of dexamethasone. These findings are a further illustration of the complex mechanisms involved in the orchestration of the inflammatory response in asthma.

Antigens, CD↗

PubMedDate not supplied

In vivo left ventricular assist induced coagulation derangements. Comparison of Sarns-3M and St. Jude Medical circuits.

An in vitro comparison of centrifugal pumping systems manufactured by Sarns-3M and St. Jude Medical revealed a difference in blood cell derangement. The purpose of this study was to compare in vivo the effects of 96 hr of left ventricular assist (LVA) on indexes of coagulopathy, hemolysis, and complement activation. Two groups of calves (each: n = 5) were instrumented with identical left atrial to thoracic aorta centrifugal pumping circuits using either Sarns-3M or St. Jude centrifugal pumps. Laboratory evaluations were performed pre-assist and at 1, 4, 24, 48, 72, and 96 hr during LVA. Platelet counts dropped significantly by 24 hr (Sarns-3M: 28%; St. Jude: 30%); no significant change in function was noted. Activated clotting time increased slightly (p > 0.05). Prothrombin time increased at 4 and 24 hr of LVA, returning to baseline by 96 hr (p < 0.05). Activated partial thromboplastin time increased with the St. Jude device from 24 to 96 hr on LVA (p < 0.05); the increase with the Sarns-3M device never reached significance. No significant changes in lactate dehydrogenase or plasma free hemoglobin were detected. Complement fraction C5a rose by 1 hr of LVA (p < 0.05), peaking at 4 hr and returning to baseline by 96 hr with both pumps. No significant difference was detected between pump groups for any of the parameters. It was concluded that 1) 96 hr Sarns-3M and St. Jude LVA caused coagulation derangement in calves, 2) neither pump demonstrated an advantage regarding coagulation and complement parameters, 3) hemolysis observed with the Sarns-3M pump in vitro was not evidenced in vivo, and 4) in vitro evidenced centrifugal pump differences may not be realized in vivo.

Animals↗

PubMed1985

Oxygen radicals in complement and neutrophil-mediated acute lung injury.

The development of experimental acute lung injury following systemic complement activation is closely related to availability of blood neutrophils. Although tissue-destructive neutrophil-derived proteinases may play a supportive role in acute pulmonary injury, it appears that oxygen radical constitute the major neutrophil product responsible for acute damage of lung tissues and cells. Intravascular activation of neutrophils by the chemotactic complement peptide C5a is related to the generation of superoxide anion. Dismutation of superoxide to hydrogen peroxide and its iron-mediated conversion to hydroxyl radical appear to constitute in vivo events that ultimately lead to acute lung microvascular injury.

Animals↗

PubMed1986

Enhancement of human polymorphonuclear leukocyte adherence to plastic and endothelium by phorbol myristate acetate. Comparison with human C5a.

The adherence of circulating neutrophils to vascular endothelium represents a necessary step in the chemotactic emigration of neutrophils to extravascular inflammatory sites. Studies of neutrophil adherence induced by phorbol myristate acetate (PMA) were undertaken to determine the ability of a nonchemotactic neutrophil stimulus to provoke increased adherence. The authors found that the adherence of human neutrophils to plastic surfaces or confluent monolayers of endothelial cells is enhanced in a concentration-dependent fashion by exposure of neutrophils to PMA. The effect of PMA concentration (0.1-5.0 ng/ml) on increased neutrophil adherence parallels that observed for superoxide anion generation and release of lysosomal enzymes from specific granules. Whereas complement C5a-treated neutrophils exhibited a fourfold to fivefold increase in adherence to endothelial cells, PMA-treated neutrophils showed a 10-fold to 20-fold increase. The ability of PMA to cause increased neutrophil adherence to endothelium appeared to be directed primarily at the neutrophil. Pretreatment of neutrophils with PMA was as effective as coincubation in causing increased adherence to plastic surfaces or confluent cultured endothelial cells, but pretreatment of endothelial cells with PMA failed to promote neutrophil adherence. Alteration of neutrophil cytoskeletal structures by cytochalasin B treatment did not prevent subsequent PMA-stimulated neutrophil adherence. These results demonstrate that increased neutrophil adherence to surfaces can be induced by a nonchemotactic stimulus and that neutrophil adherence is independent of organized microfilaments.

Cell Adhesion↗

PubMed1988

Anaphylatoxin levels in human vitreous humor.

The complement system is involved not only in host defense against infection but also in autoimmune tissue damage. Using a radioimmunoassay, we sought to measure levels of C3a, C4a and C5a (activated complement fragments with anaphylatoxin functions) in human vitreous humor from eyes with and without vitreal inflammation. Vitreous from 11 patients with clinical evidence of vitritis (Group 2) had significantly higher levels of protein, C3a and C4a and significantly higher ratios of these anaphylatoxins to protein than vitreous from 19 patients without clinical evidence of vitritis (Group 1). The finding that not only the absolute levels of anaphylatoxins but also the ratios of anaphylatoxins to protein were significantly higher in vitreous from Group 2 than vitreous from Group 1 or normal plasma suggested that complement activation was taking place in inflamed vitreous. Because of irreversible binding to leukocytes, C5a is difficult to measure and correlate with complement activation, and we were unable to detect it in any vitreous sample.

Anaphylatoxins↗

PubMed1988

The effect of L-glutamic acid on airway function and reactivity in the rabbit.

The ingestion of monosodium glutamate in sensitive individuals has been reported to cause severe asthma. We therefore studied the effects of L-glu on airway function and histamine (H) responsiveness in the rabbit. Histamine dose response curves (HDR's) were performed by measuring total lung resistance (RL) after inhalation of saline and increasing concentrations of H (1-30 mg/ml). The concentration of H producing a 20% increase in RL (PC20H) was obtained by interpolation. To assess the effects of L-glu, 8 rabbits were infused with L-glu (0.2 g/kg/hr) or saline in random order (14 days apart) for 4 hours followed by an HDRC. To look at possible late effects, a repeat HDRC was also performed in 6 rabbits 12 hours after completion of the L-glu infusion. In order to see whether rabbits rendered hyperresponsive responded to L-glu, the above protocol was performed in 7 rabbits following the inhalation of 3 micrograms of the activated complement fragment C5a des Arg. The L-glu infusions increased the plasma levels approx. ten-fold (mean +/- SEM 0.119 +/- 0.012 base-line, 1.272 +/- 0.061 mmol/l post infusion). L-glu did not increase the PC20H or baseline RL in either the normal rabbits at 4 or 12 hours or in the C5a des Arg treated rabbits at 4 hours. It is concluded that L-glu does not cause bronchoconstriction or an increase in airway responsiveness to H in the rabbit.

Administration, Inhalation↗