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PubMed2003

A complement component C3a-like peptide stimulates chemotaxis by hemocytes from an invertebrate chordate-the tunicate, Pyura stolonifera.

Recent evidence suggests that the complement system evolved as a critical host defence mechanism among invertebrates, long before the origin among vertebrates of adaptive immune responses mediated by somatically re-arranging antibodies. The current study supports that contention by identifying a complement component C3a-like peptide in the tunicate, Pyura stolonifera. Activation of P. stolonifera serum with common inflammatory elicitors (lipopolysaccharide and zymosan) resulted in the proteolytic generation of an 8.5 kDa peptide, and concomitantly conferred chemoattractant activity on the serum. The 8.5 kDa peptide shares substantial amino acid sequence homology with a previously characterised tunicate complement component C3-like protein (72% amino acid identity in an 18 amino acid overlap). It is also recognised by an anti-C3 antiserum that is known to cross react with tunicate C3 homologues. Hemocyte migration assays performed with the 8.5 kDa peptide that had been partially purified by gel filtration confirmed that the molecule acts as a powerful chemotactic agent. This suggests that the proteolytic activation of tunicate C3-like molecules can initiate inflammatory responses involving cellular recruitment by liberating a pro-inflammatory peptide akin to the vertebrate anaphylatoxin, C3a.

Amino Acid Sequence↗
PubMed1986

[A new case of bronchospasm under extracorporeal circulation].

A case of bronchospasm occurring after the termination of cardiopulmonary bypass is reported. The complement fractions C3a, C4a and C5a were measured before and right after CPB. Complement activation is not specific to CPB but may occur in any thoracotomy. The statistically significant increase in complement C3a without any pulmonary symptomatology has been reported by several authors. Complement activation cannot therefore be considered as the explanation of this bronchospasm.

Bronchial Spasm↗
PubMed1995

Levels of the terminal complement complex, C3a-desArg and C1-inhibitor in adult patients with capillary leak syndrome following bone marrow transplantation.

Capillary leak syndrome (CLS) is a severe complication after bone marrow transplantation (BMT). To investigate whether there is a pathogenetic role of the complement system, we monitored the levels of the terminal complement complex C5b-9 (TCC) and C3a-desArg as indicators of an activation of the complement system and the inhibitor of the classical pathway of the complement cascade, C1 inhibitor (C1-INH), in 48 bone marrow transplant recipients from 1 week before to 5 weeks after transplantation. Capillary leak syndrome developed in 7 out of 48 patients between days 1 and 12 after BMT. Complement activation as indicated by TCC levels was more pronounced in patients with CLS (n = 7) from day -8 to +28 (p < 0.05; day -1) and the elevation of TCC levels lasted longer in CLS patients (peak day 21) than in patients without this complication (peak day 7). Mean C3a-desArg levels were highest in patients with CLS reaching a peak at day 7. During the early posttransplant period a significant elevation of C1-INH levels (p < 0.01 and p < 0.05 respectively) compared with baseline levels (day -8) was found in patients with and without CLS, which was more pronounced in those patients with CLS (p < 0.05). Although we could not observe an absolute C1-INH deficiency as compared to healthy individuals our data support the presence of a relative deficiency of the inhibitor which might explain the reported beneficial effects of C1-INH substitution in BMT related CLS.

Adult↗
PubMed1976

Cytolytic effects of the complement cleavage product, C3a.

Purified C3a, a cleavage product of the third component of complement,was incubated with various cell types of human and mouse origin. All the tumour cell types tested were lysed by low concentrations of C3a, whereas normal human lymphocytes were relatively resistant. No lysis was produced by C3 or C3b. The possible role of C3a in immunity against tumours is discussed.

Animals↗
PubMed2002

Capillary leak syndrome after cardiopulmonary bypass in elective, uncomplicated coronary artery bypass grafting operations: does it exist?

OBJECTIVE: Operations coupled with cardiopulmonary bypass may provoke a systemic inflammatory response, and it has been suggested that this responses causes capillary leakage of proteins, edema formation, and even organ failure. However, capillary leak syndrome is mainly a clinical diagnosis and has not been verified as yet by actual demonstration of protein leakage from the circulation. We have therefore measured the disappearance of labeled plasma protein before and after cardiopulmonary bypass. METHODS: Sixteen patients scheduled for elective coronary artery bypass grafting were enrolled in a prospective controlled study. The cardiopulmonary bypass circuit was primed with crystalloids only. Tumor necrosis factor alpha, interleukin 6, interleukin 8, anaphylatoxin C3a, and terminal complement complex C5b9 levels were determined before, during, and 3 hours after cardiopulmonary bypass. The transvascular escape rate of plasma protein from the intravascular compartment was assessed by measuring the disappearance of intravenously injected Evans blue dye before and during the third hour after cardiopulmonary bypass. RESULTS: A significant inflammatory response could be demonstrated by means of the 5 measured mediators after bypass. The maximal increase, as compared with the baseline value, was found for interleukin 6 (36-fold). The transvascular escape rate of Evans blue dye was similar before and after bypass (7.6 +/- 0.6%/h vs 7.3 +/- 0.6%/h). CONCLUSIONS: The above data confirm the systemic inflammatory response induced by cardiopulmonary bypass. Contrary to expectations, the transvascular escape rate of Evans blue dye did not change when comparing values before and after bypass. The data do not support the concept of increased protein leakage in the exchange vessels after bypass. We were unable to demonstrate a capillary leak syndrome.

Aged↗
PubMed1978

Macrophage secretion and the complement cleavage product C3a in the pathogenesis of infections by mycoplasmas and L-forms of bacteria and in immunity to these organisms.

Mouse peritoneal macrophages in culture exposed to Mycoplasma pulmonis show marked biochemical changes. This micro-organism induces the release of hydrolytic enzymes from macrophages. The release is time- and dose-dependent and is not associated with loss of the cytoplasmic enzyme lactate dehydrogenase or any other sign of cell death. Secretory products of macrophages may play a role in the pathogenesis of chronic inflammatory responses elicited by mycoplasma infections. One of the products of activated macrophages is the complement cleavage product C3a. Purified C3a was incubated with M. hominis, M. pulmonis, Proteus mirabilis and an L-phase variant of this organism. All mycoplasmas and the L-phase variant were lysed by low concentrations of C3a, whereas the bacterial form of Pr. mirabilis was resistant.

Animals↗
PubMed1975

Human anaphylatoxin (C3a) from the third component of complement. Primary structure.

C3a anaphylatoxin is derived from the third component (C3) of the blood complement system. Selective proteolysis of C3 by activated proenzymes indigenous to blood generates the C3a fragment. Human C3a was isolated from inulin-activated serum containing 6-aminohexanoic acid, according to recently published procedures (Hugli, T. E., Vallota, E., and Müller-Eberhard, H. J. (1975) J. Biol. Chem. 250, 1472-1498). The human C3a fragment is a highly cationic molecule exhibiting an approximate molecular weight of 9000 and composed of 77 amino acid residues. It consists of a single polypeptide chain containing 8% cysteine and lacks both tryptophan and carbohydrate. A tentative primary structure for the human C3a molecule, deduced from overlapping peptides obtained after cyanogen bromide cleavage, tryptic and chymotryptic digestion, is: See article. Two cystelhylcysteine sequences were established at positions 22, 23 and 56, 57 in human C3a. The 6 half-cystine residues in C3a are all interconnected through three disulfide linkages intersecting in a disulfide knot. The functionally amino acid residues distributed among 14 residues at the COOH-terminal end of C3a. This unusually cationic COOH-terminal region of C3a is presumed to play an important role in the interaction of this protein molecule with cellular receptors. A comparison between the linear sequence of human C3a and the NH2-terminal sequences of light and heavy chains of human immunoglobulin indicates that limited identity exists.

Amino Acid Sequence↗
PubMed1995

Inflammatory mediators in relation to the development of multiple organ failure in patients after severe blunt trauma.

OBJECTIVE: To evaluate the posttraumatic course of several inflammatory mediators or markers (complement components C3, C3a, terminal complement complex, thromboxane B2, C-reactive protein, elastase, and neopterin) in relation to the development of multiple organ failure and mortality. DESIGN: Prospective study of a selected patient group. SETTING: Surgical intensive care units in three European trauma hospitals. PATIENTS: Patients (n = 56) with severe blunt trauma (Injury Severity Score of > or = 33). INTERVENTIONS: Arterial blood samples were sequentially obtained. MEASUREMENTS AND MAIN RESULTS: Nonsurvivors (n = 8) had significantly higher circulating C3a and elastase concentrations on the first postinjury day, compared with survivors (n = 48). No differences between these groups were found for terminal complement complex, thromboxane B2, C-reactive protein, and the neopterin/creatinine ratio. Five patients died before day 5. Eighteen patients developed multiple organ failure, which was diagnosed from day 5 onward, leaving 33 patients without multiple organ failure. The patients with subsequent multiple organ failure showed significantly higher mean circulating concentrations of C3a (914 +/- 190 [SEM] ng/mL), terminal complement complex (57 +/- 17 U/mL), and thromboxane B2 (275 +/- 37 pg/mL) at the first postinjury day than the patients without multiple organ failure (566 +/- 110 ng/mL, 27 +/- 2 U/mL, and 169 +/- 14 pg/mL, respectively). In patients with multiple organ failure, elastase concentrations were significantly higher on days 2, 3, 4, and 5 postinjury. Neopterin/creatinine ratios, on the other hand, were significantly higher in patients with multiple organ failure when the multiple organ failure had already become established (on days 8 and 10). CONCLUSION: In multiple trauma patients, excessive triggering of the inflammatory cascade-as expressed by complement activation and stimulation of neutrophils producing elastase--plays an important and early role in the development of multiple organ failure.

Adolescent↗
PubMed1994

Plasma clearance of the human C5a anaphylatoxin by binding to leucocyte C5a receptors.

The C5a anaphylatoxin is a potent complement-derived mediator of inflammation with chemotactic activity. In this study the possible role of specific high-affinity binding sites for C5a on peripheral blood leucocytes for the removal of C5a from human blood plasma was investigated. The addition of purified granulocytes or mononuclear cells to complement-activated plasma resulted in the rapid and dose-dependent removal of up to 80% of plasma C5a, as determined by ELISA. The specific role of leucocyte C5a receptors (C5aR) in the plasma clearance of C5a was demonstrated by the inhibition of C5a uptake by the preincubation of cells with the C5aR-specific monoclonal antibody S5/1. Furthermore, U937 cells which had been induced by db-cAMP to express C5aR, but not undifferentiated U937 cells, were capable of removing C5a from plasma. The inhibition of C5aR internalization by monensin did not affect C5a uptake by leucocytes. The co-incubation with leucocytes had no effect on the plasma clearance of complement activation products C3a or terminal complement complex (TCC), as determined by this in vitro assay. The binding of the C5a anaphylatoxin to cellular receptors represents an effective control mechanism that protects the organism from systemic effects of this potent phlogistic mediator.

Antibodies, Monoclonal↗
PubMed1997

Circulating complement proteins in multiple trauma patients--correlation with injury severity, development of sepsis, and outcome.

OBJECTIVE: To investigate protein complement 3a (C3a) and protein complement 3 (C3) plasma levels in trauma patients directly after the injury, in relation to the patients' outcome, the development of sepsis, or the injury severity, as determined by either the Polytrauma Score (PTS), the Injury Severity Score (ISS), or the Trauma and Injury Severity Score (TRISS). DESIGN: Prospective study. SETTING: Surgical intensive care unit in a university hospital. PATIENTS: Thirty-four patients with multiple trauma. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: C3a and C3 concentrations, as well as the C3a/C3 ratio, were determined at the time of the accident (T0), at the emergency admission (T1), 8 hrs after the accident (T2), and every 8 hrs until day 3, every 12 hrs until day 6, and once daily on days 7 and 8. The C3a plasma concentrations and the C3a/C3 ratios of nonsurvivors were significantly greater at T0 or T1 as compared with those survivors (p = .008 or .033). Patients who developed sepsis had higher C3a plasma levels at the scene of accident than patients without complications. However, these differences did not reach statistical significance (p = .051), although a clear trend was apparent. Patients were grouped according to the severity of injury, as determined by either the PTS, ISS, or TRISS. We found significant differences in the both the mean C3a values and the C3a/C3 ratio among the different groups, during the first 8 hrs after the injury. In addition, a significant correlation was observed between the C3a concentration or the C3a/C3 ratio at T0 to T2 and either the ISS (r2 = .49), PTS (r2 = .22) or the TRISS (r2 = .45), which was similar to correlations between injury severity scores themselves (r2 = .36 to .58). CONCLUSIONS: Complement activation occurs immediately after the injury. The degree of activation is a hallmark for the outcome of a patient. Determination of C3a concentrations, at the scene of the accident, may prove helpful to assess the severity of the injury and to determine the prognosis. The amount of C3a and the C3a/C3 ratio may be useful as additional parameters to the existing trauma scoring systems, such as, PTS, ISS, and TRISS.

Accidents, Traffic↗
PubMed1982

Inhibition of in vitro natural killer activity by the third component of complement: role for the C3a fragment.

Purified human native third component of complement, C3, was found to inhibit in vitro natural killer (NK) cell cytotoxicity in both mouse and human systems. The effect was dose and time dependent, a 50% inhibition being reached with 190 nM C3 (35 micrograms/ml) added during the NK assay or after a 30-min preincubation of the effector cells with this C3 concentration. C3 was shown to act at the effector-cell population level because pretreatment of the target cells did not modify the NK lysis. The inhibition was not due to general cytotoxicity nor to cell agglutination. Moreover, another in vitro cytotoxicity system (represented by alloreactive cytotoxic lymphocytes) was not affected by purified C3. Structural analysis of the active part of the C3 molecule shows that the C3-induced inhibition is supported by the C3a fragment. Release of carboxyl-terminal arginine residue by carboxypeptidase B, converting C3a into des-Arg77-C3a, did not alter the inhibitory effect displayed by this fragment. These results suggest that C3a may play an important role in the regulation of NK activity.

Animals↗
PubMed1988

Synergism between inflammatory mediators in vivo. Induction of airway hyperresponsiveness to C3a in the guinea pig.

The complement anaphylatoxin C3a causes acute bronchoconstriction after intravenous infusion in guinea pigs. At doses of 6 to 600 micrograms/kg, the peptide causes significant and dose-dependent increases in resistance (RL) and decreases in dynamic compliance (Cdyn). Inhibition of serum carboxypeptidase N, the enzyme thought to be responsible for control of C3a activity in blood, by pretreating animals with DL-2-mercaptomethyl-3-guanidinoethylthiopropanoic acid (MGPA), resulted in a 4-fold potentiation of the response to 200 micrograms/kg C3a. Responses to lower C3a doses were not significantly affected. Pretreating animals intravenously with histamine prior to administration of C3a resulted in potentiation of C3a-induced bronchoconstriction at all doses tested, decreasing the amount of C3a required to double RL by 15-fold, from 110 to 7 micrograms/kg. The effect appears to be relatively specific for C3a since histamine pretreatment did not alter airway responsiveness to methacholine. Similarly, pretreatment with methacholine at a dose that caused an increase in RL comparable to histamine did not alter subsequent responses to C3a. Administration of capsaicin, under conditions that elicit acute release of endogenous substance P, also resulted in potentiation of C3a responses, to an extent similar to that observed for histamine. These data are consistent with an increase in pulmonary vascular permeability facilitating accessibility of C3a for its receptor to cause bronchoconstriction before it is inactivated by serum carboxypeptidase N. Further, when C3a is generated in the presence of histamine-and/or substance-P-releasing agents, it may be responsible for a greater fraction of altered pulmonary mechanics than has previously been appreciated.

Airway Resistance↗
PubMed2000

Cutting edge: targeted disruption of the C3a receptor gene demonstrates a novel protective anti-inflammatory role for C3a in endotoxin-shock.

The complement anaphylatoxin C3a, on binding the C3aR, mediates numerous proinflammatory activities. In addition, recent in vitro studies with C3a have implicated C3aR as a possible anti-inflammatory receptor. Because of its possible dual role in modulating the inflammatory response, it is uncertain whether C3aR contributes to the pathogenesis of endotoxin shock. Here, the targeted-disruption of the C3aR in mice is reported. These mice exhibit an enhanced lethality to endotoxin shock with a pronounced gene dosage effect. In addition, the plasma concentration of IL-1beta was significantly elevated in the C3aR(-/-) mice compared with their littermates following LPS challenge. These findings demonstrate an important protective role for the C3aR in endotoxin shock and indicate that, in addition to its traditionally accepted functions in mediating inflammation, the C3aR also acts in vivo as an anti-inflammatory receptor by attenuating LPS-induced proinflammatory cytokine production.

Amino Acid Sequence↗
PubMed1986

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↗
PubMed1988

Anaphylatoxin C3a peptide contracts human pulmonary vasculature.

Complement anaphylatoxin C3a C-terminus octapeptide Ala-Ala-Ala-Leu-Gly-Leu-Ala-Arg (C3apep) contracted both pulmonary artery (PA) and pulmonary vein (PV) in a dose-dependent manner over the concentration range of 0.1 micrograms/ml to 100 micrograms/ml with the latter having maximal contractile activity. Removal of the terminal arginine caused complete loss of activity of C3apep. Contractions consisted of an early and a sustained component with the latter component being much greater in PV than PA. The early component was inhibited by pretreatment of tissues with the cyclooxygenase inhibitor indomethacin, or the thromboxane synthase inhibitors dazoxiben or U63,557A. The sustained contractile component was inhibited by the leukotriene antagonist FPL55712 or the 5-lipoxygenase inhibitors U60,257 (Piriprost) or nordihydroguaiiararetic (NDGA). C3apep challenge of both PA and PV resulted in the generation of leukotriene C4. These results suggest that C3apep causes contraction of human pulmonary arteries and veins by the production of thromboxane A2 and leukotrienes.

Amino Acid Sequence↗
PubMed1986

Prostaglandin and complement interaction in clinical acute respiratory failure.

This study investigated the interaction of plasma levels of circulating prostaglandins and activated complement in clinical acute respiratory failure (ARDS). Fifty patients at risk for ARDS were followed up for up to ten days. Arterial blood gases and plasma levels of complement components C3a and C5a, thromboxane B2 (TxB), and prostaglandin 6-keto-F1 alpha (PGI) and granulocyte aggregation (GA) were measured daily. Seventeen patients (34%) developed ARDS, with mortality of 41% vs 23% for patients without ARDS. Compared with patients without ARDS, the ARDS group had significantly increased plasma C3a (1,130 +/- 750 vs 636 +/- 368 ng/mL) and granulocyte aggregation (48 +/- 10 vs 17 +/- 4 percentage of the maximum light transmission [% max T]). Plasma C5a, TxB, or PGI did not change significantly with or without ARDS. No measured variable was significantly associated with mortality. Regression analysis revealed significant correlations between GA, TxB, PGI, and arterial oxygenation. Plasma C3a and GA are increased in ARDS, suggesting systemic complement activation. A complex series of interactions between the prostaglandins, complement, and GA appears to be involved in ARDS.

Acute Disease↗