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PubMed1985

Inflammatory oedema induced by synergism between calcitonin gene-related peptide (CGRP) and mediators of increased vascular permeability.

The potent vasodilator calcitonin gene-related peptide (CGRP, human synthetic), when mixed with histamine and injected intradermally in the rabbit, induced a marked potentiation of local oedema. CGRP also potentiated oedema induced by other mediators of increased microvascular permeability in the rabbit; bradykinin, platelet-activating factor (Paf), C5a des Arg, N-formylmethionyl-leucyl-phenylalanine (FMLP) and leukotriene B4 (LTB4). Substance P alone, or mixtures of substance P and CGRP, failed to induce oedema in rabbit skin. In rat skin, however, substance P induced oedema and this was potentiated by CGRP. CGRP had a protracted potentiating action following intradermal injection in the rabbit. The time for half loss of activity for CGRP was 40.1 +/- 7.5 min compared to 18 +/- 1 min for prostaglandin E2 (PGE2). No loss of potentiating activity was detected after incubation of CGRP in rabbit plasma or blood for 60 min. We postulate that endogenous CGRP, if released locally from nerve endings, could have a marked enhancing effect on oedema induced by other mediators in an inflammatory reaction.

Animals↗

PubMed1991

Human neutrophil migration into skin chambers is associated with production of NAP-1/IL8 and C5a.

Respiratory burst activity initiated by the chemoattractants fMLP, rC5a and rNAP-1/IL8 was investigated in human exudated and peripheral blood neutrophils. Exudated cells were isolated after migration into a skin chamber and the respiratory burst activity was measured as chemiluminescence amplified by luminol and horseradish peroxidase. The response to fMLP (5 x 10(-8) mol/l) was significantly enhanced (p less than 0.01) in the exudated cells but was significantly decreased after stimulation (5 x 10(-8) mol/l) with rC5a and rNAP-1/IL8 (p less than 0.05 and p less than 0.01, respectively). Analysis revealed that, in the chamber fluid, the activated complement C5a was generated during exudation (p less than 0.01). Determinations of NAP-1/IL8 showed that this substance was also produced and released into the chamber fluid (p less than 0.01). No correlation was found between the number of exudated cells and the amount of C5a or NAP-1/IL8 in the exudation fluid, thus indicating that, in vivo, the exudation process is controlled by multiple factors and not by the quantity of a single chemoattractant. The present study shows that NAP-1/IL8 and C5a are produced in humans during an aseptic inflammation, and that this occurs in parallel to the migration of neutrophils into the skin chambers. The significant desensitization of the exudated cells to NAP-1/IL8 and C5a reflects a previous exposure to these attractants. These results suggest that the novel tissue-derived cytokine NAP-1/IL8 plays a role in human neutrophil exudation in vivo.

Cell Movement↗

PubMed1991

Role of granulocytes and C5a in myocardial response to zymosan-activated serum.

Although previous studies have demonstrated that complement (C)5a causes myocardial ischemia and mechanical dysfunction, the cardiac response of endogenously produced C5a and C5a des-Arg in zymosan-activated serum (ZAS) and the critical role of granulocytes in this process are poorly understood. Therefore, we compared the coronary and cardiac effects of ZAS and purified C5a and investigated the role of leukocyte adhesion-promoting receptors (i.e., CD11/CD18). Like purified C5a, ZAS (0.5 ml) significantly reduced coronary artery blood flow and regional segment shortening, whereas coronary venous granulocyte concentration and myocardial lactate extraction were significantly decreased. A monoclonal antibody (MoAb) to C5a/C5a des-Arg attenuated ZAS-induced cardiac alterations. Three minutes of continuous infusion of C5a or ZAS induced sustained decreases in coronary venous granulocyte concentrations, although coronary flow and segment shortening returned to control levels after 2 min. Another MoAb, IB4, directed against CD18, significantly inhibited ZAS-induced granulocyte extraction and associated cardiac effects. Thus, cardiac dysfunction occurs after activation of the complement cascade with zymosan resulting in extraction of granulocytes mediated by the CD18 adherence glycoprotein. Furthermore, intramyocardial retention of granulocytes appears necessary for the initial and full ZAS-induced cardiac dysfunction.

Anaphylatoxins↗

PubMed1990

The influence of the geometry of the dialyzer and the composition of the dialysate in activating the complement system.

During hemodialysis there is a complex interaction between the patient and the extracorporeal circuit that activates the complement system, among others. To better understand the influence of the dialyzer geometry and the dialysate composition, we compared hollow fiber versus parallel plate dialyzers and acetate versus bicarbonate dialysates and their role in the production of C3a, C4a and C5a. There was no significant difference in the plasmatic levels of these anaphylotoxins and their des-Arg derivates, as measured by RIA, in either dialyzer. The same was true when the dialysate in question had a different composition. We thus concluded that neither the geometric configuration of the dialyzer nor the composition of the dialysate influence their biocompatibility as regards the activation of the complement system, and that the differences that have been described shall have to be explained in another manner or assessed by methods other than those used in this study.

Adult↗

PubMed1992

Anticoagulation-dependent inhibition of in vitro complement activation by anti-apo-B sepharose 4B CL.

During LDL apheresis, various combinations of heparin and citrate are used for anticoagulation. With an in vitro batch system we examined whether heparin/citrate combinations can be optimized in terms of complement activation inhibition without the loss of anticoagulant potency. Plasma anticoagulated by using six clinically applicable regimens was incubated with anti-apo-B antibody-coupled Sepharose 4B CL, and the anaphylatoxin content of the supernatant was investigated. A significant dose-dependent reduction of complement activation was achieved by anticoagulating whole blood with 10 U/ml heparin (p < 0.05) if compared with serum whereas citrate inhibited more effectively the generation of C5a (desarg) even at a low concentration (ACD-B 1:20) (p < 0.01). The lowest anaphylatoxin level was generated when heparin (10 U/ml) plus citrate (ACD-B 1:10) were applied, although such an approach may be of limited clinical interest. The empirically chosen heparin plus citrate ratio (2 U/ml, 1:20, respectively) provides for an optimal and almost ideal inhibition of complement activation and contributes considerably to the good tolerability of the immunoadsorbent.

Apolipoproteins B↗

PubMed1992

Anaphylatoxin generation and distribution during in vitro LDL apheresis.

The extent of anti-apo-B IgG-Sepharose-induced complement activation in serum and plasma (heparin 2 U/ml and ACD-B 1:20) was investigated using an in vitro model of LDL apheresis. The total volume of serum or plasma loaded to the chromatography column was collected in defined aliquots. The washing, desorption and regeneration fluids were processed in the same way. From the obtained values of generated complement split products C3a (desarg), C4a (desarg), C5a (desarg) and complement proteins C3, C4, C5, the conversion rates of the precursor were calculated. In the experiments with serum, 19% of C3, 8% of C4 and 2.3% of C5 were converted by the immunoadsorbent, whereas with plasma 7, 6, and 0.6%, respectively, were found. Furthermore, only 60-74% of total anaphylatoxins were found in the effluent during the loading process. The residual 26-40% was removed from the column with the subsequent washing fluids. Therefore, in the clinical routine, only a reduced part of generated anaphylatoxins will be retransfused to the patient. The fact that C5 is converted to the most limited extent to its biologically active fragment additionally contributes to the understanding of the good clinical tolerability of the LDL apheresis.

Anaphylatoxins↗

PubMed1989

Identification of two endogenous neutrophil-activating peptides in psoriatic skin and inflammatory cells: C5ades arg and NAP.

Migration of polymorphonuclear leukocytes (PMN) into the upper layers of involved epidermis represents a characteristic feature of psoriasis. By analysis of psoriatic scale material we were able to identify two potent proinflammatory peptides, which are present in the upper epidermis from psoriatic lesions. Both factors (C5ades arg and NAP) show strong chemotactic activity for human neutrophils in vitro as well as in vivo. Whereas C5ades arg is a known mediator activated by either alternative or classical activation of the complement cascade, NAP represents a newly detected peptide with a molecular weight of 8,000 daltons which is produced by a variety of cells participating in the psoriatic tissue reaction.

Cell Movement↗

PubMed1989

C5 neoepitopes appearing during activation.

After activation of serum complement, a neoantigen was reported to appear on a 54,000-dalton fragment of C5. On the other hand, a monoclonal antibody (MoAb), No. 568, revealed that an epitope on the beta-chain of C5 became masked after the formation of SC5b-9 complex. Murine MoAbs were obtained to human C5a-des-Arg. Some of them are specific only to C5a-des-Arg but not to C5a or C5. Using these MoAbs, a sandwich immunoassay was devised for detection and measurement of C5a-des-Arg. The neoepitopes for these MoAbs were analyzed by their reactivities to synthetic peptide derivatives of human and porcine C5a, and the structural changes of C5a were suggested to occur after the removal of the carboxyl terminal arginine residue.

Animals↗

PubMed1991

A sensitive enzyme immunoassay for the quantitation of human C5a/C5a(desArg) anaphylatoxin using a monoclonal antibody with specificity for a neoepitope.

The direct quantitation of C5a/C5a(desArg) in human plasma was achieved by a specific and highly sensitive ELISA which is based on the neoepitope-specific monoclonal antibody C17/5. The error-prone removal of C5 from plasma prior to the assay is therefore not required. With a detection limit of 20 pg C5a/ml plasma, the sensitivity of this assay allowed to define normal ranges (1.94 +/- 1.49 ng C5a/nl, mean +/- SD) of C5a/C5a(desArg) in human blood plasma. This assay will also be applicable to the quantitation of C5a in specimens with low protein content where precipitation-based assays fail to accurately determine C5a. In addition, the mAb C17/5 turned out to efficiently block the binding of C5a/C5a (desArg) to its cellular receptor and therefore provides a valuable tool in the delineation of C5a effects in complex biologic systems in the presence of native C5, such as under in vivo conditions.

Adenosine Triphosphate↗

PubMed1991

Formation of mixed aggregates of human polymorphonuclear leukocytes and platelets by C5a-desArg.

Human blood platelets are not aggregated by C5a-desArg. They are brought to aggregation, however, when human polymorphonuclear leukocytes (PMN) are present in the platelet suspension. Then, mixed aggregates form upon activation with C5a-desArg. The platelets do not adhere only to PMN but also stick to each other, indicating that they are activated. This is also evident from their morphology which shows pseudopod formation. The formation of mixed aggregates requires the presence of Ca2+ and Mg2+, it does not occur at temperatures below 20 degrees C. The results suggest that the platelets are activated indirectly, by a mediator released from the PMN upon stimulation with C5a-desArg. When mixed with platelets, PMN partially aggregate already upon addition of Ca2+. This effect is not seen in pure PMN suspensions. C5a-desArg causes additional aggregation which includes the platelets. The indirectly stimulated platelets in turn enhance the aggregation of the PMN in the mixtures incubated with C5a-desArg. This may cause a positive feedback.

Cell Aggregation↗

PubMed1990

Inactivation of chemotactic factor inactivator by cigarette smoke. A potential mechanism of modulating neutrophil recruitment to the lung.

Activation of the complement system with generation of the potent neutrophil chemotactic factor C5a has been proposed to play a significant role in the neutrophil accumulation in the lungs of cigarette smokers. Chemotactic factor inactivator (CFI) can inhibit C5a-directed neutrophil chemotaxis by binding to the C5a cochemotaxin GcGlobulin (GcG), a vitamin-D-binding protein, and inhibiting the capacity of GcG to enhance the chemotactic activity of C5a. Because cigarette smoke can inhibit the function of some proteins, a loss of CFI functional activity induced by cigarette smoke would allow an increased capacity of GcG to augment C5a-directed neutrophil chemotaxis. In order to test this hypothesis, cigarette smoke was bubbled through a CFI solution, and the solution was evaluated for its ability to inhibit the chemotactic activity of C5a and GcG. Smoke-treated CFI inhibited only 36% of the C5a-GcG chemotactic activity. In contrast, a CFI solution treated with air inhibited 62% of the chemotactic activity (p less than 0.001). Consistent with these observations, smoke-treated CFI exhibited a decreased capacity to bind to GcG and a decreased capacity to inhibit the binding of C5a des Arg to GcG. CFI contained in the bronchial lavage fluids obtained from patients with chronic obstructive pulmonary disease secondary to cigarette smoking and asymptomatic smokers exhibited a decreased capacity to inhibit C5a-GcG neutrophil chemotaxis and to bind to GcG (p less than 0.05, both comparisons). Furthermore, smoke bubbled through normal bronchial lavage fluid decreased the capacity of CFI to bind to GcG.(ABSTRACT TRUNCATED AT 250 WORDS)

Aminopeptidases↗

PubMed1991

Gcglobulin functions as a cochemotaxin in the lower respiratory tract. A potential mechanism for lung neutrophil recruitment in cigarette smokers.

Activation of the complement pathway with generation of the potent chemotaxin C5a may play a significant role in the neutrophil accumulation seen in the lungs of patients with smoking-associated diseases. Although C5a is rapidly degraded to the less potent chemotaxin C5a des Arg, binding of this peptide with its cochemotaxin Gcglobulin (GcG) can restore its chemotactic potency. Therefore, modulation of Gcglobulin levels in smoking-induced lung disease could affect the accumulation of neutrophils seen in this disorder. To test this hypothesis GcG was measured by an enzyme-linked immunosorbent assay in bronchoalveolar lavage fluids (BALF) obtained from non-smokers, asymptomatic smokers, and patients with chronic obstructive pulmonary disease (COPD). Antigenic amounts of GcG in BALF were increased in COPD patients and asymptomatic smokers compared with nonsmokers (6.35 +/- 1.02 and 5.15 +/- 1.07 versus 2.82 +/- 0.37 micrograms/mg albumin, p less than 0.05). In addition, we found that BALF enhanced C5a des Arg-mediated chemotaxis (48.3 +/- 5.6 versus 11.2 +/- 1.6 cells/high power field, p less than 0.05), an effect that was not seen in the presence of GcG antibody. Furthermore, BALF GcG was similar to serum GcG using Western blot analysis, and the interaction of GcG with C5a des Arg was not inhibited by cigarette smoke. These data demonstrate that elevation of BALF GcG levels occurs in smoking-associated lung disease and that this protein is biologically active and capable of increasing C5a des Arg-mediated chemotaxis. This suggests that modulation of GcG levels may be important in smoking-associated lung diseases.

Adult↗

PubMed1992

Neutrophil chemotactic factors in the respiratory tract of patients with chronic airway diseases or idiopathic pulmonary fibrosis.

This study was designed to clarify the contributions of specific neutrophil chemotactic factors (NCF) in neutrophil accumulation in the human respiratory tract associated with various diseases. The activity and characteristics of the NCF in the bronchoalveolar lavage (BAL) fluid and culture media of alveolar macrophages obtained from normal volunteers, control patients, patients with chronic airway diseases (CAD) and patients with idiopathic pulmonary fibrosis (IPF) were examined. The BAL fluid from normal volunteers contained NCF comparable with the chemotactic factors interleukin-8 (IL-8) and leukotriene B4 (LTB4). Analysis of the biochemical characteristics of NCF released from alveolar macrophages suggests that they are derived from alveolar macrophages. The NCF activities in BAL fluids from patients with CAD and IPF were higher than those in BAL fluids from normal volunteers and control patients. Biochemical analysis demonstrated that several kinds of NCF, including those derived from the complement component C5 and alveolar macrophages, were present in the BAL fluid from patients with CAD and respiratory infections. The especially marked increase of C5-derived NCF indicate their importance in neutrophil accumulation in the respiratory tract of patients with CAD. Alveolar macrophages released different types of NCF after different lengths of culture periods (4 h and 24 h). Alveolar macrophages from patients with IPF released larger amounts of NCF than alveolar macrophages from normal volunteers, indicating the importance of alveolar-macrophage-derived NCF as well as C5-derived NCF in neutrophil accumulation in the respiratory tract of patients with IPF. These results suggest that various types of NCF increase in response to different disease states of the respiratory tract and serve to regulate the accumulation of neutrophils.

Adult↗

PubMed1988

Differential effects of the complement peptides, C5a and C5a des Arg on human basophil and lung mast cell histamine release.

The ability of purified anaphylatoxins to induce human lung mast cell mediator release was investigated. In eight anti-IgE responsive (histamine release = 22 +/- 5%, mean +/- SEM) mast cell preparations of 1-96% purity, C5a and C5a des Arg (0.55 pg/ml to 55 micrograms/ml), failed to elicit or potentiate histamine release; lung fragments were similarly unresponsive. The related peptide C3a was also inactive. All anaphylatoxins failed to induce mast cell leukotriene C4 (LTC4) and prostaglandin D2 (PGD2) release. LTC4 release was also negligible from basophils where C5a was a potent histamine release stimulus. Supernatants from C5a-challenged mast cells remained fully active on basophils, excluding carboxypeptidase inactivation of C5a as an explanation for the lung mast cell results. In contrast to lung, skin mast cells were C5a-responsive (histamine release = 8 +/- 1%, at 55 micrograms/ml, n = 2). We conclude that C5a, though devoid of activity on the human lung mast cell, is a human basophil and skin mast cell secretagogue. These findings demonstrate significant organ-specific heterogeneity in mast cell responsiveness.

Basophils↗

PubMed1992

Effect of psoralen + ultraviolet-A on the chemotactic activity of polymorphonuclear neutrophils towards anaphylatoxin C5a des Arg.

It was shown that psoralen + UV-A inhibits the chemotactic activity of polymorphonuclear neutrophils towards anaphylatoxin C5a des Arg. This reaction required oxygen and there is a high possibility that the active oxygen species was in a singlet state. Oxygen did not act directly on C5a des Arg, but rather produced oxidized psoralen which inhibited C5a des Arg activity. The effect was dependent on the concentration and types of psoralen and on the UV-A dose. Among the psoralens, the inhibitory effect of 4,5',8-trimethylpsoralen was the strongest, followed by 8-methoxypsoralen and 3-carbethoxypsoralen and finally 4,4',6-trimethylangelicin. Psoralen + UV-A failed to inhibit the chemotactic activity towards chemotactants other than anaphylatoxin C5a such as casein, the cultured filtrate of E. coli, platelet-activating factor, leukotriene B4, 5-hydroxy-6,8,11,14-eicosatetraenoic acid and 12-L-hydroxy-5,8,10,14-eicosatetraenoic acid.

Chemotaxis, Leukocyte↗

PubMed1991

In vitro activation of human complement by nitrogen bubbles.

Complement activation may be responsible for some of the symptoms of decompression sickness. In the present study, complement activation was studied by exposing human sera with or without red blood cells to nitrogen bubbles. Nitrogen bubbles activated human complement as measured by generation of the fluid-phase, complement-split product C5a des Arg. In addition, we found that complement activation continued after exposure to bubbles was stopped. This continued complement activation may explain the failure of recompression treatment in some patients. Complement activation induced by nitrogen bubbles in human sera was enhanced when red cells were present. Red cells may be able to provide a stable membrane surface on which complement activation by bubbles can occur more efficiently. Complement activation by nitrogen bubbles in serum also led to the binding of activated C3 to red cells. Quantitation of bystander red-cell-bound C3d may allow the assessment of complement activation occurring by nitrogen bubbles in individuals undergoing decompression.

Complement Activation↗

PubMed1989

Protein synthesis dependent and independent mechanisms of neutrophil emigration. Different mechanisms of inflammation in rabbits induced by interleukin-1, tumor necrosis factor alpha or endotoxin versus leukocyte chemoattractants.

Inflammation constitutes the body's principal mode of defense against infection and other harmful agents. Neutrophil leukocytes are the primary effector cells in this process. The role of protein synthesis in neutrophil emigration into acute inflammatory lesions was examined. Local intradermal injections of actinomycin D, cycloheximide or puromycin could inhibit in a dose- and time-dependent manner neutrophil emigration induced by interleukin-1, tumor necrosis factor alpha or endotoxin, but not by the leukocyte chemoattractants C5a des arg (zymosan-activated plasma), n-formyl-methionyl-leucyl-phenylalanine or leukotriene B4. Maximal inhibition, measured at the time of peak emigration, was greater than 90%. The onset of neutrophil emigration induced by the cytokines or by endotoxin was delayed by 30 to 60 minutes in comparison to the leukocyte chemoattractants. These results demonstrate at least two mechanisms of neutrophil emigration: one with a slower onset and dependence on local RNA transcription and translation and the other rapid in onset and independent of protein synthesis.

Animals↗

PubMed1989

Inflammatory properties of human C5a and C5a des Arg/ in mast cell-depleted human skin.

C5a and its degradation product, C5a des Arg, elicit immediate cutaneous inflammatory reactions after intradermal injection. Histologically, these reactions are characterized by neutrophil-rich leukocytic infiltrates, leukocytoclasis, edema, and dermal mast cell degranulation. It has not been possible to assess in vivo the relative contributions of resident mast cells and circulating leukocytes to this reaction because the accumulation of leukocytes and degranulation of mast cells occur simultaneously after injection of these anaphylatoxins. To assess the role of mast cells in these inflammatory reactions, we have examined the reactivity of human skin selectively depleted of dermal mast cells by local corticosteroid treatment. Corticosteroid-treated skin became virtually devoid of dermal mast cells within 4-6 wk as assessed by light microscopy, immunofluorescence with fluorescein-conjugated avidin, or electron microscopy. Mast cell-depleted skin demonstrated normal vasopermeability and vasodilatory responsiveness to intradermal injection of histamine, but the reactivity of these sites to the mast cell secretagogue, morphine, was absent. Moreover, no clinical reactions were detectable in mast cell-depleted human skin after intradermal challenge with 50 ng of either C5a or C5a des Arg, despite the fact that biopsies of these sites revealed substantial, neutrophil-rich infiltrates. These infiltrates were qualitatively and quantitatively identical to C5a or C5a des Arg-induced infiltrates in mast cell replete skin. This experimental approach in vivo has allowed the independent analysis of the anaphylactogenic and chemoattractant activities of human C5a and C5a des Arg in human skin, demonstrated the importance of dermal mast cells in these clinical responses, and shown that leukocytes can accumulate at these injection sites directly in response to these mediators.

Adrenal Cortex Hormones↗