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PubMedDate not supplied

Biochemical pathways of acute lung injury.

Complement fragments (C3, C3d, C5a), thromboxane B2 (TxB2), 6-keto-PGF1 alpha and immunoreactive trypsin (IRT) were measured in 98 patients at risk of developing the adult respiratory distress syndrome (ARDS): 53 multiple trauma, 28 abdominal surgery and 17 acute pancreatitis. Sixty-five of these patients developed ARDS: 30 multiple trauma, 19 abdominal surgery and 16 acute pancreatitis patients. Forty of the 65 ARDS patients and 9 out of the 33 non-ARDS patients died. Mean value of the C3d to C3 ratio was abnormal in both ARDS and non-ARDS patients. C5a-like activity was detected in 70 out of the 98 patients (49 ARDS and 22 non-ARDS patients). TxB2 abnormal values (greater than 100 pg . ml-1) were found in 70% of the patients, especially when sepsis occurred. No correlation could be made between abnormal 6-keto PGF1 alpha values and ARDS or sepsis. The mean peak IRT value was 675 micrograms . 1(-1) for ARDS patients and 274 micrograms . 1(-1) for non-ARDS patients (p less than 0.05). A firm correlation was also measured between IRT and sepsis (p less than 0.01). C5a-like activity was regularly detected soon after injury, while TxB2 and IRT tend to appear later in patients developing ARDS. Neither C3d/C3, nor C5a-like activity, nor TxB2, nor IRT are specific markers of ARDS, since they also appeared in severely ill patients who did not develop ARDS.

6-Ketoprostaglandin F1 alpha↗
PubMed1986

Interaction of prostaglandins, activated complement, and granulocytes in clinical sepsis and hypotension.

Activated complement, thromboxane A2, prostacyclin, and activated granulocytes have been implicated in hemodynamic dysfunction after trauma, in sepsis, and in hypovolemic and septic shock. This study evaluated the interaction of plasma concentrations of complement components C3a and C5a, thromboxane B2 (TxB), prostaglandin 6-keto-F1 alpha (PGI), and granulocyte aggregation in clinical sepsis and hypotension. Forty-eight critically ill patients were followed clinically for as long as 10 days. Plasma C3a, C5a, TxB, and PGI were measured daily by the radioimmunoassay method. Granulocyte aggregation, the percentage of maximum aggregation of zymosan-activated plasma standard curves, was performed with patient plasma and normal human leukocytes. Patients were studied in four groups: group I, nonseptic, normotensive; group II, hypovolemic shock, group III, normotensive severe sepsis; and group IV, septic shock. Plasma from 12 normal adults was the control value. PGI, TxB, C3a, C5a, and granulocyte aggregation in patients were greater than that in the control subjects. Granulocyte aggregation was increased in groups III and IV versus groups I and II. C3a was increased in group IV versus groups II and III. C5a and TxB did not vary between groups. PGI was greatly increased in group IV compared with groups I through III. C3a and C5a decreased in nonsurvivors. PaO2/FiO2 ratios correlated directly with PGI and inversely with C3a and TxB/PGI. Plasma PGI and C3a are increased in septic shock. C3a and TxB/PGI imbalances are involved in hypovolemic and septic shock.

Adolescent↗
PubMedDate not supplied

Elevation of chemotactic factor inactivator in alcoholic liver disease.

Defective regulation of neutrophil chemotaxis occurs in patients with alcoholic liver disease. One potent mediator of neutrophil chemotaxis is the complement-derived neutrophil chemoattractant, C5a, which can be inhibited by a serum protein, chemotactic factor inactivator. We hypothesized that chemotactic factor inactivator elevation might, in part, explain the defective neutrophil chemotaxis seen in patients with alcoholic hepatitis. To test this hypothesis, sera were collected from 22 patients with alcoholic hepatitis and 9 normal controls, and evaluated for the antigenic presence of chemotactic factor inactivator using an ELISA test. Chemotactic factor inactivator levels were found to be markedly elevated in patients with alcoholic hepatitis (162 +/- 24 micrograms per ml) compared to normals (60 +/- 3 micrograms per ml, p less than 0.01). Subdividing the hepatitis patients revealed that the elevation of chemotactic factor inactivator was found to be greatest in those patients with mild alcoholic hepatitis (prothrombin time within normal limits and bilirubin less than or equal to 5 mg per dl, 256 +/- 44 micrograms per ml, p less than 0.001), while the group with the severest hepatic dysfunction (prolonged prothrombin time and bilirubin greater than 5 mg per dl) did not differ significantly from controls (71 +/- 11 micrograms/ml, p less than 0.2). Importantly, the inhibition of C5a-induced chemotactic activity by partially purified chemotactic factor inactivator correlated with antigenic amounts of chemotactic factor inactivator in serum (r = 0.63, p less than 0.05). The C5a inhibitory activity in sera obtained from patients with alcoholic hepatitis coprecipitated with chemotactic factor inactivator when serum was precipitated by ammonium sulfate precipitation (45 to 64% saturation).(ABSTRACT TRUNCATED AT 250 WORDS)

Aminopeptidases↗
PubMed2002

Neutrophil adhesion molecule expression and serum concentration of soluble adhesion molecules during and after pediatric cardiovascular surgery with or without cardiopulmonary bypass.

BACKGROUND: Increased neutrophil activation by cardiopulmonary bypass (CPB) during cardiovascular surgery is thought to be responsible for postoperative complications. In children, the contribution of cardiovascular surgery alone to this response is not well-characterized. METHODS: Children undergoing surgery with CPB (CPB group, n = 35) and without CPB (control, n = 22) were studied (age, 3-17 yr). Blood was drawn 24 h preoperatively before medication, after anesthesia, after connection to CPB, at reperfusion, 4 h to 2 days after surgery, at discharge, and months after surgery. Neutrophil antigen expression and serum concentration of adhesion molecules, interleukin 8, and C5a (fragment of C5 complement) were analyzed by flow cytometry and enzyme-linked immunosorbent assay, respectively. RESULTS: With and without CPB, anesthesia and surgery induced decreased LFA-1 (CD11a-CD18), Mac-1 (CD11b-CD18), CD45, and CD54 (intercellular adhesion molecule 1) surface expression and sICAM-1 serum concentrations (all P < 0.001). sL-selectin serum concentration decreased with CPB (P < 0.001) but was not significantly altered in the control. In contrast, CD62L expression increased during CPB (P < 0.001). The time course of all analyzed markers was not significantly different between CPB and control, with the exception of sL-selectin (P = 0.017). One-day preoperative baseline values were reached days to months after surgery. Interleukin 8 and C5a serum concentrations increased after surgery in both the CPB group and the control group. CONCLUSIONS: Pediatric cardiovascular surgery leads to reduced adhesiveness and activity of circulating neutrophils. This reduction is more pronounced and sustained with CPB. These data may be useful in the assessment of novel therapeutic strategies.

Adolescent↗
PubMed1983

Expression of C5a-like biological activities by the fifth component of human complement (C5) upon limited digestion with noncomplement enzymes without release of polypeptide fragments.

Experimental conditions required for the expression of maximum C5 activation upon limited trypsin hydrolysis were determined to be 0.008 mol of trypsin/mol C5 in a reaction mixture containing 1 mg C5/ml veronal-buffered saline incubated at 37 degrees C for 30 min. Employing these optimal incubation conditions, the primary or preferred site of trypsin hydrolysis of the C5 alpha-chain resulted in the production of C5 alpha 1 (molecular weight, 90,000) and C5 alpha 5 (molecular weight, 25,000) fragments that remained disulfide bonded to the modified C5 molecule (C5'try). Detailed structural-functional analyses clearly indicated the trypsin-mediated conversion of the C5 alpha-chain to C5 alpha 1 and C5 alpha 5 was responsible for the acquisition of neutrophil lysosomal enzyme-releasing and chemotactic activities. Gel filtration column chromatography under physiological ionic strength, pH 7.4, or in the presence of 0.2% SDS further demonstrated that at least 90% of the total recoverable C5a-like biological activity was mediated by the 210,000 molecular weight forms of trypsin-modified C5. Other physiologically relevant, noncomplement protease enzymes (alpha-thrombin, plasmin, and elastase) also activated C5 to express C5a-like reactivities. Analysis of alpha-thrombin-induced, C5 alpha-chain cleavage events by SDS-polyacrylamide slab gel electrophoresis indicated that the mechanism of alpha-thrombin-activation of C5 is similar to that described for trypsin. Reconciliation of this novel mechanism of C5 activation by trypsin with previously published results, and a discussion of the biological significance of noncomplement enzyme-mediated activation of C5 as it might relate to inflammatory processes in vivo, was presented.

Chemotaxis, Leukocyte↗
PubMed1985

Labeling the granulocyte C5a receptor with a unique photoreactive probe.

Human C5a anaphylatoxin is a complement-derived chemotactic factor that binds to specific receptors that are found in the granulocyte plasma membrane. These receptors, or a specific subunit of these receptors, can be covalently labeled with a unique photoreactive analog of human C5a. This photoaffinity probe, p-azidobenzoyl-2-mercapto-N-ethylamide-C5a (ABMEA-SC5a), was synthesized by coupling p-azidobenzoyl-2-mercapto-N-ethylamide-2'-thiopyridine disulfide to human C5a after it had been partially reduced with dithiothreitol. Both direct and competitive binding studies demonstrated that a radioiodinated ABMEA-SC5a derivative retained the capacity to specifically bind to either neutrophil or U937 cell C5a receptors. Half-maximal binding of the photoreactive analog was observed at a concentration of 1 to 2 nM, a value that is comparable to that observed when 125I-C5a is employed as the ligand. The covalent adducts that were formed after irradiation of 125I-ABMEA-SC5a that had been prebound to either neutrophil or U937 cell plasma membranes were found to have an apparent molecular mass of 52,000 daltons when analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis techniques. These findings demonstrate that the C5a receptors found on human neutrophils and other granulocytes are not only functionally similar, but biochemically similar as well.

Affinity Labels↗
PubMed1988

Dialysis leukopenia, hypoxemia, and anaphylatoxin formation: effect of membrane, bath, and citrate anticoagulation.

The goal of these prospective studies was to determine the effect of different dialyzer membranes and dialysate composition on leukopenia and hypoxemia during hemodialysis with citrate anticoagulation. Significant early leukopenia was found with a cuprophane membrane, while a cellulose acetate membrane was associated with mild early leukopenia. Bath composition had no effect. Bicarbonate dialysate, compared with acetate, eliminated hypoxemia in cellulose acetate membranes and reduced its degree and duration with cuprophane. Membrane composition had no effect on hypoxemia during acetate dialysis. The findings indicate that leukopenia is directly and exclusively related to membrane composition while hypoxemia only relates in part to membrane effects. Serial determinations of complement components C3a and C5a showed significant increases in parallel with leukopenia during heparin anticoagulation, but the anaphylatoxin concentration changes were dissociated during dialysis with citrate anticoagulation. The concentrations of anaphylatoxins C3a and C5a appear not to be directly related to dialysis-induced leukopenia. The dissociation between anaphylatoxin concentrations and leukopenia may be related to changes in generation or unmasked changes in leukocyte response. Citrate anticoagulation may provide a useful probe for further studies on membrane-leukocyte interactions in vivo.

Acetates↗
PubMed1995

Blockade of C5a and C5b-9 generation inhibits leukocyte and platelet activation during extracorporeal circulation.

Complement activation contributes to the systemic inflammatory response induced by cardiopulmonary bypass. At the cellular level, cardiopulmonary bypass activates leukocytes and platelets; however the contribution of early (3a) versus late (C5a, soluble C5b-9) complement components to this activation is unclear. We used a model of simulated extracorporeal circulation that activates complement (C3a, C5a, and C5b-9 formation), platelets (increased percentages of P-selectin-positive platelets and leukocyte-platelet conjugates), and neutrophils (upregulated CD11b expression). to specifically target complement activation in this model, we added a blocking mAb directed at the human C5 complement component and assessed its effect on complement and cellular activation. Compared with a control mAB, the anti-human C5 mAb profoundly inhibited C5a and soluble C5b-9 generation and serum complement hemolytic activity but had no effect on C3a generation. Additionally, the anti-human C5 mAb significantly inhibited neutrophil CD11b upregulation and abolished the increase in P-selectin-positive platelets and leukocyte-platelet conjugate formation compared to experiments performed with the control mAb. This suggests that the terminal components C5a and C5b-9, but not C3a, directly contribute to platelet and neutrophil activation during extracorporeal circulation. Furthermore, these data identify the C5 component as a site for therapeutic intervention in cardiopulmonary bypass.

Antibodies, Monoclonal↗
PubMed2002

Albutensin A and complement C3a decrease food intake in mice.

Albutensin A (Ala-Phe-Lys-Ala-Trp-Ala-Val-Ala-Arg) derived from serum albumin dose-dependently decreased food intake after intracerebroventricular (10-50 nmol/mouse) or peripheral (0.3-1.0 micromol/mouse) administration in fasted conscious ddY mice. Albutensin A delayed gastric emptying and elevated blood glucose levels. Although albutensin A showed low affinity for bombesin receptor, it decreased food intake in bombesin receptor knockout mice, indicating that its inhibitory effect on feeding was not mediated through bombesin receptor. Then, we investigated whether the albutensin A-induced decrease in food intake was mediated by complement C3a and C5a receptors, because albutensin A had affinities for these receptors. Des-Arg-albutensin A, lacking affinity for C3a and C5a receptors, did not inhibit food intake. We found for the first time that centrally administered C3a (10-100 pmol/mouse) by itself decreased food intake in fasted mice. In contrast, C5a increased food intake after central injection. Based on these results, we conclude that the inhibitory effect of albutensin A on food intake is mediated through the C3a receptor.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1997

cDNA cloning and characterization of rat C5a anaphylatoxin receptor.

Activation of the complement cascade plays an essential role in the early stages of inflammation. C5a and its receptor are particularly active in anaphylaxis. To determine the pathological roles played by C5a and C5a receptor (C5aR) in rats, we cloned C5aR cDNA and analyzed distribution of its mRNA in various organs including lung from an LPS-stimulated rat. Furthermore, we generated a polyclonal antiserum which specifically recognizes rat C5aR, as confirmed by its specific interaction with cells transfected with rat C5aR cDNA.

Animals↗
PubMed2005

Pharmacological targeting of anaphylatoxin receptors during the effector phase of allergic asthma suppresses airway hyperresponsiveness and airway inflammation.

Airway hyperresponsiveness and airway inflammation are hallmarks of allergic asthma, the etiology of which is crucially linked to the presence of Th2 cytokines. A role for the complement anaphylatoxins C3a and C5a in allergic asthma was suggested, as deficiencies of the C3a receptor (C3aR) and of complement factor C5 modulate airway hyperresponsiveness, airway inflammation, and Th2 cytokine levels. However, such models do not allow differentiation of effects on the sensitization phase and the effector phase of the allergic response, respectively. In this study, we determined the role of the anaphylatoxins on the effector phase of asthma by pharmacological targeting of the anaphylatoxin receptors. C3aR and C5a receptor (C5aR) signaling was blocked using the nonpeptidic C3aR antagonist SB290157 and the neutralizing C5aR mAb 20/70 in a murine model of Aspergillus fumigatus extract induced pulmonary allergy. Airway hyperresponsiveness was substantially improved after C5aR blockade but not after C3aR blockade. Airway inflammation was significantly reduced in mice treated with the C3aR antagonist or the anti-C5aR mAb, as demonstrated by reduced numbers of neutrophils and eosinophils in bronchoalveolar lavage fluid. Of note, C5aR but not C3aR inhibition reduced lymphocyte numbers in bronchoalveolar lavage fluid. Cytokine levels of IL-5 and IL-13 in bronchoalveolar lavage fluid were not altered by C3aR or C5aR blockade. However, blockade of both anaphylatoxin receptors markedly reduced IL-4 levels. These data suggest an important and exclusive role for C5aR signaling on the development of airway hyperresponsiveness during pulmonary allergen challenge, whereas both anaphylatoxins contribute to airway inflammation and IL-4 production.

Animals↗
PubMed2004

[Clinical applications of recombinant complement inhibitors].

The complement system constitutes an important part of the innate immune system. Complement activation leads to the generation of C3a, C4a and C5a anaphylatoxins and the membrane attack complex. The anaphylatoxins mediate multiple reactions in the acute inflammatory response. Membrane attack complex inserts molecules into target membranes and causes cell lysis. The complement system can not discriminate between self and non-self cells and the inappropriate complement activation may lead to host cell damage. This destructive activity is tightly regulated by family of structurally and functionally related soluble and membrane-bound proteins, which act as inhibitors of complement system. The inappropriate complement activation plays an essential role in the pathogenesis of many diseases. In the therapy of these diseases specific recombinant complement inhibitors can be used. Recombinant complement inhibitors can be produced in large amounts by different eukaryotic or prokaryotic systems. The choice of the system depends on kind of the post-translational modifications of proteins.

Anaphylatoxins↗
PubMed1987

Neutral endopeptidase-like enzyme controls the contractile activity of substance P in guinea pig lung.

The responsiveness of isolated guinea pig lung parenchymal strips to substance P was enhanced by at least 100-fold in the presence of the endopeptidase inhibitors phosphoramidon (1 microM) or thiorphan (1 microM), but not with the converting enzyme inhibitor, captopril, or an inhibitor of serum carboxypeptidase N (both 1 microM). Responses of guinea pig tracheal rings to substance P were also markedly potentiated by phosphoramidon. The increase in tissue responsiveness by these inhibitors was relatively specific for substance P among several other spasmogenic peptides, including formyl-methionyl-leucyl-phenylalanine and the complement peptides C3a and C5a. The enhanced responses appear to result from a decrease in the rate of substance P degradation in the presence of neutral endopeptidase inhibitors. Specific binding of substance P to its receptor on bronchial membranes was increased by three- to fourfold in the presence of phosphoramidon. These data demonstrate an enhanced potential for substance P to contract lung tissues when degradation by a neutral endopeptidase-like enzyme is blocked.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1989

Analysis of the proinflammatory property of epidermal cyst contents: chemotactic C5a anaphylatoxin generation.

We investigated in vitro the contents of epidermal cysts for complement activation and found that they activated complement mainly through the alternative pathway. Chemotactic C5a anaphylatoxin produced by the cyst contents after contact with serum most likely plays a significant role in the initiation and aggravation of inflammation in ruptured epidermal cysts. Our additional study disclosed that components of three representative follicular resident microorganisms (Pityrosporum ovale, Propionibacterium acnes, and Staphylococcus epidermidis) also produced C5a anaphylatoxin mainly through the alternative pathway; the C5a production was more vigorous than that by a virulent pathogen, Staphylococcus aureus. These results suggest that accidental colonization of the cyst contents by these follicular microbial flora further augments the inflammatory changes in ruptured epidermal cysts.

Adult↗
PubMed1990

Complement activation and reinfusion of wound drainage blood.

Eighteen patients undergoing total hip replacement (n = 13) or knee arthroplasty (n = 5) due to osteoarthritis or osteoarthrosis were prospectively studied in an investigation of complement activation and anaphylatoxin release in association with reinfusion of aspirated wound blood. Twelve of the patients needed blood transfusions and received an average of 390 +/- 75 ml (+/- SD) of autologous blood within 45 min. Plasma complement components, anaphylatoxins, and inhibitors were studied 1 min before and 15 min after the start of and 15 min after the completion of autologous transfusion. Samples also were taken from the collected blood, before and after passing it through a microporous filter. Blood gases and systemic complement samples were drawn simultaneously. There were no significant changes in systemic complement variables before, during, or after transfusion of autologous blood. However, in the aspirated blood, increased concentration of anaphylatoxins (C3a and C5a) and terminal complement complexes (TCC) were present (P less than 0.001). There were no differences observed between samples drawn before and after filtration of the blood. The concentration of C5 was less in the collected blood than in the systemic blood (P less than 0.05). No changes in blood gases were observed. This study demonstrated that postoperatively salvaged whole blood underwent anaphylatoxin formation and complement activation. However, after reinfusion of this blood, neither systemic complement activation nor clinical complications were observed.

Adult↗
PubMed1981

Mediation of increased vascular permeability after complement activation. Histamine-independent action of rabbit C5a.

Intradermal injection of zymosan into nonsensitized rabbits induces plasma exudation, which is dependent on two mediators: C5a generated in extravascular tissue fluid and a vasodilator prostaglandin generated from substrates localized in cell membranes. This relationship between the complement system and the prostaglandin synthesis system had not previously been explored, and complement activation has generally been associated with increased vascular permeability via histamine release. We report that C5a increases vascular permeability by a mechanism that is not dependent on histamine release; however plasma exudation is virtually undetectable in the absence of a vasodilator substance. Because the permeability-increasing activity is stable in plasma, analogy with other species suggests that the activity is a result of C5a devoid of its carboxyl terminal arginine (C5a des Arg). This relates the observed permeability-increasing activity with effects on leukocytes rather than effects as an anaphylatoxin.

Animals↗
PubMed2004

Cloning, expression, cellular distribution, and role in chemotaxis of a C5a receptor in rainbow trout: the first identification of a C5a receptor in a nonmammalian species.

C3a, C4a, and C5a anaphylatoxins generated during complement activation play a key role in inflammation. C5a is the most potent of the three anaphylatoxins in eliciting biological responses. The effects of C5a are mediated by its binding to C5a receptor (C5aR, CD88). To date, C5aR has only been identified and cloned in mammalian species, and its evolutionary history remains ill-defined. To gain insights into the evolution, conserved structural domains, and functions of C5aR, we have cloned and characterized a C5aR in rainbow trout, a teleost fish. The isolated cDNA encoded a 350-aa protein that showed the highest sequence similarity to C5aR from other species. Genomic analysis revealed the presence of one continuous exon encoding the entire open reading frame. Northern blot analysis showed significant expression of the trout C5a receptor (TC5aR) message in PBLs and kidney. Flow cytometric analysis showed that two Abs generated against two different areas of the extracellular N-terminal region of TC5aR positively stained the same leukocyte populations from PBLs. B lymphocytes and granulocytes comprised the majority of cells recognized by the anti-TC5aR. More importantly, these Abs inhibited chemotaxis of PBLs toward a chemoattractant fraction purified from complement-activated trout serum. Our data suggest that the split between C5aR and C3aR from a common ancestral molecule occurred before the emergence of teleost fish. Moreover, we demonstrate that the overall structure of C5aR as well as its role in chemotaxis have remained conserved for >300 million years.

Amino Acid Sequence↗
PubMed2001

Carboxypeptidase R is an inactivator of complement-derived inflammatory peptides and an inhibitor of fibrinolysis.

Carboxypeptidase R (CPR) exists in precursor form (proCPR) in plasma in contrast to carboxypeptidase N (CPN), which is present in the active state. CPR plays two important roles, one of which appears to be the control of the inflammatory response by inactivation of anaphylatoxins such as complement-derived C3a and C5a. Therefore, an increase in CPR activity may facilitate rapid inactivation of these inflammatory mediators generated at the site of bacterial infection. Upregulation of proCPR expression during the inflammatory response initiated for instance by endotoxin (lipopolysaccharide) should play a role in suppressing hyper-reactivity as seen in septic shock. CPR also functions as an inhibitor of fibrinolysis, where its ability to prevent binding of plasminogen to lysine residues on fibrin clots significantly lengthens tissue plasminogen activator (tPA)-induced fibrinolysis time. Therefore, upregulation of proCPR production during the inflammatory response may exacerbate thrombosis contributing to the development of disseminated intravascular coagulation as well as other conditions involving thrombosis. Co-administration of tPA and a specific inhibitor of CPR, such as potato carboxypeptidase inhibitor, which does not affect CPN, may be useful in thrombolytic therapy.

Anaphylatoxins↗