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PubMed2003

Elevated complement C3a in plasma from patients with severe acute asthma.

BACKGROUND: Complement component C3a, an anaphylatoxin, provokes acute inflammatory responses, including smooth muscle contraction, mucus hypersecretion, increase in vascular permeability, and recruitment of inflammatory cells. Thus C3a may be related to airway inflammation and bronchoconstriction in acute asthma exacerbation. OBJECTIVE: We sought to determine whether plasma C3a is elevated in patients presenting for emergency treatment of acute asthma exacerbations and to correlate C3a concentrations with response to therapy. METHODS: Plasma C3a and serum eosinophil cationic protein were measured in 52 patients with acute asthma with peak expiratory flow of < or =50% the predicted value. Control subjects were 42 patients with stable chronic asthma. Patients with severe acute asthma were classified into 2 groups (admitted and discharged), according to how effective inhaled bronchodilators and systemic corticosteroids were in the first 2 hours of treatment. RESULTS: Concentrations of C3a in plasma from subjects in the admitted group (median, 256 ng/mL; range, 94 to 454) were significantly higher than those in the discharged group (197 ng/mL; 72 to 300) or those in patients with stable chronic asthma (166 ng/mL; 89 to 254; P <.0001). Elevated plasma C3a concentrations in admitted asthmatic patients decreased significantly by 7 days after admission (P =.0005). No significant difference was evident in serum eosinophil cationic protein concentration between the admitted group (33.1 microg/L; 6.3 to 143) and the discharged group (32.7 microg/L; 14.6 to 160; P =.99). CONCLUSIONS: Concentrations of C3a, which can induce airway inflammation and bronchoconstriction, were associated with differences in response to emergency treatment of severe asthma exacerbation.

Acute Disease↗
PubMed2002

Complement c3a and c5a induce different signal transduction cascades in endothelial cells.

In leukocytes, C3a and C5a cause chemotaxis in a G(i)-dependent, pertussis toxin (PT)-sensitive fashion. Because we found that HUVECs and immortalized human dermal microvascular endothelial cells express small numbers of C3aRs and C5aRs, we asked what the function of these receptors was on these cells. Activation of the C3aR caused transient formation of actin stress fibers, which was not PT-sensitive, but depended on rho activation implying coupling to G(alpha12) or G(alpha13). Activation of the C5aR caused a delayed and sustained cytoskeletal response, which was blocked by PT, and resulted in cell retraction, increased paracellular permeability, and facilitated eosinophil transmigration. C5a, but not C3a, was chemotactic for human immortalized dermal microvascular endothelial cells. The response to C5a was blocked by inhibitors of phosphatidylinositol-3-kinase, src kinase, and of the epidermal growth factor (EGF) receptor (EGFR) as well as by neutralizing Abs against the EGFR and heparin-binding EGF-like factor. Furthermore, immune precipitations showed that the EGFR was phosphorylated following stimulation with C5a. The C5aR in endothelial cells thus uses a signaling cascade-transactivation of the EGFR-that does not exist in leukocytes, while the C3aR couples to a different G protein, presumably G(alpha12/13).

Anaphylatoxins↗
PubMed2003

Regulation by complement C3a and C5a anaphylatoxins of cytokine production in human umbilical vein endothelial cells.

C3a and C5a anaphylatoxins are cytokine-like polypeptides generated during complement (C) system activation and released at the inflammatory site. They exert several biological activities through binding to the G-protein-coupled receptors C3aR and C5aR, respectively. Cloning and Northern blot experiments have indicated that both receptors are expressed by myeloid as well as nonmyeloid cells (e.g., endothelial and epithelial cells). To better understand the roles of C anaphylatoxins during inflammation, we investigated their effects on the expression of cytokine and chemokine genes by cultured human umbilical cord endothelial cells (HUVEC). HUVEC constitutively expressed both anaphylatoxin receptors, and addition of physiological concentrations of C3a or C5a (nM range) caused a strong up-regulation of IL-8, IL-1beta, and RANTES mRNA in a time- and dose-dependent manner. Conversely, a decrease in IL-6 mRNA was observed, but only with C5a stimulation. These variations in mRNA levels were inhibited by pretreatment with anti-C5aR and anti-C3aR antibodies as well as pertussis toxin, indicating that G-proteins are involved in anaphylatoxin-activated signal transduction pathways. Finally, we showed that C3a and C5a both strongly activate downstream MAP kinase signaling pathways (p44 and p42 Erk kinases).

Antigens, CD↗
PubMed2006

Increased serum levels of complement C3a anaphylatoxin indicate the presence of colorectal tumors.

BACKGROUND & AIMS: Late diagnosis of colorectal carcinoma results in a significant reduction of average survival times. Yet despite screening programs, about 70% of tumors are detected at advanced stages (International Union Against Cancer stages III/IV). We explored whether detection of malignant disease would be possible through identification of tumor-specific protein biomarkers in serum samples. METHODS: A discovery set of sera from patients with colorectal malignancy (n = 58) and healthy control individuals (n = 32) were screened for potential differences using surface-enhanced laser desorption/ionization time-of-flight mass spectrometry. Candidate proteins were identified and their expression levels were validated in independent sample sets using a specific immunoassay (enzyme-linked immunosorbent assay). RESULTS: By using class comparison and custom-developed algorithms we identified several m/z values that were expressed differentially between the malignant samples and the healthy controls of the discovery set. Characterization of the most prominent m/z values revealed a member of the complement system, the stable form of C3a anaphylatoxin (ie, C3a-desArg). Based on a specific enzyme-linked immunosorbent assay, serum levels of complement C3a-desArg predicted the presence of colorectal malignancy in a blinded validation set (n = 59) with a sensitivity of 96.8% and a specificity of 96.2%. Increased serum levels were also detected in 86.1% of independently collected sera from patients with colorectal adenomas (n = 36), whereas only 5.6% were classified as normal. CONCLUSIONS: Complement C3a-desArg is present at significantly higher levels in serum from patients with colorectal adenomas (P < .0001) and carcinomas (P < .0001) than in healthy individuals. This suggests that quantification of C3a-desArg levels could ameliorate existing screening tests for colorectal cancer.

Adenoma↗
PubMed2006

Ablation of the complement C3a anaphylatoxin receptor causes enhanced killing of Pseudomonas aeruginosa in a mouse model of pneumonia.

The C3a anaphylatoxin is a 77-amino acid peptide that is generated by enzymatic cleavage of C3 during activation of the complement system. C3a mediates numerous biological functions on binding its receptor (C3aR), which is present on both myeloid and nonmyeloid cells. To investigate the biological impact of C3a-mediated effects during acute pneumonia caused by Pseudomonas aeruginosa, we subjected C3aR-deficient mice and matched wild-type (WT) mice to P. aeruginosa pulmonary infection. C3aR-deficient mice exhibited increased killing of P. aeruginosa in the lungs, less dissemination of bacteria into the bloodstream, and a decreased inflammatory response to P. aeruginosa pulmonary infection compared with WT mice. To examine whether the absence of C3aR would impact the humoral immune response to P. aeruginosa, we immunized WT and C3aR-deficient mice via intraperitoneal injection with live P. aeruginosa. Both groups of mice developed similar levels of antibody specific to P. aeruginosa. Immunized C3aR-deficient and WT mice were subjected to P. aeruginosa pulmonary infection, and C3aR-deficient mice again displayed increased killing of P. aeruginosa in the lungs, less dissemination of bacteria into the bloodstream, and a decreased inflammatory response in the lungs. Collectively, these data demonstrate that independently of antibody production, absence of C3aR causes enhanced killing of P. aeruginosa despite a diminished inflammatory response in a mouse model of pneumonia.

Animals↗
PubMed2005

Complement C3a and C4a increased in plasma of patients with aspirin-induced asthma.

RATIONALE: Aspirin-induced asthma (AIA) is a distinct clinical syndrome that affects up to 10% of adults with asthma. Although eicosanoid metabolites appear to play an important role in AIA, the exact pathogenic mechanism for the syndrome remains obscure. In addition, the proposed mechanism fails to explain why aspirin does not cause bronchoconstriction in all individuals. OBJECTIVES: We aimed to identify proteins that were differentially expressed in between AIA and aspirin-tolerant asthma (ATA) plasma. METHODS AND MAIN RESULTS: By using a proteomics approach, six proteins were found to be differentially expressed in plasma between patients with AIA and patients with ATA at baseline, and eight proteins were significantly up- or down-regulated after aspirin challenge in patients with AIA. These proteins, which were identified by matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry, can be classified into four groups: complement components, apolipoproteins, modified albumin, and unknown proteins. Among them, the complement component levels in plasma were validated by using ELISA. Plasma concentrations of C3a and C4a were higher in patients with AIA (n = 30) than in patients with ATA (n = 24). After the aspirin challenge, C3 decreased in both patients with AIA and those with ATA, but the C3a concentration increased in the AIA patient group (p = 0.019). Moreover, C3a and C4a levels and the ratios of C3a/C3 and C4a/C4 were correlated with the changes of FEV(1) values after aspirin challenge. CONCLUSIONS: Aspirin intolerance may be related to alterations in the levels of complements, as well as those of lipoprotein and other proteins.

Adult↗
PubMed1983

Induction of thromboxane release from macrophages by anaphylatoxic peptide C3a of complement and synthetic hexapeptide C3a 72-77.

Guinea pig peritoneal macrophages were examined for their response to homologous anaphylatoxic peptide C3a of complement. C3a caused the release of considerable amounts of thromboxane A2 from macrophages maintained in serum-free culture for up to 12 hr. Preincubation of C3a with the Fab portion of a monoclonal anti-C3a IgG abrogated its stimulatory capacity. C3a desarg was found to be rather ineffective in eliciting thromboxane release. Hexapeptide C3a 72-77, comprising the C-terminal amino acids of human C3a, proved also to stimulate the cyclooxygenation pathway of macrophage arachidonic acid metabolism, following the same routes of receptor-ligand interactions (rapid onset of activation, low dose, and cumulative desensitization) as proven for other anaphylatoxin-cell interactions. This novel effect of anaphylatoxins C3a and C3a 72-77 could contribute to inflammatory reactions in which macrophages play a role.

Animals↗
PubMed2006

Human plasmacytoid dendritic cells express receptors for anaphylatoxins C3a and C5a and are chemoattracted to C3a and C5a.

The presence of plasmacytoid dendritic cells (pDC) was recently demonstrated in lesions of inflammatory skin diseases. Since anaphylatoxins or their precursors were also found in such lesions, we investigated a possible interaction between pDC and anaphylatoxins C3a and C5a. pDC precursors isolated from peripheral blood did not express the receptors for C3a and C5a, complement C3a receptor (C3aR) and complement C3a receptor (C5aR). If these pDC precursors were cultured with IL-3, the resultant immature pDC expressed both receptors. Expression of C3aR and C5aR could also be demonstrated on pDC in lesions of cutaneous lupus erythematosus and allergic contact dermatitis. Such pDC were immature since they lacked the expression of the maturation marker CD83. Blood-derived pDC matured with CpG oligonucleotides downregulated the receptors. Immature pDC responded to C3a and C5a (but not C3adesArg) stimulation with increased F-actin polymerization and chemotactic migration. In contrast, interferon alpha production, surface molecule expression, and T-cell stimulatory capacity were not significantly modulated by C3a or C5a. Thus, immature pDC represent another type of antigen-presenting cell that express C3aR and C5aR, and respond to anaphylatoxins with chemotaxis. This might be relevant in the direction of pDC to cutaneous lesions of inflammation, for example, in lupus erythematosus or contact dermatitis.

Anaphylatoxins↗
PubMed2006

Preservation of antimicrobial properties of complement peptide C3a, from invertebrates to humans.

The human anaphylatoxin peptide C3a, generated during complement activation, exerts antimicrobial effects. Phylogenetic analysis, sequence analyses, and structural modeling studies paired with antimicrobial assays of peptides from known C3a sequences showed that, in particular in vertebrate C3a, crucial structural determinants governing antimicrobial activity have been conserved during the evolution of C3a. Thus, regions of the ancient C3a from Carcinoscorpius rotundicauda as well as corresponding parts of human C3a exhibited helical structures upon binding to bacterial lipopolysaccharide permeabilized liposomes and were antimicrobial against gram-negative and gram-positive bacteria. Human C3a and C4a (but not C5a) were antimicrobial, in concert with the separate evolutionary development of the chemotactic C5a. Thus, the results demonstrate that, notwithstanding a significant sequence variation, functional and structural constraints imposed on C3a during evolution have preserved critical properties governing antimicrobial activity.

Amino Acid Sequence↗
PubMed1986

Complement mediated inhibition of immune precipitation and solubilization generate different concentrations of complement anaphylatoxins (C4a, C3a, C5a).

Complement prevents the formation of insoluble immune complexes (inhibition of immune precipitation (IIP], and solubilizes preformed immune aggregates (solubilization (SOL]. Since the mechanism of complement activation differs in these two reactions, it is possible that they differ also in the amount of complement fragments released, in particular the anaphylatoxins C3a, C5a and C4a. We measured C4 and C3 consumption, and the formation of complement anaphylatoxins during IIP and SOL using two different immune complex models (BSA, rabbit anti-BSA; tetanus toxoid (TT), human anti-TT). At equal immune complex concentrations in both models, SOL was more efficient than IIP at cleaving C3, and more C3a and C5a was released. Comparing the two reactions, C3a formation was followed by more C5 cleavage (C5a) during SOL. Similarly C4a formation (classical pathway activation) was followed by more C3 cleavage (C3a: classical and alternative pathway activations), during SOL. It is suggested that in vivo SOL of insoluble complexes is rapidly accompanied by a damaging phlogistic reaction, whereas IIP produces less inflammation.

Antigen-Antibody Complex↗
PubMed1994

Complement system activation during orthotopic liver transplantation in man. Indications of peroperative complement system activation in the gut.

Sixteen patients with acute and chronic liver disease undergoing OLT were studied regarding the role of the liver and the gut in complement activation. Also, the relation between complement activation and clinical manifestations during the liver transplantation reperfusion period was investigated. Blood samples for measurement of complement anaphylatoxin C3a (C3a), complement anaphylatoxin C5a (C5a), and terminal C5b-9 complement complex (TCC) were taken simultaneously from the central venous catheter and the radial arterial line before starting the operative procedure, 1 min before declamping, and 1-2 min, 5 min, 30 min and 6-12 hr after declamping. Simultaneous blood sampling from the radial arterial line, central venous catheter, portal vein, and hepatic vein was performed 1-2 min and 5 min after completed unclamping. Elevated plasma levels of C3a and TCC were found upon reperfusion, while C5a levels remained unchanged throughout the operation compared with the preoperative levels. The levels of C3a in the portal vein were higher compared with the levels in the simultaneously obtained samples from the radial artery. The results indicate complement cascade activation located to the gut during the reperfusion phase of OLT. Seventy-five percent of the patient studied suffered from the postreperfusion syndrome, indicated by profound hypotension upon reperfusion of the transplanted liver. There was a significant correlation between high concentration of C3a anaphylatoxin and development of profound hypotension.

Adult↗
PubMed1987

Guillain-Barré syndrome: activated complement components C3a and C5a in CSF.

Plasma and spinal fluid levels of complement activation products C3a and C5a were quantitated by radioimmunoassay in a group of 16 patients suffering from acute monophasic Guillain-Barré syndrome (GBS). Median CSF levels of C3a (118 ng/ml) and of C5a (9.6 ng/ml) were significantly elevated when compared with samples from a control group of patients with noninflammatory neurologic diseases. Plasma concentrations of these anaphylotoxic peptides were not significantly different between the two populations. Our findings indicate that the complement system is activated in the CSF of patients with acute GBS. Complement activation products may contribute to the inflammatory changes observed in this disorder.

Complement C3↗
PubMed1994

Complement peptides C3a- and C5a-induced mediator release from dissociated human skin mast cells.

The complement peptides C3a and C5a have been shown previously to release histamine from human basophils but not human lung mast cells. As skin mast cells differ from those of the lung in both immunocytochemical and functional properties, we examined the ability of these anaphylatoxins to release preformed and newly generated mediators from human dispersed skin mast cells. In concentration-response studies, both C3a and C5a released histamine in a concentration related manner with C5a being 40-50 times more potent. However, the extent of histamine, 15-20%, was considerably less than that released from basophils. This was not due to catabolism of the peptides by mast cell proteases, mast cell supernatants that contained C5a being effective in releasing basophil histamine. Removal of the C-terminal arginine from C3a and C5a abolished their activity on skin mast cells. In time-course studies, histamine release induced by C3a and C5a was complete within 15 seconds. Complement-induced histamine release is a non-cytotoxic process as evidenced by 2-deoxy-D-glucose and antimycin A, inhibitors of glycolysis and oxidative phosphorylation, respectively. In contrast to IgE-dependent stimulation, anaphylatoxin-induced histamine release from human skin mast cells is independent of extracellular calcium. Both C3a and C5a at concentrations that induced 10-16% net histamine release caused a negligible release of the newly generated mediator, PGD2. The results suggest that C3a and C5a stimulate human skin mast cells in a manner similar to substance P and related basic secretagogues. However, the activation site for C3a and C5a appears to be different to that for substance P as the substance P antagonist (D-Pro4, D-Trp7,9,10) SP4-11 inhibited histamine release stimulated by substance P but not that induced by C3a and C5a.

Anaphylatoxins↗
PubMed2000

Characterization of synthetic C3a analog peptides on human eosinophils in comparison to the native complement component C3a.

The C3a anaphylatoxin is a potent proinflammatory mediator derived from the complement system inducing biologic effects of human eosinophils like Ca2+ transients and the activation of the respiratory burst. These findings support an important role for C3a in diseases typically associated with a peripheral blood or tissue eosinophilia. Synthetic human C3a analogue peptides with variations at the C-terminal effector domain have been evaluated with respect to their binding affinity and signaling potency on human eosinophils. Flow cytometrical analysis and RT-PCR revealed that the C3a receptor is constitutively expressed on human eosinophils. Peptides bearing an N-terminal 9-fluorenylmethoxycarbonyl and the 6-aminohexanoyl motif were the most powerful peptides tested. Amino acid replacements in the conserved C-terminal pentapeptide decreased binding affinity and functional potency substantially. In addition, synthetic C3a analogue peptides induced C3aR internalization, led to transient changes of intracellular Ca2+ concentration, and did release reactive oxygen species in human eosinophils indicating the in vivo relevance of C3a-related sequences. The tripeptide LAR was found to be essential for C3a receptor binding on human eosinophils. Moreover, the putative binding motif of C3a anaphylatoxin is also crucial for the induction of biologic effects in the human system such as changes of intracellular Ca2+ concentration and the release of reactive oxygen species. This study demonstrates that the carboxyl terminus is important for the interaction with the C3aR and the biologic potency of C3a anaphylatoxin in the human system and plays a key role in the activation process of human eosinophils.

Calcium↗
PubMed1995

Complement peptide C3a inhibits IgE-mediated triggering of rat mucosal mast cells.

The relationship between mast cells' secretory response to stimulation via their type 1 Fc epsilon receptors (Fc epsilon RI) and that provided by the C3a fragment of the complement system was investigated in the rat mucosal-type mast cell line RBL-2H3. These cells are known to be unresponsive to the so-called 'peptidergic' stimulus provided by cationic agents, such as anaphylatoxins, neuropeptides or polyamines. We now observed that C3a effectively inhibits the Fc epsilon RI clustering induced secretion of RBL-2H3 cells. This inhibition is dose-dependent and takes place at a C3a concentration range of 0.4-12.5 nM, i.e. at least three orders of magnitude lower than those where this anaphylatoxin exerts its secretory stimulus to 'serosal' mast cells. In order to identify where C3a interferes in the Fc epsilon RI coupling cascade, we have studied its effect on the cells' protein phosphorylation pattern, hydrolysis of phosphatidyl inositides, transient rise in free cytosolic Ca2+ ion concentration and Ca2+ uptake. All these processes were found to be inhibited by a similar C3a concentration range.

Animals↗
PubMed2004

Complement factors c3a, c4a, and c5a in chronic obstructive pulmonary disease and asthma.

Studies of animal models have shown that the activation of the complement system could have a role in chronic obstructive pulmonary disease (COPD) and asthma by promoting inflammation and enhancing airway hyperresponsiveness. We sought to determine whether the levels of complement factors C3a, C4a, and C5a are elevated at the site of inflammation in patients with COPD and patients with asthma. We analyzed the induced sputum of seven patients with COPD, ten patients with asthma, and twelve healthy nonsmokers. The concentrations of anaphylatoxins in the induced sputum were measured by cytometric bead array. We found significantly increased C5a/C5a desArg concentrations in supernatants of the induced sputum of patients with COPD (P = 0.007) and those with asthma (P = 0.002) compared with the control group. In patients with COPD the C5a/C5a desArg concentrations were significantly negatively correlated with lung diffusion coefficient (r = -0.71, P = 0.035). There was no significant difference in C3a/C3a desArg or C4a/C4a desArg measurements between the three groups of subjects. These in vivo results propose the involvement of complement factor C5a in the pathogenesis of COPD and asthma.

Aged↗