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PubMed1984

Severe pulmonary hypersensitivity associated with passive transfusion of a neutrophil-specific antibody.

A life-threatening pulmonary hypersensitivity reaction accompanied by profound leucopenia and transient hypocomplementaemia developed in a 73-year-old man after repair of an abdominal aortic aneurysm. A neutrophil-specific antibody, anti-NA2) was demonstrated by granulocyte immunofluorescence and microagglutination in one of the transfused donor units. In addition, activated complement component C5a was generated in vitro by incubation of the patient's serum with the aortic graft material. This severe clinical reaction may have resulted from the interaction of the transfused anti-NA2 antibody with complement activation induced by the aortic graft material.

Aged↗

PubMed2002

Pulmonary leukostasis and the inhibition of airway neutrophil recruitment are early events in the endotoxemic rat.

Neutrophil (polymorphonuclear leukocyte [PMN]) migration into pulmonary airspaces is a prerequisite for clearance of bacteria commonly found in nosocomial pneumonia. Patients at risk for nosocomial pneumonia often experience endotoxemia, and neutrophil dysfunction is associated with endotoxemia in both humans and animals. Using a rodent model of endotoxemia-associated pneumonia, we characterized the altered kinetics of pulmonary PMN trafficking and addressed the roles of platelets, tumor necrosis factor (TNF), and products of complement activation as potential mediators in the modulation of PMN migratory function. In male Sprague-Dawley rats made endotoxemic with intravenously (i.v.) administered endotoxin (lipopolysaccharide [LPS]), recruitment of PMNs into the lung airspaces in response to intratracheally (i.t.) instilled LPS was inhibited. In animals given IT LPS alone (0.5 mg/rat), numbers of airway PMNs were significantly elevated by 2 h, and immunohistochemical evaluation revealed PMNs in alveolar airspaces, alveolar walls, and in interstitium surrounding large airways. LPS (2 mg/kg i.v.) caused neutropenia and pulmonary PMN sequestration within 15 min of administration. Inhibition of airway PMN accumulation occurred by 30 min and lasted for at least 6 h after i.v. LPS. Factors present or activated after 30 min of endotoxemia were hypothesized to mediate the inhibitory effect of i.v. LPS. We found that pretreatment of rats with cobra venom factor to deplete complement (and C5a production) or immunodepletion of platelets or TNF did not affect the ability of i.v. LPS to inhibit pulmonary PMN recruitment or to cause pulmonary leukostasis. In summary, our results show that the inhibitory effects of i.v. LPS on PMN trafficking are rapid and persist for several hours and suggest that neither TNF, C5a, nor platelets are sufficient to mediate the inhibitory response.

Animals↗

PubMed2003

Analysis of C5a-mediated chemotaxis by lentiviral delivery of small interfering RNA.

Immune cells respond to chemotactic signals by means of G protein-coupled receptors. Attempts to elucidate the function of specific G protein family members in these responses is complicated by redundancy among the different G protein isoforms. We have used lentiviral-based RNA interference to eliminate expression of specific G protein subunits selectively in J774A.1 mouse macrophages. The chemotactic response to the complement factors C5a and C3a is ablated in cells lacking G beta(2) but is unaffected in cells lacking G beta(1), G alpha i(2), or G alpha i(3). Similarly, the C5a-mediated calcium response of single cells is either absent or significantly delayed and weakened by G beta(2) knockdown. Assessment of Akt1 phosphorylation levels in response to C5a shows rapid and sustained phosphorylation in both wild-type cells and cells lacking G beta(1). Cells lacking G beta(2) retain the rapid response but cannot sustain phospho-Akt1 levels. The phenotype of cells lacking G beta(2) can be reversed by overexpression of either human G beta(2) or mouse G beta(1). These data demonstrate the usefulness of lentiviral-based RNA interference in the systematic analysis of a signaling pathway, and they suggest that in J774A.1 cells, G beta(2)-derived G beta gamma is the most effective mediator of chemotaxis to C5a.

Animals↗

PubMed2002

TNF-alpha potentiates C5a-stimulated eosinophil adhesion to human bronchial epithelial cells: a role for alpha 5 beta 1 integrin.

Cooperative action of inflammatory mediators and adhesion molecules orchestrates eosinophil recruitment during allergic inflammation in the airways. This study investigated the mechanisms involved in increasing eosinophil adhesion to human bronchial epithelial cells (HBEC) following priming and activation of eosinophils with TNF-alpha and complement protein C5a, respectively. Under primed conditions, eosinophil adhesion increased 3-fold from basal (16%), and the effect was significantly greater (p < 0.05) than the increase following stimulation with C5a alone (2-fold). Eosinophil contact with HBEC was essential for priming. In contrast to C5a, adhesion of eotaxin-stimulated eosinophils to HBEC was not primed with TNF-alpha nor IL-5, a known eosinophil-priming agent. Priming caused activation of alpha(M)beta(2) integrin; mAb against either the common beta(2) integrin subunit or its ICAM-1 ligand reduced the primed component of adhesion. Using mAbs against beta(1) or alpha(5), but not alpha(4) integrin subunit, together with anti-beta(2) integrin mAb, reduced stimulated adhesion to basal levels. Cross-linking alpha(5)beta(1) integrin increased alpha(M)beta(2) integrin-dependent adhesion of eosinophils. There are no known adhesion molecule ligands of alpha(5)beta(1) integrin expressed on HBEC; however, fibronectin, the major matrix protein ligand for alpha(5)beta(1) integrin, was detected in association with HBEC monolayers. A mAb against fibronectin, in combination with anti-beta(2) integrin mAb, reduced adhesion to basal levels. In conclusion, alpha(5)beta(1) integrin may provide a contact-dependent costimulus for eosinophil priming that, together with TNF-alpha, potentiated C5a activation of alpha(M)beta(2) integrin and increased eosinophil adhesion to ICAM-1. Fibronectin, associated with HBEC, may act as a ligand for alpha(5)beta(1) integrin. Dual regulation of eosinophil priming may prevent inappropriate activation of eosinophils in the circulation.

Adjuvants, Immunologic↗

PubMed1990

Antiinflammatory peptides (antiflammins) inhibit synthesis of platelet-activating factor, neutrophil aggregation and chemotaxis, and intradermal inflammatory reactions.

Synthetic peptides corresponding to the region of highest similarity between human lipocortin I and rabbit uteroglobin inhibit phospholipase A2 and show potent antiinflammatory activity on the carrageenan-induced rat footpad edema. The peptide HDMNKVLDL (antiflammin-2) inhibits the synthesis of platelet-activating factor (PAF) induced by TNF or phagocytosis in rat macrophages and human neutrophils, and by thrombin in vascular endothelial cells. The peptide MQMKKVLDS (antiflammin-1) is less inhibitory than antiflammin-2 for macrophages and not inhibitory for neutrophils after a 5-min preincubation. This finding suggests that antiflammin-1 is inactivated by neutrophils secretory products, possibly oxidizing agents. Synthesis of PAF is inhibited by antiflammin-2 without an appreciable lag, but this inhibition is reversed when neutrophils or macrophages are washed and incubated in fresh medium. Therefore, antiflammins must be continuously present to inhibit PAF synthesis. Antiflammins block activation of the acetyltransferase required for PAF synthesis, suggesting that this enzyme is another target for the inhibitory activity of antiflammins. These peptides inhibit neutrophil aggregation and chemotaxis induced by complement component C5a. Antiflammin-2 suppresses the increase in vascular permeability and the leukocyte infiltration induced in rats by an Arthus reaction or by intradermal injection of rTNF and C5a.

Anti-Inflammatory Agents, Non-Steroidal↗

PubMed1998

Role of complement in in vitro and in vivo lung inflammatory reactions.

Complement is one of the integral buttresses of the inflammatory response. In addition to host defense activities, proinflammatory properties of several complement components are described. This overview elucidates the role of complement in inflammatory reactions in vitro and in vivo, focusing on the complement activation products, C5a, and the membrane attack complex, C5b-9. Using several approaches, the impact of these complement components in mechanisms relevant to neutrophil recruitment is emphasized. In addition, the participation of complement in endothelial superoxide generation and its essential requirement for full expression of lung injury is demonstrated, as are the involved intracellular signal transduction pathways. Understanding the mechanisms of complement-induced proinflammatory effects may provide a basis for future therapeutic blockade of complement and/or its activation products.

Complement Activation↗

PubMed1992

Bacterial evasion of the antibody response: human IgG antibodies neutralize soluble but not bacteria-associated group B streptococcal C5a-ase.

Most strains of group B streptococci (GBS) possess an enzyme that inactivates the human anaphylatoxin C5a by cleaving a heptapeptide from the carboxyl terminus of C5a. This enzyme, called GBS C5a-ase, has been purified to homogeneity and cleaves and inactivates C5a in physiologic buffer. The enzymatic activity of soluble C5a-ase is completely inhibited, however, in the presence of plasma or serum from normal human adults. The neutralization of soluble C5a-ase by plasma and serum results largely from naturally occurring IgG antibodies directed against C5a-ase. IgG does not neutralize C5a-ase present on intact encapsulated type III GBS but does neutralize the C5a-ase activity associated with a transposon-induced mutant strain of type III GBS that lacks capsule. The location of GBS C5a-ase on the surface of encapsulated type III GBS permits the C5a-ase to inactivate C5a while evading neutralization by IgG antibodies.

Adhesins, Bacterial↗

PubMed1972

The relationship of the chemotactic behavior of the complement-derived factors, C3a, C5a, and C567, and a bacterial chemotactic factor to their ability to activate the proesterase 1 of rabbit polymorphonuclear leukocytes.

The inhibition profiles obtained when a series of p-nitrophenyl ethyl alkylphosphonates and of p-nitrophenyl ethyl chloroalkylphosphonates were used to interfere with the chemotactic activity of polymorphonuclear leukocytes stimulated by C3a, C5a, and bacterial factor were the same as found previously when C567 was the chemotactic agent. This indicates that as in the chemotactic activity induced by C567, an obligatory step in the chemotaxis caused by C3a, C5a, and bacterial factor is the activation of proesterase 1 of the rabbit polymorphonuclear leukocyte. C5a and C3a activate proesterase 1 of peripheral blood polymophonuclear leukocytes as measured by the increase of acetyl DL-phenylalanine beta-naphthyl esterase activity. Attempts to detect in a like manner the proesterase 1 of the same leukocytes using bacterial factor under varying circumstances have consistently failed. It is concluded that bacterial factor, for unknown reasons, is unable to activate proesterase 1 to the same extent as the complement-derived chemotactic factors. The hypothesis of there being a quantitative difference in the ability of bacterial factor to activate proesterase 1 compared with the complement-derived factors explains the previous observations that bacterial factor can not deactivate to itself or to the complement-derived factors, although these latter factors can deactivate to themselves, to each other, and to the bacterial factor. The quantitative difference in the ability of bacterial factor to activate proesterase 1 compared to the complement-derived factors is also associated with and explains the finding that the maximal chemotactic activity attainable when bacterial factor is the chemotactic agent is distinctly less than that obtained using either C3a, C5a, or C567. These results indicate that the activation of proesterase 1 is a general requirement for the chemotactic activity of rabbit polymorphonuclear leukocytes with known macromolecular chemotactic agents and suggest that under several different circumstances the level of chemotactic activity attained is related to the degree of such activation.

Animals↗

PubMed1984

Regulation of neutrophil migratory function in burn injury by complement activation products.

Polymorphonuclear neutrophils were isolated from patients with burn injury and random mobility, chemotaxis in response to C5adesArg (as agarose-activated control serum) and to N-formyl-methionyl-leucyl-phenylalanine (F-Met-Leu-Phe) were assessed. For a group of eight patients identified as not experiencing systemic infection, all three neutrophil migratory functions were observed to fall below control levels, beginning 4 to 6 days following burn injury, and to return to control levels after 21 to 30 days of hospitalization. Over this time the chemotactic differential (distance chemotactic migration-distance random migration) for F-Met-Leu-Phe remained positive, while the chemotactic differential for activated serum became nil after postburn day 4. This temporal, specific loss of a chemotactic response to activated serum was associated with rises in immunoreactive plasma C3a and C5a. This pattern of loss of chemotactic function was associated with a selective loss of C5a but not F-Met-Leu-Phe binding activity. These results demonstrate that burn injury can alter neutrophil migratory functions generally, and specifically depress chemotactic responsiveness to activated serum. The mechanism of the latter phenomenon appears to be related to desensitization of circulating neutrophils to C5a due to complement activation.

Adolescent↗

PubMed1989

Decreased releasability of basophils from patients with cold urticaria after cold exposure.

Histamine release from peripheral blood basophils challenged with C5a, f-met-peptides and calcium ionophore was studied in patients with cold urticaria before and after exposure to low environmental temperatures. Compared to healthy controls, stimulated mediator release before cold exposure was increased in 7 of 11 patients. When challenged by cold exposure mediator release from in vitro-stimulated basophils was decreased. This decrease was more pronounced after stimulation with receptor-mediated stimuli (e.g. C5a) as compared to receptor-unrelated stimuli, e.g. calcium ionophore. In 4 of 11 patients stimulated mediator release before cold exposure was moderately increased. Also after cold exposure only a weak decrease of stimulated histamine release was seen. Levels of activated complement components (C3a) before and after cold exposure failed to provide evidence for complement activation in vivo. Also the number of circulating basophils as well as their cellular histamine content remained normal after cold exposure. The results show that in these patients release of histamine is altered before and after cold exposure. These changes in basophil responsiveness are not due to complement activation in vivo.

Basophils↗

PubMed1984

Selective inhibition by phenytoin of chemotactic factor - stimulated neutrophil functions.

We have found that pretreatment of human neutrophils with phenytoin (0.05 to 0.8 mM) results in concentration-dependent, reversible inhibition of both superoxide anion generation and release of lysosomal enzymes (myeloperoxidase, lysozyme, beta-glucuronidase) provoked by either the synthetic peptide, N-formyl-methionyl-leucyl-phenylalanine (FMLP) or the complement fragment C5a. In contrast, phenytoin did not inhibit either enzyme release or superoxide anion generation by neutrophils stimulated with phorbol myristate acetate or serum-opsonized zymosan particles. Phenytoin did not provoke leakage from neutrophils of the cytoplasmic enzyme, lactate dehydrogenase, and did not inhibit directed migration (chemotaxis) of neutrophils toward either FMLP or C5a. Specific binding of 3H-FMLP to neutrophil membrane receptors was not altered significantly by pretreatment of the cells with a wide range of concentrations of phenytoin. With flow microfluorometry and the fluorochrome, 3,3'-dipentyloxacarbocyanine, phenytoin was shown to prevent FMLP-induced changes in fluorescence intensity (i.e., apparent neutrophil membrane depolarization). These data indicate that various neutrophil functions may be regulated independently at other than the receptor level and that neutrophil chemotactic responses to FMLP and C5a do not appear to be dependent on membrane events registered by 3,3'-dipentyloxacarbocyanine.

Animals↗

PubMed1988

C5a decreases regional coronary blood flow and myocardial function in pigs: implications for a granulocyte mechanism.

Granulocytes cause some of the pathophysiological effects associated with the capillary no-reflow phenomenon during ischemia and in ischemia-reperfusion injury. However, no study has examined the consequences of in vivo granulocyte activation during normal perfusion pressures. In this study, we examined the effects of intracoronary administration of the complement component C5a, which is known to be a potent granulocyte activating factor. Nine open-chest, anesthetized pigs were instrumented to monitor regional coronary blood flow and segment shortening, left ventricular dP/dt, heart rate, and pulmonary artery and aortic blood pressures and to sample arterial and regional coronary venous blood for oxygen content and complete blood counts. Intracoronary infusion of human or porcine C5a in doses ranging from 10 to 500 ng produced a significant reduction in regional coronary blood flow and myocardial function. Although perfusion pressure and heart rate remained constant, venous oxygen content fell, indicating an imbalance between myocardial oxygen supply and demand. In addition, the arteriovenous difference of white blood cells was increased significantly after anaphylatoxin infusion, indicating intravascular trapping in the myocardium. Granulocytes accounted entirely for the differences in leukocyte counts because no significant changes in platelet, lymphocyte, or hematocrit levels were observed. Injection of vehicle alone did not alter any of the monitored variables.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed2000

In vitro cleavage by asbestos fibers of the fifth component of human complement through free-radical generation and kallikrein activation.

Chrysotile and crocidolite fibers incubated in normal human plasma (NHP) generated from the C5 component of complement C5a-type fragments that stimulated polymorphonuclear leukocyte (PMN) chemotaxis. Absorption of NHP with antiserum against C5a totally abolished neutrophil chemotactic activity. Asbestos fibers also produced C5a small peptides in the presence of ethylene glycol bis(beta-aminoethyl ether) N,N,N'N'-tetraacetic acid (EGTA) but not ethylene diamine tetraacetic acid (EDTA). Activation of C5 was significantly inhibited when asbestos fibers were pretreated with iron chelators such as sodium dithionite (DTN), deferoxamine (DFX), or ascorbate (AA). Concentration-related inhibition of C5 activation was also observed when asbestos fibers were added concurrently to plasma in the presence of DFX, 1,3-dimethyl-2-thiourea (DMTU), a strong hydroxyl scavenger, or aprotinin (APR), a specific protease inhibitor. Further, chrysotile and crocidolite significantly increased plasma kallikrein activity. Data demonstrate that asbestos-induced C5 activation plays a role in inflammatory reactions characteristic of asbestosis through mechanisms involving iron ions, hydroxyl radicals, and oxidized C5-ike fragments. The ferrous ions present at the asbestos fiber surface trigger this activation and catalyze, via Fenton reaction, the production of hydroxyl radicals, which in turn convert native C5 to an oxidized C5-like form. This product is then cleaved by kallikrein, activated by the same asbestos fibers, yielding an oxidized C5a with the same functional properties as C5a.

Adult↗

PubMed2000

[From gene to disease; marenostrine and familial Mediterranean fever].

Familial mediterranean fever (FMF) is an autosomal recessive hereditary disorder associated with mutations in the gene on chromosome 16 encoding the protein pyrine (marenostrine). Marenostrine is thought to stimulate the production of an inactivator of a chemotactic factor (possibly C5a). The mutations result in ongoing inflammation, a hallmark of FMF. DNA diagnosis of FMF is operational in Leiden University, the Netherlands, for one year now.

Complement C5a↗

PubMed2002

Expression and function of C5a receptor in mouse microvascular endothelial cells.

The complement-derived anaphylatoxin, C5a, is a potent phlogistic molecule that mediates its effects by binding to C5a receptor (C5aR; CD88). We now demonstrate specific binding of radiolabeled recombinant mouse C5a to mouse dermal microvascular endothelial cells (MDMEC) with a K(d50) of 3.6 nM and to approximately 15,000-20,000 receptors/cell. Recombinant mC5a competed effectively with binding of [(125)I]rmC5a to MDMEC. Enhanced binding of C5a occurred, as well as increased mRNA for C5aR, after in vitro exposure of MDMEC to LPS, IFN-gamma, or IL-6 in a time- and dose-dependent manner. By confocal microscopy, C5aR could be detected on surfaces of MDMEC using anti-C5aR Ab. In vitro expression of macrophage inflammatory protein-2 (MIP-2) and monocyte chemoattractant protein-1 (MCP-1) by MDMEC was also measured. Exposure of MDMEC to C5a or IL-6 did not result in changes in MIP-2 or MCP-1 production, but initial exposure of MDMEC to IL-6, followed by exposure to C5a, resulted in significantly enhanced production of MIP-2 and MCP-1 (but not TNF-alpha and MIP-1alpha). Although LPS or IFN-gamma alone induced some release of MCP-1 and MIP-2, pre-exposure of these monolayers to LPS or IFN-gamma, followed by addition of C5a, resulted in synergistic production of MIP-2 and MCP-1. Following i.v. infusion of LPS into mice, up-regulation of C5aR occurred in the capillary endothelium of mouse lung, as determined by immunostaining. These results support the hypothesis that C5aR expression on MDMEC and on the microvascular endothelium of lung can be up-regulated, suggesting that C5a in the co-presence of additional agonists may mediate pro-inflammatory effects of endothelial cells.

Adjuvants, Immunologic↗

PubMed1987

Induction of chemotaxis in mouse peritoneal macrophages by activators of protein kinase C.

Two activators of calcium and phospholipid dependent protein kinase (protein kinase C), the tumor promoter, 12-O-tetradecanoyl-phorbol-13-acetate (TPA) and the synthetic diacylglycerol, 1-oleoyl-2-acetylglycerol (OAG), were compared as chemotactic agents for mouse peritoneal macrophages. Both of these compounds were found to induce chemotaxis in the macrophages to a similar extent in a time and dose dependent manner. Induction of chemotaxis was observed in the concentration range of 10-100 nM for TPA and 25-250 microM for OAG. Two structurally related synthetic sn 1,2-diacylglycerols, 1,2-dioctanoylglycerol (diC8) and 1,2-didecanoylglycerol (diC10), were also found to be chemotactic for macrophages, while monoacylglycerol (2-monoolein) was inactive. Of the diacylglycerols, OAG was found to be the most active followed by diC8 and diC10. In contrast to TPA, the synthetic diacylglycerols had no effect on superoxide anion release by the cells, suggesting that the mechanism of superoxide anion release by TPA in macrophages is distinct from chemotaxis. Phorbol-12,13-diacetate, a biologically inactive phorbol ester analog that inhibits the binding of TPA to its cellular receptors, inhibited macrophage chemotaxis induced by TPA, the synthetic diacylglycerols, and the complement fragment, C5a. Taken together, our results suggest that chemotaxis in macrophages may be mediated by activation of protein kinase C.

Animals↗

PubMed1993

Complement fragment C3a stimulates Ca2+ influx in neutrophils via a pertussis-toxin-sensitive G protein.

The signal pathways of neutrophils following stimulation with the complement fragment C3a (C3a) were studied in neutrophils and compared to the pathways activated by complement fragment C5a (C5a). Analysis of polyphosphoinositol lipid turnover showed that C5a, but not C3a, activated phosphatidylinositol-bisphosphate-3-kinase (PtdInsP2 3-kinase) indicating that different signal pathways are activated by the two anaphylatoxins. To examine whether C3a stimulated Ca2+ transients, cytosolic free Ca2+ levels were analyzed in Fluo-3-labelled neutrophils by flow cytometry. C3a stimulated a fast and concentration-dependent increase of cytosolic free Ca2+. Comparison of the C3a response with that of C5a revealed a more pronounced C5a-triggered Ca2+ rise. Addition of EGTA to the extracellular buffer prior to stimulation did not significantly alter the initial Ca2+ rise at low C5a concentrations, but reduced the time course of the Ca2+ transients at high concentrations. In marked contrast, EGTA completely blocked the Ca2+ response stimulated by C3a in neutrophils labeled with either Indo-1/AM or Fluo-3. Preincubation of neutrophils with pertussis toxin inhibited both C3a- and C5a-stimulated Ca2+ transients, indicating the involvement of guanine-nucleotide-binding proteins (G proteins) in these processes. In order to examine whether the C3a receptor is coupled to G proteins, binding of guanosine 5'-O-(3-[35S]thiotriphosphate) ([35S]GTP[S]) to purified neutrophil plasma membranes was studied. Both C3a and C5a stimulated high-affinity binding of [35S]GTP[S] up to 1.5-fold and 3-fold, respectively. These data suggest that the two anaphylatoxins activate pertussis-toxin-sensitive G proteins, which then trigger different signal transduction pathways. C3a specifically stimulated Ca2+ influx from the extracellular medium, whereas C5a additionally activated the PtdInsP2 3-kinase and stimulated Ca2+ mobilization from intracellular stores.

Calcium↗

PubMed1982

Serum stimulatory activity and polymorphonuclear leucocyte movement in patients with fulminant hepatic failure.

Serum from 27 patients with fulminant hepatic failure and grade IV encephalopathy had reduced ability to stimulate the movement in vitro of normal polymorphonuclear leucocytes. All patients had a deficiency of serum complement factors C3 and C5 and there was a significant positive correlation between C5 and serum stimulatory activity. However, in addition to this complement defect, serum from 22% of patients contained an antagonist to normal serum stimulatory factors. This antagonism was attributed to at least two different substances in the serum on the basis of differences in heat lability, dialysability and action on complement factor C5a. Polymorphonuclear leucocytes from eight of 13 patients had reduced movement toward serum, but serum from only one patient contained an antagonist acting on the cells; this was probably related to an underlying carcinoma of the breast. During the early stages of clinical recovery, serum stimulatory and complement activity returned to normal. These serum and cellular defects have not been reported previously in patients with fulminant hepatic failure and represent major defects in the body's defenses against bacterial infection.

Adolescent↗