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 811 records · Page 45Linked to original sources
PubMed1984

Monokine generation as a consequence of binding of human C5a anaphylatoxin to specific cell-surface receptors.

The addition of human C5a to antigen-stimulated cultures results in dose-dependent augmentation of the primary antibody response to antigen. The specificity of this effect is confirmed by the ability of C5ades Arg, but not of the structurally analogous C3a anaphylatoxin, to act in a parallel fashion. This effect appears to be mediated by interaction of C5a with cells of the monocytoid/macrophage lineage. These cells have been shown to bear surface receptors specific for C5a. In order to examine the role of soluble mediators in these events, culture supernatants were generated from splenic adherent cells or macrophage cell lines after exposure to a brief pulse of human C5a. Supernatants from the macrophage-like cell line P388D1, which bears surface receptors for C5a, enhance the PFC response to antigen, whereas those from the closely related cell line P388, which lacks surface receptors for C5a, fail to cause enhancement. Supernatants from splenic adherent cells, which also bear C5a receptors, similarly augment the SRBC response. Active supernatants, but not those devoid of activity, contain IL-1 activity. None of the supernatants contain IL-2 activity. These observations suggest that the recently described role of human C5a as an immunopotentiating modulator is mediated by its ability to induce production of IL-1 upon binding to specific receptors at the macrophage cell surface.

Antibody Formation↗
PubMed1997

Inflammatory response to aorto-bifemoral graft surgery.

OBJECTIVE: To evaluate the systemic release of major cytokines and complemental activation during elective aorto-bifemoral bypass surgery and the influence on the postoperative course. DESIGN: Prospective randomised study. SETTING: University hospital, Sweden. PATIENTS: Fourteen consecutive patients with aorto-iliac occlusive disease were randomised to receive either a bifurcated e PTFE graft with stretch properties or a collagen coated Dacron graft. MAIN OUTCOME MEASURES: Immunologic parameters were assessed and included the cytokines TNF alpha (tumor necrosis factor), IL-6, IL-8, S-IL-2R and complemental factor C5a. Furthermore, acute plasma proteins, including C-reactive protein, and the different white blood cell fractions were determined. Sampling was performed frequently during surgery and postoperatively up to one month. RESULTS: An increase of serum-TNF alpha levels was observed early after declamping. This response preceded an increase of IL-6 levels and of C-reactive protein. No release of IL-8 was identified. A significant correlation between TNF alpha, IL-6 and C-reactive protein was observed (p < 0.001). A positive correlation was also observed for the degree of surgical trauma (blood loss). No significant differences between the two graft materials were encountered. The complemental system was also involved in the acute reactions and a marked increase of C5a levels was noted. A decrease of S-IL-2R levels as well as lymphocyte concentrations was also observed postoperatively and was interpreted as a downregulation of the immune-system in the immediate postoperative course. CONCLUSIONS: The results demonstrate an early and generalized inflammatory response during and after aortic surgery with involvement of different cytokines as well as the complemental system. TNF alpha appears to play a central role in the release of other cytokines, but IL-6 seemed to correlate best with later development of nonvascular complications. Few differences were found between the different grafts and the response seems to be influenced by other factors such as the surgical procedure and ischaemia/reperfusion injury.

Aged↗
PubMed1992

[Activation of complement and serial changes of anaphylatoxin (C3a, C5a) in patients for open-heart surgery using a membrane oxygenator].

Activation of complement and serum changes in anaphylatoxin (C3a and C5a) were studied in 8 patients who underwent open-heart surgery using a membrane oxygenator. C1 esterase inhibitor (C1-EI), C3, C5, CH50, C3a and C5a were measured serially at 7 points. C1-EI, C3, and C5 were measured by single radial immunodiffusion, CH50 by Mayer's method, and C3a and C5a by radioimmunoassay. Levels of C1-EI, C3 and C5 decreased significantly from 10 min after initiation to 120 min after the end of CPB compared with base line values. Degree of activation of complement increased in proportion to duration of CPB. Significant decreases of C3 and C5 continued until first postoperative day. Level of C3a increased significantly 10 min after initiation of CPB, and gradually increased till immediately after the end of CPB, when the level was maximum (4625 +/- 560 ng.ml-1) among 7 points. Level of C3a decreased gradually till 120 min after end of CPB. C5a was not detected during whole course. No patient showed respiratory distress of pulmonary edema. In conclusion, membrane oxygenator activated classical pathway of complement at 10 min after initiation of CPB. C3a increased significantly from 10 min after initiation of CPB to 120 min after end of CPB, but C5a was not detected at all during the whole course. The significant activation of complement continued till first postoperative day.

Aged↗
PubMed1993

Ebselen is a specific inhibitor of LTB4-mediated migration of human neutrophils.

Ebselen is a seleno-organic anti-inflammatory compound with glutathione peroxidase-like activity that has the unique characteristic of mediating the isomerization of 5-HETE and LTB4 to their biologically inactive trans isomers, both directly in fluid phase and indirectly through metabolic pathways in stimulated peripheral blood leukocytes. LTB4 is an inflammatory mediator with potent chemotactic activity for neutrophilic leukocytes. We studied the effects of ebselen on the chemotactic and chemokinetic responses with human-blood-derived neutrophils. With the use of 120-microns-thick 5-microns-pore durapore filters and low BSA concentrations (0.05%) in the chemotaxis buffers, ebselen was evaluated for its effect on both chemotactic and chemokinetic responses to LTB4, C5a, and fMLP. Ebselen at 3-20 microM concentrations inhibited both chemotactic and chemokinetic responses to optimal concentrations of LTB4 without altering chemotactic responses to C5a or fMLP. Likewise, ebselen at 20 microM specifically inhibited LTB4-stimulated transendothelial migration of neutrophils, while not altering responses to C5a nor fMLP.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1994

Decapeptide agonists of human C5a: the relationship between conformation and spasmogenic and platelet aggregatory activities.

A series of decapeptide analogues corresponding to the C-terminal region of human C5a anaphylatoxin (C5a65-74) was synthesized with residue substitutions to restrict conformational flexibility in the C-terminus. These conformationally constrained peptides behaved as agonists of C5a in spasmogenic assays (smooth muscle contraction in human fetal artery, guinea pig ileum, and guinea pig lung parenchyma) as well as guinea pig platelet aggregation. There were significant correlations in the potencies of these peptides between the various assays. A structure-function analysis led to the identification of a preferred backbone conformation that correlated with the expression of these biological responses. These backbone structural motifs were consistent with a helix-like conformation for residues 65-69, an elongated structure for residues 70-71, and a beta-turn of either type II or type V for residues (71)72-74. The most potent of these agonists expressed almost 5% of the potency of natural C5a.

Amino Acid Sequence↗
PubMed2001

Elastase controls the binding of the vitamin D-binding protein (Gc-globulin) to neutrophils: a potential role in the regulation of C5a co-chemotactic activity.

The vitamin D-binding protein (DBP) binds to the plasma membranes of numerous cell types and mediates a diverse array of cellular functions. DBP bound to the surface of leukocytes serves as a co-chemotactic factor for C5a, significantly enhancing the chemotactic activity of pM concentrations of C5a. This study investigated the regulation of DBP binding to neutrophils as a possible key step in the process of chemotaxis enhancement to C5a. Using radioiodinated DBP as a probe, neutrophils released 70% of previously bound DBP into the extracellular media during a 60-min incubation at 37 degrees C. This was suppressed by serine protease inhibitors (PMSF, Pefabloc SC), but not by metallo- or thiol-protease inhibitors. DBP shed from neutrophils had no detectable alteration in its m.w., suggesting that a serine protease probably cleaves the DBP binding site, releasing DBP in an unaltered form. Cells treated with PMSF accumulate DBP vs time with over 90% of the protein localized to the plasma membrane. Purified neutrophil plasma membranes were used to screen a panel of protease inhibitors for their ability to suppress shedding of the DBP binding site. Only inhibitors to neutrophil elastase prevented the loss of membrane DBP-binding capacity. Moreover, treatment of intact neutrophils with elastase inhibitors prevented the generation of C5a co-chemotactic activity from DBP. These results indicate that steady state binding of DBP is essential for co-chemotactic activity, and further suggest that neutrophil elastase may play a critical role in the C5a co-chemotactic mechanism.

Cell Membrane↗
PubMed1981

Neutrophil dysfunction in sepsis. II. Evidence for the role of complement activation products in cellular deactivation.

Abnormalities in chemotactic and bactericidal activity have been identified in patients suffering from burn injury, trauma, and infection. Such abnormalities may lead to bacteremia or nosocomial infection. The mechanism for these abnormalities is unclear. We studied the role of chemotactic deactivation by complement component C5a in 47 patients with intra-abdominal infection and with disordered neutrophil function. Plasma C5a levels in such patients were elevated (102.1 +/- 8.3 versus 52.6 +/- 3.4 ng/ml for control subjects, P less than 0.01). There was a linear relationship between C5a and chemotaxis (r = 0.56, P less than 0.01). Examination of patients' neutrophils showed changes consistent with nonspecific deactivation. There were parallel losses of chemotaxis to N-formyl methionyl-leucyl-phenylalanine (FMLP) and activated serum (C5a) (r = 0.74, P less than 0.001), chemotaxis and intracellular beta-glucuronidase (r = 0.82, P less than 0.001), and C5a and FMLP chemotaxis and (r = 0.56, P less than 0.01). Receptor assays revealed specific loss of C5a binding but intact FMLP binding. Exposure of normal neutrophils to plasma from patients with depressed chemotaxis caused similar loss of C5a receptors and loss of FMLP and activated serum-induced chemotaxis at high plasma concentrations and selective loss of activated serum response at lower concentrations. These data support the concept that a major factor leading to neutrophil dysfunction during intra-abdominal infection is nonspecific chemotactic deactivation of neutrophils after in vivo exposure to high levels of chemoattractants such as C5a.

Adolescent↗
PubMed2006

High-affinity interaction between fibronectin and the group B streptococcal C5a peptidase is unaffected by a naturally occurring four-amino-acid deletion that eliminates peptidase activity.

The streptococcal C5a peptidase (ScpB) of group B streptococci (GBS) is found in virtually all clinical GBS isolates and is required for mucosal colonization in a neonatal mouse model. ScpB inhibits neutrophil chemotaxis by enzymatically cleaving the complement component C5a. We previously identified a second function of ScpB as a fibronectin (Fn) adhesin using phage display. However, phage display can identify low-affinity interactions. We therefore measured the affinity of both full-length recombinant ScpB (FL-ScpB) and the 110-amino-acid phage display fragment (Scp-PDF) for immobilized Fn using surface plasmon resonance. The affinity for Fn was very high for both FL-ScpB (equilibrium dissociation constant [KD] = 4.0 nM) and Scp-PDF (KD = 4.4 nM) and is consistent with a biologically significant role for the adhesin activity of ScpB. We also studied the Fn adhesin activity of a common natural variant of ScpB (ScpBDelta) that contains a 4-amino-acid deletion that eliminates peptidase activity. The integrity of scpB is otherwise maintained, suggesting that the Fn adhesin activity of ScpB may be responsible for its conservation in these strains. The affinities of both FL-ScpBDelta (KD = 2.4 nM) and ScpBDelta-PDF (KD = 1.4 nM) for Fn are unaffected by the deletion. Complementation in trans by both scpB and scpBDelta corrected the Fn-binding defect of an scpB deletion mutant GBS strain to an identical degree. The high affinity of ScpB for Fn and the maintenance of this affinity in ScpBDelta support our hypothesis that the Fn adhesin activity of scpB plays a role in virulence.

Adhesins, Bacterial↗
PubMed1982

[Pathological effects of recently isolated complement derived peptides].

The C3a and C5a polypeptides release, under conditions of complement activation, causes a change in PMN shape and adhesiveness with formation of leukoemboli in microvascular districts. Those modified granulocytes produce oxygen radicals with toxic activity. This mechanism seems to play a role in different pathological situations like pulmonary distress in hemodialysis, leukapheresis, cardiopulmonary by-pass and extent of necrosis in acute myocardial infarction. The same mechanism has been largely investigated in Adult Respiratory Distress Syndrome (A.R.D.S.). In this condition the leukoembolization toxicity seems to be the most important pathogenetic factor of the alveolo-capillary membrane damage which is the base of the disease.

Animals↗
PubMed1999

Synergistic enhancement of chemokine generation and lung injury by C5a or the membrane attack complex of complement.

Complement plays an important role in many acute inflammatory responses. In the current studies it was demonstrated that, in the presence of either C5a or sublytic forms of the complement-derived membrane attack complex (MAC), rat alveolar macrophages costimulated with IgG immune complexes demonstrated synergistic production of C-X-C (macrophage inflammatory protein-2 and cytokine-induced neutrophil chemoattractant) and C-C (macrophage inflammatory protein-1alpha and monocyte chemoattractant-1) chemokines. In the absence of the costimulus, C5a or MAC did not induce chemokine generation. In in vivo studies, C5a and MAC alone caused limited or no intrapulmonary generation of chemokines, but in the presence of a costimulus (IgG immune complexes) C5a and MAC caused synergistic intrapulmonary generation of C-X-C and C-C chemokines but not of tumor necrosis factor alpha. Under these conditions increased neutrophil accumulation occurred, as did lung injury. These observations suggest that C5a and MAC function synergistically with a costimulus to enhance chemokine generation and the intensity of the lung inflammatory response.

Animals↗
PubMed2004

Inhibition of C5 or absence of C6 protects from sepsis mortality.

Inhibiting complement anaphlytoxin C5a during sepsis may prevent sepsis mortality. Although human anti-C5 antibodies exist, their therapeutic use in microbial sepsis has been avoided because of the hypothesis that inhibiting C5b will prevent formation of the bactericidal membrane attack complex (MAC) and worsen clinical outcome. We wished to test the hypothesis that inhibition of C5 would improve outcomes in sepsis. Sepsis was induced in rats by laparotomy and cecal ligation and puncture (CLP) by an IACUC-approved protocol. Sham animals underwent laparotomy without CLP. Following CLP rats were randomized to receive a single IV dose of purified IgG ant-C5 antibody (Ab) or control IgG Ab. Anti-C5 Ab treated rats (n = 20) had significantly lower mortality vs. controls (n = 21), 20% vs. 52% (P = 0.019, log-rank). Analysis of bacterial load by culture of spleen and liver homogenates showed a reduction in colony forming units in anti-C5 Ab treated rats vs. control IgG (P = 0.003 and 0.009, respectively). Anti-C5 treatment reduced lung injury as measured by total MPO content of lung tissue (P = 0.024). Finally, rats genetically deficient in C6 production, unable to form MAC but capable of producing C5a and C5b, were protected from CLP-induced sepsis mortality. Our results show that in anti-C5 antibody therapy prevents CLP sepsis-induced mortality and improves lung injury. Inhibition of the complement MAC does not increase bacterial load or mortality, therefore, the use of anti-C5 therapy may be beneficial rather than detrimental in sepsis.

Animals↗
PubMed1994

Endothelial injury during extracorporeal circulation: neutrophil-endothelium interaction induced by complement activation.

This study was designed to understand the physiologic intravascular and intradevice events at the cellular level following complement system activation during extracorporeal circulation. The addition of anaphylatoxin C5a or complement-activated serum into neutrophil- or endothelial cell-suspensions resulted in a dose-dependent transmembrane stimulation that was assessed by an intracellular free calcium ion mobilization technique using a calcium-sensitive photoprotein, aequorin. The adhesion and ruffle formation of neutrophils on endothelial cell monolayers were markedly enhanced when both cell types were treated with C5a or activated serum. The significance of complement activation on intravascular events during extracorporeal circulation is emphasized and discussed from the viewpoint of surface-expressed adhesion molecules.

Calcium↗
PubMed1996

The anaphylatoxin C5a, a new parameter in the diagnosis of renal allograft rejection.

In the underlying study the diagnostic value of the anaphylatoxin C5a was evaluated in kidney transplantation. In 49 transplant patients the following parameters were measured daily for a mean period of 25.1 days: plasma C5a [P-C5a], urine C5a [U-C5a], serum amyloid A [SAA], serum neopterin [S-NEOP] and urine neopterin [U-NEOP]. Sensitivity, specificity and day of first significant parameter increase (exceeding a cut-off level of > 50%) were evaluated retrospectively during 30 periods of rejection and 30 periods of stable graft function. U-C5a was the parameter with the highest sensitivity (84%) and specificity (84%), increasing in the mean 1.3 days before clinical diagnosis of rejection. Sensitivity and specificity of the other markers was lower: SAA 77% and 77%, U-NEOP 68% and 65%, S-NEOP 45% and 77%, and P-C5a 45% and 48%, respectively. During four instances of cytomegalovirus disease extremely high U-NEOP (> or = 1520 +/- 518 mumol/mol creatinine) and slightly increased P-C5a levels (> or = 1.5 +/- 1.4 ng/ml) occurred. Elevated urinary excretion of C5a seems to be a reliable and early marker of renal allograft rejection. In combination with SAA and U-NEOP, the daily assessment of U-C5a differentiates between viral infection and allograft rejection.

Adult↗
PubMed1988

A proton nuclear magnetic resonance study of the conformation of bovine anaphylatoxin C5a in solution.

The solution conformation of bovine anaphylatoxin C5a has been investigated by nuclear magnetic resonance (NMR) spectroscopy. The 1H-NMR spectrum is assigned in a sequential manner using a variety of two-dimensional NMR techniques. A qualitative interpretation of the short range nuclear Overhauser enhancement data involving the NH, C alpha H and C beta H protons suggests that C5a has four helices comprising residues 5-11, 15-25, 33-39 and 46-61, and is composed of a globular head (residues 5-61) and a C-terminal tail. The polypeptide fold was determined by hybrid distance geometry-dynamical simulated annealing calculations on the basis of 203 approximate interproton distance restraints, 22 distance restraints for 11 intrahelical hydrogen bonds (identified on the basis of the pattern of short range NOEs and slowly exchanging backbone amide protons) and restraints for the 3 disulfide bridges. The overall polypeptide fold is similar to that of the sequence related human recombinant anaphylatoxin C5a [(1988) Proteins 3, 139-145].

Amino Acid Sequence↗
PubMed1999

Determination of structural elements related to the biological activities of a potent decapeptide agonist of human C5a anaphylatoxin.

The structural features related to the biologic activities of a potent, response-selective decapeptide agonist of human C5a, YSFKPMPLaR (C5a65-74, Y65, F67, P69, P71, D-Ala73), were identified by NMR analysis in H2O, DMSO and TFE. This investigation showed that the KPM residues in H2O and the SFKPM residues in DMSO exhibited an extended backbone conformation, whereas a twisted conformation was found in this region in TFE. In H2O, the C-terminal region (PLaR) adopted a distorted type II beta-turn or a type II/V beta-turn. In the type IIN beta-turn, Leu72 exhibited a conformation typical of a type II beta-turn, whereas D-Ala73 exhibited a conformation characteristic of a type V beta-turn. Furthermore, a gamma-turn involving residues LaR overlapped with the type II/V beta-turn. In DMSO, the C-terminal region had the analogous turn-like motif (type II/V beta-turn overlapping with gamma-turn) found in H2O. In TFE, no beta-turn motifs were formed by the PLaR residues. These turn-like motifs in the C-terminal region of the peptide in both H2O and DMSO were in agreement with the biologically important conformations predicted earlier by a structure-function analysis of a related panel of decapeptide analogs. The motifs determined by the NMR analysis of YSFKPMPLaR in H2O and DMSO may represent structural elements important for C5a agonist activity and thus can be used to design the next generation of C5a agonist, partial agonist and antagonist analogs.

Amino Acid Sequence↗
PubMed2004

Role of C5a-C5aR interaction in sepsis.

C5a-C5aR signaling plays an essential role in innate immunity of neutrophils. However, excessive interaction of C5a-C5aR results in harmful effects in these cells. In sepsis, robust generation of C5a occurs; blockade of either C5a or C5aR greatly improves survival in experimental sepsis following cecal ligation and puncture (CLP). The beneficial effects derived from C5a-C5aR interaction are associated with preservation of neutrophil innate immune functions (chemotaxis, phagocytosis, respiratory burst), attenuation of the inflammatory reaction, amelioration of coagulopathy, alteration in adhesion molecule expression, and modulation of apoptosis. Following CLP, C5aR expression is significantly elevated in organs, perhaps setting the stage for C5a-induced organ dysfunction. In contrast, C5aR content on neutrophils drops significantly at early stages of sepsis and progressively increases at later time points. Re-expression of C5aR on neutrophils during sepsis appears to be associated with the functional recovery of neutrophil innate immune functions. Following CLP, there is a positive correlation between C5aR content on blood neutrophils and survival of individual animals; high levels of C5aR on neutrophils are associated with survival, whereas low levels of C5aR on neutrophils predict mortality. These data suggest that in sepsis C5a-C5aR signaling is excessive, resulting in paralysis of neutrophil function. Interception of either C5a or C5aR dramatically improves survival during experimental sepsis.

Animals↗
PubMed1995

Role of C5a-ase in group B streptococcal resistance to opsonophagocytic killing.

Type III group B streptococci (GBS) can be subdivided into three subtypes, RDP III-1, III-2, and III-3, on the basis of numerical analysis of HindIII restriction endonuclease digestion patterns (HindIII RDP) with their chromosomal DNAs. In the present study, the effect of C5a on opsonophagocytic killing of a representative strain from each RDP type was investigated by using a novel optical method for determining opsonophagocytic killing, and the effect of C5a-ase treatment of C5a on opsonophagocytic killing was also investigated. Pre-stimulation of polymorphonuclear leukocytes (PMNs) with C5a significantly increased opsonophagocytic killing of all three strains. The increase in killing was abolished by pretreating the C5a with GBS that express C5a-ase, a treatment that also destroyed the chemoattractant activity of the C5a. The kinetics of killing of the RDP III-2 strain differed from those of the other two strains. The survival of the RDP III-2 bacteria continued to decline over the entire 60-min incubation of the opsonophagocytic assay when PMNs were prestimulated with C5a or with C5a that had been inactivated with GBS C5a-ase (dC5a). In contrast, killing of the RDP III-1 and III-3 strains almost ceased after 20 or 60 min when PMNs were prestimulated with dC5a or C5a, respectively. A difference in bacterial killing between the III-2 strain and the III-1 and III-3 strains therefore became increasingly apparent with prolonged incubation time. The percentage of bacteria surviving in the extracellular fluid was approximately the same as the percentages of bacteria surviving in both intracellular and extracellular locations when PMNs were prestimulated with either C5a or dC5a. These data imply that the majority of bacterial killing occurred following phagocytosis and suggest that the enhanced killing of GBS following prestimulation of PMNs with C5a resulted from increased ingestion of the bacteria.

Adhesins, Bacterial↗