C1 esterase inhibitor (C1-INH) can reduce plasma concentrations of the complement activation product C5a.
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Capillary Permeability↗
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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↗
C5a fragment of bovine complement. Purification, bioassays, amino-acid sequence and other structural studies.
C5a and des-Arg-C5a have been purified from bovine serum in milligram amounts. The progress of the purification was followed by measuring the chemotactic activity of the complement fragments. The two polypeptides induce activation of neutrophil-oriented locomotion and secretion with very similar dose/response effects. After preparing a rabbit antiserum to bovine C5a/des-Arg-C5a, a competitive enzyme-linked immunosorbent assay (ELISA) was set up for the detection of C5a from 5 ng/mol to 1 microgram/ml. The complete primary structure of bovine C5a, which consists of 74 amino acids, has been determined by sequence analysis of the tryptic peptides, aligned by peptides derived from a chymotryptic digest, and by partially sequencing the intact molecule. Bovine C5a has a sequence homology of 78% and 70% with porcine and human C5a, respectively, reacts with an antiserum to porcine C5a and is recognized by cell surface receptors on human neutrophils. Finally, the secondary structure of bovine C5a was investigated by circular dicroic spectroscopy and predicted from the amino acid sequence. A comparison of the content and distribution of alpha-helical and/or hydropathic regions, suggests that the three-dimensional structure of C5a might be modeled from the known crystal structure of the homologous C3a molecule.
Amino Acid Sequence↗
Chemotactic factor for tumor cells derived from the C5a fragment of complement component C5.
Previously, we have stablished that the fifth component of complement (C5) serves as an important source of mediators that have locomotory (chemotactic) activity for leukocytes and tumor cells. C5a, a fragment (Mr 11,200) derived from the NH2-terminal portion of the alpha chain of C5, is the major chemotactic peptide for leukocytes. The present studies demonstrate that cleavage of C5a with trypsin generates a derivative peptide that is chemotactic for tumor cells (Walker carcinosarcoma). This fragment has an estimated Mr of 6000 as assessed by gel filtration and does not require the COOH-terminal arginine of C5a, because equivalent amounts of chemotactic activity for tumor cells can be generated from des-Arg-C5a by digestion with trypsin. The C5a-derived chemotactic peptide for tumor cells demonstrates peak activity at approximately 1 pM. These studies emphasize the key role of the C5a region of the C5 molecule in the generation of peptides that affect locomotory responses of cells.
Animals↗
Complement-dependent proinflammatory properties of the Alzheimer's disease beta-peptide.
Large numbers of neuritic plaques (NP), largely composed of a fibrillar insoluble form of the beta-amyloid peptide (Abeta), are found in the hippocampus and neocortex of Alzheimer's disease (AD) patients in association with damaged neuronal processes, increased numbers of activated astrocytes and microglia, and several proteins including the components of the proinflammatory complement system. These studies address the hypothesis that the activated complement system mediates the cellular changes that surround fibrillar Abeta deposits in NP. We report that Abeta peptides directly and independently activate the alternative complement pathway as well as the classical complement pathway; trigger the formation of covalent, ester-linked complexes of Abeta with activation products of the third complement component (C3); generate the cytokine-like C5a complement-activation fragment; and mediate formation of the proinflammatory C5b-9 membrane attack complex, in functionally active form able to insert into and permeabilize the membrane of neuronal precursor cells. These findings provide inflammation-based mechanisms to account for the presence of complement components in NP in association with damaged neurons and increased numbers of activated glial cells, and they have potential implications for the therapy of AD.
Alzheimer Disease↗
Biological properties of human C5a: selected in vitro and in vivo studies.
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Complement Activation↗
Leukocyte aggregation response to quantitative plasma levels of C3a and C5a.
Granulocyte aggregation (GA) response has previously been described as a sensitive assay for complement activation in sepsis. Complement component C5a has been implicated as the plasma factor responsible for GA. The quantitative interaction of complement components C3a and C5a with GA, however, is not clearly defined. This study evaluates the relationship of GA responses to plasma levels of C5a and C3a in zymosan-activated plasma (ZAP). The C3a and C5a levels were measured by radioimmunoassay in serial dilutions of ZAP. Granulocyte aggregation responses of normal human leukocytes were determined for each ZAP dilution. The C5a levels in a 1:16 dilution of ZAP were higher than in normal plasma (22 +/- 7 vs 9 +/- 3 ng/mL), as were GA responses (24 +/- 1 vs 11 +/- 2 percentage of maximum light transmission). The C3a levels in a 1:8 dilution of ZAP are elevated above those of normal plasma (656 +/- 167 vs 411 +/- 29 ng/mL). Correlation coefficients were .9809 for C3a vs GA, .9788 for C5a vs G, and .9860 for C3a vs C5a. Complement components C3a and C5a are involved in GA in vitro. Granulocyte aggregometry can detect low levels of activated complement in ZAP but may not be specific for C5a. The relative contribution of C3a and C5a to observed GA is not clear from the data.
Cell Aggregation↗
Inactivation of interleukin-8 by the C5a-inactivating protease from serosal fluid.
The complement fragment C5a and the cytokine interleukin-8 (IL-8) are proinflammatory peptides with potent chemotactic activity toward neutrophils. We have previously shown that C5a can be inactivated by a protease that is found in normal synovial and peritoneal fluids but is absent from serosal fluids obtained from patients with familial Mediterranean fever (FMF). We report here that serosal fluids can also eliminate the chemotactic activity of IL-8. The agent responsible for IL-8 elimination appears to be the C5a-inactivating protease, because the pure protease can inactivate IL-8, inactivation of IL-8 by normal peritoneal fluid is partly prevented by an antibody raised against the purified C5a-inactivating protease, and IL-8 is not inactivated by peritoneal fluids from patients with FMF. The ability of this protease to inactivate both, early (C5a) and late (IL-8) inflammatory mediators identifies it as a potentially significant regulator of inflammation.
Ascitic Fluid↗
Effect of platelet depletion and inhibition of platelet cyclooxygenase on C5a-mediated myocardial ischemia.
Activation of the complement cascade is involved in the myocardial injury resulting from transient ischemia and reperfusion. We previously showed that the complement anaphylatoxin C5a causes myocardial ischemia in vivo, mediated in part via thromboxane (Tx) A2. In the present study, we assess the role of platelets in the C5a-induced myocardial ischemia and Tx release. The left anterior descending coronary artery of anesthetized pigs was perfused with arterial blood at constant pressure and measured flow (coronary blood flow). Segment function (percent segment shortening) was measured with sonomicrometry, and regional coronary venous blood was sampled and assayed for TxB2 (by radioimmunoassay). We found that the C5a-induced decrease in coronary blood flow and percent segment shortening and the release of Tx were indistinguishable whether the left anterior descending coronary artery bed was perfused with normal arterial blood, with arterial blood obtained from animals depleted of platelets (cyclophosphamide, n = 6), or with arterial blood from aspirin-treated animals (n = 9) in which the platelets were unable to produce Tx. These data demonstrate that platelet-derived Tx does not contribute to the C5a-induced myocardial ischemia and Tx release in this model and that these cells do not play an integral role in this phenomenon.
Animals↗
A comparative study of complement activation by Denaflex, Bioflow, and BioPolyMeric vascular grafts.
This study was performed to evaluate the degree of complement activation by three bovine arterial graft materials: Bioflow (Bio-Vascular Inc., a bovine artery fixed with dialdehyde starch), BioPolyMeric (St. Jude Medical Inc., a collagen conduit of bovine arterial origin, tanned with glutaraldehyde and covered with a Dacron mesh), and Denaflex (Baxter Edwards CVS Division, a bovine artery fixed with polyepoxy compounds). The grafts were rinsed by following the manufacturer's recommended procedures and thereafter incubated with normal human serum. CH50 assays were performed on the serum after incubation, and the percentage of complement activation for each sample was calculated relative to its control serum. The results indicated that the BioPolyMeric grafts activated the most complement, with about a 48% decrease in the CH50. The BioPolyMeric graft is composed of an outer polyester mesh and an inner collagenous tubing, exhibiting a nonreversible negative surface charge. After the polyester mesh was removed, the BioPolyMeric graft showed the highest complement activation in this study, suggesting that the glutaraldehyde fixed graft is more prone to complement activation than either the polyepoxy compound or dialdehyde starch fixed grafts. The complement fragment, C5a, generated during complement activation is strongly chemotactic for polymorphonuclear leukocytes and monocytes, which likely play early and long-lasting roles in regulating tissue reaction to the implanted graft.
Bioprosthesis↗
Vasoconstriction in response to activated leukocytes: implications for vasospasm.
Three sets of experiments are presented demonstrating that activated leukocytes produce significant vasoconstriction. (1) Responses to human mononuclear leukocytes were studied in intact femoral arteries in vitro. Vasoconstriction of about 35-40% of the maximal effect obtained with KCl was found with mononuclear cells activated by thrombin or complement component C5a, but not with unactivated mononuclear cells. This vasoconstriction was endothelium-independent, and could not be inhibited by radical scavengers or by pre-treatment of the cells with inhibitors of the cyclooxygenase or lipoxygenase pathway. Additional experiments suggest that this contractile effect is partially mediated by the release of a stable factor. (2) Vascular responses to intra-arterial complement C5a (10 and 100 micrograms) were studied in the blood-perfused hind limb of normal and atherosclerotic monkeys in vivo. C5a injection produced pronounced constriction of the hind limb large arteries in atherosclerotic, but not in normal animals. Perfusion of the hind limb with a cell-free blood substitute almost abolished C5a-induced vasoconstriction. These findings suggest that C5a induces vasoconstriction by activation of blood cells, probably leukocytes. (3) Vascular responses to the chemotactic peptide, N-formyl-methionyl-leucyl-phenylalanine (fMLP), were studied in the human coronary circulation. Intracoronary fMLP (1 x 10(-8) moles) produced a transient increase in blood flow velocity and a significant decrease of the diameter of the epicardial arteries. This effect was accompanied by a decrease in leukocyte count in the coronary sinus blood. These studies suggest that activated leukocytes produce vasoconstriction by the release of vasoactive factor(s), and thus may contribute to the pathogenesis of cardiovascular complications in patients with atherosclerosis.
Animals↗
Role of arachidonate metabolites in C5a-induced bronchoconstriction.
The complement cleavage product, C5a, causes a bronchoconstriction in the guinea pig as evidenced by a decrease in dynamic lung compliance and an increase in pulmonary resistance. Previous studies had demonstrated that the antihistamine pyrilamine and the cyclooxygenase inhibitor indomethacin inhibited the C5a-induced bronchoconstriction but the leukotriene (LT)D4 antagonist L-649,923 did not. As an extension of those studies, the purpose of the present study was to determine the contribution of specific cyclooxygenase products and/or LTB4 in mediating C5a-induced bronchoconstriction. To assess the role of the various potential mediators, plasma levels of thromboxane (TX)B2, prostaglandin (PG)D2 and PGF2 alpha were monitored. In addition, guinea pigs were treated either with the TX synthetase inhibitor U-63557A, treated with the TX receptor antagonist SQ 29,548 or made tachyphylactic to the bronchoconstrictor actions of LTB4. C5a challenge caused an increase in plasma concentrations of TXB2, which peaked before the maximum of the bronchoconstriction. However, no significant increase in plasma concentrations of PGD2 or PGF2 alpha was seen. Both U-63557A at 80 mg/kg and SQ 29,548 significantly inhibited the C5a-induced bronchoconstriction, whereas 10 mg/kg of U-63557A did not. The inability of 10 mg/kg of U-63557A to inhibit the response could be explained by both incomplete inhibition of TX synthesis as well as possibly by the increased plasma concentrations of the potent bronchoconstrictor PGD2, which occurred with C5a challenge in the presence of U-63557A. In animals tachyphylactic to LTB4, the maximum of the C5a-induced bronchoconstriction was no different from control.(ABSTRACT TRUNCATED AT 250 WORDS)
Airway Resistance↗
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↗
Inflammatory properties of human C5a and C5a des Arg in mast cell-depleted human skin.
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Complement C5a↗
The C5a receptor of neutrophils and macrophages.
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Animals↗
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↗
Bacterial lipopolysaccharide enhances chemoattractant-induced elastase secretion by human neutrophils.
Bacterial lipopolysaccharide (LPS) has previously been shown to enhance a number of chemoattractant-induced responses by human neutrophils. The possible role of elastase, a neutral protease with broad substrate specificity, in neutrophil-mediated vascular injury of a variety of diseases prompted us to examine a) whether or not LPS enhances the direct chemoattractant-induced secretion of elastase, b) the quantitative requirements of LPS and chemotactic factors, and c) some structural requirements of LPS for this effect. Our results show that LPS at 10 ng/ml and above, enhanced formyl-methionyl-leucyl-phenylalanine-induced neutrophil secretion of elastase, as well as secretion of myeloperoxidase and vitamin B12-binding protein. This effect was independent of cytochalasins or surface stimulation, and thus may occur during chemotactic factor stimulation in vivo. LPS also enhanced neutrophil secretory responses to the complement fragments C5a, C5a des arg, and, to a lesser degree, to leukotriene B4 and platelet-activating factor. This enhancement effect appeared to require the presence of the lipid A moiety and/or parts of the core polysaccharide but not the O-antigen portion of the LPS molecule. Our findings identify a possible LPS-dependent mechanism of neutrophil elastase-mediated tissue injury in Gram-negative infections.
Antigens, Bacterial↗
Effects of anti-C5a antibodies on the adult respiratory distress syndrome in septic primates.
In vitro and in vivo studies have suggested that human complement component C5a plays a key role in neutrophil injury in the adult respiratory distress syndrome (ARDS). First, using leukocyte aggregometry, we demonstrated that the addition of a recently developed rabbit anti-human polyclonal antibody to C5a des arg to endotoxin-activated plasma prevented leukocyte aggregation in vitro. We then administered the anti-C5a des arg antibody to septic primates (Macaca fascicularis). Three groups of primates, control, septic, and anti-C5a antibody treated septic, were studied (n = 4 in each group). A 30-min infusion of Escherichia coli (1 X 10(10)/kg) resulted in severe sepsis and ARDS. Primates were killed 4 h after completion of the E. coli infusion. Septic animals not treated with anti-C5a antibody had 75% mortality (3/4), decreased oxygenation, severe pulmonary edema, and profound hypotension. Septic primates treated with anti-C5a antibodies did not die and did not develop decreased oxygenation (P less than 0.05) or increased extravascular lung water (P less than 0.05). They also had a marked recovery in their mean arterial blood pressure (P less than 0.05). This study demonstrates that treatment with rabbit anti-human C5a des arg antibodies attenuates ARDS and some of the systemic manifestations of sepsis in nonhuman primates.
Animals↗