Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Complement C5a”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 487 records · Page 27Linked to original sources
PubMed1986

Neutrophil-mediated injury to endothelial cells. Enhancement by endotoxin and essential role of neutrophil elastase.

The neutrophil has been implicated as an important mediator of vascular injury, especially after endotoxemia. This study examines neutrophil-mediated injury to human microvascular endothelial cells in vitro. We found that neutrophils stimulated by formyl-methionyl-leucyl-phenylalanine (FMLP), the complement fragment C5a, or lipopolysaccharide (LPS) (1-1,000 ng/ml) alone produced minimal endothelial injury over a 4-h assay. In contrast, neutrophils incubated with endothelial cells in the presence of low concentrations of LPS (1-10 ng/ml) could then be stimulated by FMLP or C5a to produce marked endothelial injury. Injury was maximal at concentrations of 100 ng/ml LPS and 10(-7) M FMLP. Pretreatment of neutrophils with LPS resulted in a similar degree of injury, suggesting that LPS effects were largely on the neutrophil. Endothelial cell injury produced by LPS-exposed, FMLP-stimulated neutrophils had a time course similar to that induced by the addition of purified human neutrophil elastase, and different from that induced by hydrogen peroxide (H2O2). Further, neutrophil-mediated injury was not inhibited by scavengers of a variety of oxygen radical species, and occurred with neutrophils from a patient with chronic granulomatous disease, which produced no H2O2. In contrast, the specific serine elastase inhibitor methoxy-succinyl-alanyl-alanyl-prolyl-valyl-chloromethyl ketone inhibited 63% of the neutrophil-mediated injury and 64% of the neutrophil elastase-induced injury. However, neutrophil-mediated injury was not inhibited significantly by 50% serum, 50% plasma, or purified alpha 1 proteinase inhibitor. These results suggest that, in this system, chemotactic factor-stimulated human neutrophil injury of microvascular endothelial cells is enhanced by small amounts of LPS and may be mediated in large part by the action of neutrophil elastase.

Amino Acid Chloromethyl Ketones↗
PubMed2000

Histamine H(2) receptors mediate the inhibitory effect of histamine on human eosinophil degranulation.

The effect of histamine on human eosinophil degranulation and the receptor mediating such effect were studied in vitro using the complement C5a-mediated eosinophil peroxidase (EPO) release model. Following pre-treatment with 5 microg ml(-1) cytochalasin B(CB), C5a induced a concentration-dependent release of EPO from eosinophils isolated from healthy donors. Histamine (0.1-50 microM), but not L-histidine, inhibited concentration-dependently C5a-induced EPO release with IC(50) (95% CI) of 0.6 microM (0.3-1.2 microM) and maximal inhibition of approximately 60%. A similar effect was seen with the selective H(2) agonists dimaprit (IC(50) (95% CI)=6.9 microM (3.2-10.6 microM)) and amthamine (IC(50) (95% CI)=0.4 microM (0.2-0.7 microM)). Neither the selective H(1) agonist 6-(2-(4-imidazolyl)ethylamino)-N-(4-trifluoromethylphenyl) heptanecarboxamide(HTMT), nor the selective H(3) agonists imetit (up to 100 microM) had any significant effect. The inhibition by histamine was reversed by cimetidine (0.1-30 microM) and other H(2) antagonists, but not the H(1) antagonist mepyramine (1.0- 100 microM), nor the H(3) antagonist thioperamide (1.0-100 microM). Cimetidine (1-30 microM) shifted to the right the dimaprit log dose-response curve, producing a pA(2) value of 5.9 and Schild's plot slope of 0.98, thus confirming simple competitive antagonism. Histamine (10-100 microM) increased intracellular level of adenosine 3',5'-cyclic monophosphate, which was completely abolished by cimetidine (30 microM), but not mepyramine or thioperamide. The cyclic AMP analogue - dibutyryl cyclic AMP - also inhibited degranulation (IC(50) approximately 300 microM). The cyclic AMP phosphodiesterase(PDE) IV inhibitor rolipram (10 microM) synergistically enhanced the inhibition of EPO release by histamine. These results suggest that histamine, via stimulation of H(2) receptors and a consequent elevation of intracellular levels of cyclic AMP, inhibits human eosinophil degranulation.

Adenylyl Cyclases↗
PubMed1994

Role of CD18 in the accumulation of eosinophils and neutrophils and local oedema formation in inflammatory reactions in guinea-pig skin.

1. Intradermal injection of the complement fragment C5a des Arg induces local oedema formation that, in rabbits and man, is dependent on circulating neutrophils. Monoclonal antibodies to the leukocyte adhesion molecule CD11/CD18 block neutrophil accumulation and prevent neutrophil-dependent oedema formation. The role of CD11/CD18 in mediating eosinophil accumulation in vivo is less established. In this study we have used an anti-human CD18 monoclonal antibody, 6.5E, to investigate the neutrophil-dependency of oedema formation induced by C5a des Arg in guinea-pig skin. We also studied the role of CD18 in mediating eosinophil accumulation in the same model. 2. Stimulated adhesion of 111In-labelled guinea-pig neutrophils and eosinophils to serum-coated plastic was inhibited in a dose-dependent manner by 6.5E suggesting that the monoclonal antibody recognizes and blocks the guinea-pig CD18 adhesion molecule. 3. The accumulation of 111In-labelled neutrophils induced by zymosan-activated plasma (ZAP, as a source of C5a des Arg) in skin sites was reduced by up to 89% in animals treated intravenously with F(ab')2 fragments of 6.5E. ZAP-induced accumulation of 111In-labelled eosinophils was also greatly reduced (by up to 78%) by treatment with 6.5E. 4. Despite the inhibition of ZAP-induced neutrophil accumulation by 6.5E, local oedema formation in the same skin sites was unaffected, except at the top dose of ZAP, by treatment with the anti-CD18 monoclonal antibody, suggesting that the oedema response was largely neutrophil-independent. Indeed, ZAP-induced oedema formation was reduced by up to 81% by the H1 receptor antagonist, mepyramine. 5. Accumulation of 111 In-labelled eosinophils in a passive cutaneous anaphylactic (PCA) reaction was also blocked by treatment with 6.5E, while oedema formation in the same skin sites was unaffected.Intradermal injection of cationic protein-containing extracts of Schistosoma mansoni larvae also induced the accumulation of 111 In-labelled neutrophils and eosinophils which was abrogated by intravenous 6.5E.In contrast, extract-induced local oedema formation was similar in control and 6.5E-treated guinea-pigs.6. In summary, the local accumulation of radiolabelled neutrophils at sites of inflammation in guinea pigskin was dependent on the adhesion molecule CD18 while, in contrast, there was no evidence for neutrophil-dependent oedema formation in this species. Accumulation of radiolabelled eosinophils was also dependent on CD18.

Animals↗
PubMed1993

Albumin inhibits neutrophil spreading and hydrogen peroxide release by blocking the shedding of CD43 (sialophorin, leukosialin).

Spreading of neutrophils on protein-coated surfaces is a pivotal event in their ability to respond to soluble, physiologic agonists by releasing large amounts of hydrolases and oxidants. Using neutrophils plated on serum-, fibrinogen- or fibronectin-coated surfaces, we investigated the effect of human serum albumin (HSA) on spreading-dependent neutrophil responses. HSA suppressed the respiratory burst of neutrophils in response to tumor necrosis factor-alpha (TNF), complement component C5a or formylated peptide, but not phorbol myristate acetate. HSA was suppressive only if added before the onset of the respiratory burst, and suppression was reversed when HSA was removed. Likewise, HSA selectively and reversibly inhibited TNF-induced cell spreading and the associated fall in cAMP. However, HSA did not hinder TNF-induced cell adherence to the same protein-coated surfaces. We investigated cell surface sialoproteins as modulators of cell spreading and as targets for the anti-spreading action of HSA. Oxidation of the cell surface with periodate followed by reduction with 3H-borohydride and immunoblotting with specific mAbs helped identify the predominant sialoprotein on human neutrophils as CD43 (sialophorin, leukosialin). Treatment of neutrophils with C. perfringens sialidase desialylated CD43, markedly enhanced the ability of the cells to respond to TNF by spreading and undergoing a respiratory burst, and antagonized the ability of HSA to inhibit these responses. TNF-treated, adherent neutrophils shed CD43, and this was blocked by HSA, but not by ovalbumin. Exogenous neutrophil elastase removed CD43 from the neutrophil surface. HSA blocked the actions of both sialidase and elastase on CD43. In contrast, ovalbumin did not block the action of sialidase on CD43, and HSA did not inhibit the ability of sialidase to hydrolyze a synthetic substrate. These results suggested that HSA might bind CD43. In fact, the extracellular portion of CD43 bound to HSA-Sepharose, but not to ovalbumin- or glycylglycine-Sepharose. Finally, two mAbs recognizing different epitopes on CD43 mimicked HSA's inhibitory effects on neutrophil function. Thus, HSA can dissociate attachment of neutrophils from spreading. This dissociation may help neutrophils migrate along a chemotactic gradient, while decreasing their release of oxidants. CD43, a long, rigid molecule with a markedly negative charge, antagonizes neutrophil spreading. HSA appears to inhibit spreading-dependent neutrophil functions by binding to CD43 and interfering with the ability of neutrophils to shed it.

Antigens, CD↗
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↗
PubMed1986

The effects of methylprednisolone on complement-mediated neutrophil activation during cardiopulmonary bypass.

Complement-mediated neutrophil activation (CMNA) has been implicated as an important pathophysiologic mechanism contributing to acute microvascular lung injury in the adult respiratory distress syndrome (ARDS). Using cardiopulmonary bypass (CPB) as a clinical model for complement-mediated microvascular injury, we studied the effects of methylprednisolone (MPSS) pretreatment on manifestations of CMNA in 28 pediatric patients undergoing CPB. Six patients not receiving MPSS served as controls. Results demonstrated that MPSS did not prevent complement activation as noted by 4.5- and 7.7-fold increases in plasma C3a des Arg levels during and immediately after CPB, respectively. However, detectable in vivo and in vitro manifestations of CMNA were altered. Neutropenia during CPB was attenuated to 65% of prebypass values compared with 47% in the control group. Neutrophil selective chemotactic desensitization toward C5a/C5a des Arg during the on bypass and postbypass periods was evident in the control group (0.41 and 0.76 cm specific migration, respectively) and prevented in the MPSS group (1.55 and 2.00 cm specific migration, respectively). We conclude that CMNA during CPB is ameliorated and/or prevented by MPSS pretreatment. These findings suggest that MPSS pretreatment may ameliorate complement-mediated microvascular (lung) injury in CPB and ARDS.

Anaphylatoxins↗
PubMed2002

Brain edema after intracerebral hemorrhage: the effects of systemic complement depletion.

The complement cascade is activated after experimental intracerebral hemorrhage (ICH) and may play an important, role in edema formation. This study investigated the effects of systemic complement depletion on brain edema formation following ICH. Thirty-six pentobarbital-anesthetized Sprague-Dawley rats were used. Treatment animals were complement-depleted with cobra venom factor (CVF) while controls received an equal volume of saline injection (i.p.). In both treatment and control rats, autologous blood (100-microL) was infused stereotactically into the right basal ganglia. Rats were sacrificed one and three days later for brain water and ion content measurements and immunohistochemical studies. Immunohistochemistry was used to detect complement C3d, C5a, and C9. Western blot analysis was applied for C9 semiquantitation. Perihematomal brain edema was reduced by systemic complement depletion at one and three days. The water content of the cerebellum (a tissue distant from the hematoma site) was unaffected by complement depletion. Immunocytochemistry found complement depletion significantly reduced perihematomal C9 deposition, C3d production, and C5a positive cell accumulation. In conclusion, complement depletion by CVF attenuates brain edema in ICH perhaps by inhibiting the inflammatory response and membrane attack complex (MAC) formation.

Animals↗
PubMed1996

Aortobifemoral surgery induces complement activation and release of interleukin-6 but not tumour necrosis factor-alpha.

The aim of the present study was to determine the inflammatory response by an extended analysis of complement in 16 patients undergoing aortobifemoral bypass surgery. The patients were randomized to receive either a bifurcated expanded polytetrafluoroethylene graft (n = 8; group I) or a collagen-impregnated knitted Dacron graft (n = 8; group II) to determine whether differences in graft surface properties might influence the inflammatory response during and after the procedure. The following components of complement: C1q, C4, C3, C3d, C5a and terminal complement complexes were all analysed. C-reactive protein and interleukin-6 were also determined to assess the acute phase response. The complement data were corrected for haemodilution, which was assessed from alpha 2-macroglobulin concentrations. A significant decrease of C1q (P < 0.0001) and an increase in C5a (P < 0.0005) was observed in both groups. C4 and C3 levels showed slight fluctuations in group I, whereas in group II these proteins increased significantly (P < 0.05, P < 0.005, respectively) between 2 and 7 days after surgery. Terminal complement complexes remained unchanged in both groups. Interleukin-6 levels peaked at 12-24 h and the C-reactive protein at 24-72 h. Higher interleukin-6 levels (P < 0.05) were found in group II 6 h after surgery compared with group I; no release of tumour necrosis factor-alpha was identified. An early inflammatory response was found in all patients. The patterns of the complement proteins varied with a C1q depletion and a C5a increase, interpreted as complement activation. Whether the variations between the two graft groups represent any differences in graft surface properties has to be further elucidated.

Aged↗
PubMed1981

Complement activation during cardiopulmonary bypass: evidence for generation of C3a and C5a anaphylatoxins.

We observed complement activation in 15 adults undergoing total cardiopulmonary bypass. Plasma levels of C3a were significantly elevated (P < 0.0001) at the beginning of the procedure, and they continued to increase steadily thereafter. At the end of the procedure, C3a levels were more than five times higher than preoperative levels. Plasma levels of C5a (a factor that binds avidly to neutrophils) did not change significantly during cardiopulmonary bypass. Instead, there was significant neutrophilia (P = 0.03) during bypass, and significant transpulmonary neutropenia (P = 0.0002) occurred when cardiopulmonary circulation was reestablished at partial bypass. The neutropenia is consistent with pulmonary-vascular sequestration of C5a-activated granulocytes. We also found that incubation of blood with the nylon-mesh liner of bubble oxygenators, as well as vigorous oxygenation of whole blood, promotes conversion of complement. We conclude that the complement-derived inflammatory mediators C3a and C5a produced during extracorporeal circulation may contribute to the pathogenesis of "post-pump syndromes."

Adult↗
PubMed1997

Controlling the complement system in inflammation.

Inappropriate or excessive activation of the complement system can lead to harmful, potentially life-threatening consequences due to severe inflammatory tissue destruction. These consequences are clinically manifested in various disorders, including septic shock, multiple organ failure and hyperacute graft rejection. Genetic complement deficiencies or complement depletion have been proven to be beneficial in reducing tissue injury in a number of animal models of severe complement-dependent inflammation. It is therefore believed that therapeutic inhibition of complement is likely to arrest the process of certain diseases. Attempts to efficiently inhibit complement include the application of endogenous soluble complement inhibitors (C1-inhibitor, recombinant soluble complement receptor 1- rsCR1), the administration of antibodies, either blocking key proteins of the cascade reaction (e.g. C3, C5), neutralizing the action of the complement-derived anaphylatoxin C5a, or interfering with complement receptor 3 (CR3, CD18/11b)-mediated adhesion of inflammatory cells to the vascular endothelium. In addition, incorporation of membrane-bound complement regulators (DAF-CD55, MCP-CD46, CD59) has become possible by transfection of the correspondent cDNA into xenogeneic cells. Thereby, protection against complement-mediated inflammatory tissue damage could be achieved in various animal models of sepsis, myocardial as well as intestinal ischemia/reperfusion injury, adult respiratory distress syndrome, nephritis and graft rejection. Supported by results from first clinical trials, complement inhibition appears to be a suitable therapeutic approach to control inflammation. Current strategies to specifically inhibit complement in inflammation have been discussed at a recent meeting on the 'Immune Consequences of Trauma, Shock and Sepsis', held from March 4-8, 1997, in Munich, Germany. The Congress (chairman: E. Faist, Munich, Germany), which was held in close cooperation with various national and international shock and trauma societies, was attended by about 2000 delegates from 40 countries. The major objective of the meeting was to provide an overview on the most state-of-the-art methods to prevent multiple organ dysfunction syndrome (MODS)/multiple organ failure (MOF) following the systemic inflammatory response (SIRS) to severe trauma. One of the largest symposia held within the Congress was devoted to current aspects of controlling complement in inflammation (for abstracts see: Shock 1997, 7 Suppl., 71-75). After providing the audience with information on the scientific background by addressing the clinical relevance of complement activation (G.O. Till, Ann Arbor, MI, USA) and discussing recent developments in modern complement diagnosis (J. Köhl, Hannover, Germany), B.P. Morgan (Cardiff, UK) introduced the symposium's special issue by giving an overview on complement regulatory molecules. Selected topics included overviews on the application of C1 inhibitor (C.E. Hack, Amsterdam, NL), sCR1 (U.S. Ryan, Needham, MA, USA), antibodies to C5 (Y. Wang, New Haven CT, USA) and to the anaphylatoxin C5a (M. Oppermann, Göttingen, Germany), and a report on complement inhibition in cardiopulmonary bypass (T.E. Mollnes, Bodø, Norway). The growing interest of clinicians in complement-directed anti-inflammatory therapy, and the fact that only some of the various aspects of therapeutic complement inhibition could be addressed on the meeting, has motivated the author to expand a Congress report into a short comprehensive review on recent strategies to control complement in inflammation.

Anaphylatoxins↗
PubMed2003

Neutrophil C5a receptor and the outcome in a rat model of sepsis.

Complement fragment 5a (C5a)-C5a receptor (C5aR) signaling plays an essential role in neutrophil innate immunity. Blockade of either the ligand or the receptor improves survival rates in experimental sepsis. In the current study, sepsis was induced in rats by cecal ligation/puncture. Early in sepsis C5aR content on neutrophils significantly dropped, reached the nadir at 24 h after onset of sepsis, and progressively elevated thereafter. Western-blot, RT-PCR, and confocal microscopy analyses revealed that the loss and re-expression of C5aR during sepsis might be due, at least in part, to the receptor internalization and reconstitution. The reduction and reconstitution of C5aR correlate with the loss and restoration of innate immune functions of blood neutrophils (chemotaxis and reactive oxygen species production), respectively. Quantitative measurements of C5aR on blood neutrophils are highly predictive of survival or death during sepsis. These data suggest that neutrophil C5aR content represents an essential component of an efficient defense system in sepsis and may serve as a prognostic marker for the outcome.

Animals↗
PubMed1989

Increase of glucose and lactate output and decrease of flow by human anaphylatoxin C3a but not C5a in perfused rat liver.

The complement fragments C3a and C5a were purified from zymosan-activated human serum by column chromatographic procedures after the bulk of the proteins had been removed by acidic polyethylene glycol precipitation. In the isolated in situ perfused rat liver C3a increased glucose and lactate output and reduced flow. Its effects were enhanced in the presence of the carboxypeptidase inhibitor DL-mercaptomethyl-3-guanidinoethylthio-propanoic acid (MERGETPA) and abolished by preincubation of the anaphylatoxin with carboxypeptidase B or with Fab fragments of an anti-C3a monoclonal antibody. The C3a effects were partially inhibited by the thromboxane antagonist BM13505. C5a had no effect. It is concluded that locally but not systemically produced C3a may play an important role in the regulation of local metabolism and hemodynamics during inflammatory processes in the liver.

Anaphylatoxins↗