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PubMed1987

Mediators of C5a-induced bronchoconstriction.

Previous studies had suggested that histamine and products of arachidonate metabolism were mediators of the bronchoconstriction induced in guinea pigs by the complement cleavage product C5a. The present study was conducted to further define the arachidonate metabolite(s) involved. Tracheal airflow and transpulmonary pressure were measured in anesthetized and artificially ventilated guinea pigs and pulmonary resistance and dynamic lung compliance were calculated as a measure of bronchoconstriction. The effect of the peptido-leukotriene antagonist L-649,923 and the thromboxane synthetase inhibitor U-63557A on the C5a-induced bronchoconstriction was determined. Also, the response to C5a was evaluated in animals made tachyphylactic to the bronchoconstrictor actions of LTB4. C5a-induced bronchoconstriction was not altered in animals treated with L-649,923 or made tachyphylactic to LTB4 suggesting that LTB4 and peptido-leukotrienes are not major mediators of the response. C5a challenge caused a significant increase in plasma thromboxane B2 levels which was prevented in part by the thromboxane synthetase inhibitor U-63557A. In addition, C5a-induced bronchoconstriction was significantly inhibited by U-63557A. Thus, these studies suggest that thromboxane is the arachidonate metabolite at least in part responsible for C5a-induced bronchoconstriction.

Animals↗
PubMed1987

High-level C5a gene expression and recovery of recombinant human C5a from Escherichia coli.

Poor expression of a synthetic gene for the inflammatory mediator, C5a, was observed in E. coli grown in rich media. Varying the media composition markedly improved expression, although C5a levels still declined rapidly at the end of log phase. Using a protease-deficient strain, C5a was recovered at stationary phase in high yield (13 mg/liter of culture). Recovery was dependent on guanidinium hydrochloride extraction to solubilize the protein and glutathione treatment to promote correct folding. Two-thirds of the C5a retained an amino-terminal methionine. Both forms of recombinant C5a had activity similar to serum-derived C5a in binding to human neutrophil receptors and inducing chemotaxis. The 700-fold improvement in yield made it feasible to obtain gram amounts of C5a and provides an efficient system for site-directed mutagenesis.

Cloning, Molecular↗
PubMed1987

Inhibition of C5a-induced basophil degranulation by disodium cromoglycate.

Injection of purified porcine C5a into 24-hr basophil-rich cutaneous basophil hypersensitivity sites in the dose range 10(-12)-10(-10) moles/site produced cutaneous basophil anaphylaxis (CBA). The H1 antihistamine antagonist mepyramine, given orally (3.0-30 mg/kg), inhibited the vasopermeability, but not the basophil degranulation, characteristic of CBA. The antiallergy agent disodium cromoglycate (DSCG), administered intravenously (3.0-30 mg/kg), inhibited vasopermeability and basophil degranulation. DSCG inhibition of mast cell degranulation was not important in the inhibition of CBA, since intact mast cells were found to be depleted at basophil-rich sites and absent at C5a-induced CBA sites from animals treated with DSCG. C5a at 10(-11) moles/site also induced vasopermeability and mast cell degranulation in normal guinea pig skin. Vasopermeability, but not mast cell degranulation, was inhibited by mepyramine at 30 mg/kg p.o. However, DSCG at 10 mg/kg i.v. failed to inhibit either the vasopermeability or the mast cell degranulation of this reaction. These results indicate that C5a induces the degranulation of both basophils and mast cells in the guinea pig, and that C5a-induced degranulation of basophils, but not mast cells, is inhibited by DSCG.

Anaphylaxis↗
PubMed1984

Relationship between the transient cAMP increase, exocytosis from specific and azurophil granules and chemotaxis in neutrophil granulocytes.

The short transient increase of the intracellular cAMP concentration during the first minute following stimulation, exocytosis from specific and azurophil granules, random and directional locomotion were assessed following stimulation of human and equine neutrophils with f-Met-Leu-Phe, C5ades Arg, standard gamma globulin (SGG) and the ionophore A23187. Different leucocyte-activating agents elicited distinct patterns of responses. The results showed that: Chemotactic factors produced exocytosis of small amounts of vitamin B12-binding proteins but not beta-glucuronidase, in the absence of cytochalasin B. Chemotaxis, the appearance of the transient cAMP peak and exocytosis from specific granules in response to cytotaxins were strictly correlated in the absence of cytochalasin B but not if exocytosis was measured in the presence of cytochalasin B. Thus comparison of exocytosis measured in the presence of cytochalasin B with other functions may be misleading. The non-chemotactic agents tested (SGG, A23187) produced secretion but no cAMP peak within 1 minute after stimulation, indicating that the cAMP peak is no obligatory event for triggering exocytosis in general. The ionophore A23187 alone at a concentration of 10(-6) M produced exocytosis from specific granules only, increased motility of cells in suspension and a marked increment of neutrophil adhesion to glass and after a lag period a sustained increase in cAMP. SGG elicited release of both vitamin B12-binding proteins and beta-glucuronidase.

Calcimycin↗
PubMed1988

In vitro inhibition of the classical and alternate pathways of activation of human complement by N acetyl aspartyl glutamic acid (NAAGA).

A synthetic dipeptide, magnesium salt of N-acetyl-L-aspartyl-glutamic acid (NAAGA) identical to a natural dipeptide found as traces in cerebral tissues of mammalian brains, was shown to inhibit, in vitro, the hemolytic activity of both classical and alternate pathways complement; the required concentration of NAAGA was 2 to 10 mM. Cross immuno electrophoretic analysis demonstrated an inhibition of C3 cleavage by both classical and alternate pathway C3 convertases with 24 mM NAAGA. As expected, if C3 convertases were really the target of inhibition, the release of highly inflammatory C3a, C5a fragments scored by R.I.A. was impaired when complement was incubated with activators of classical and alternate pathways. Such a low molecular weight dipeptide, quite atoxic and inhibiting the complement dependent cytotoxicity and release of phlogistic by-products could be interesting for pharmacological manipulation of complement activation in inflammatory processes.

Complement Activation↗
PubMed1988

Inhibition of the accumulation of macrophages and the generation of macrophage chemotactic activity by dexamethasone in concanavalin A-induced peritonitis of mice.

A delayed-type inflammatory response was evoked in mice using concanavalin A (Con A) as a stimulus, and the effect of various anti-inflammatory agents on the inflammation was examined. The intraperitoneal injection of Con A in the mouse resulted in the marked accumulation of leukocytes, especially macrophages, in the peritoneal cavity between 16 and 48 hr after the injection. Prior to the accumulation of macrophages, the chemotactic activity for macrophages appeared in the peritoneal fluid, and was associated with protein(s) in the molecular weight range from 10,000 to 100,000 daltons. When the effect of various agents on Con A-induced peritonitis was examined, neither anticomplementary agents (FUT-175 and K-76 COONa), bromophenacyl bromide, nordihydroguaiaretic acid nor indomethacin affected the generation of chemotactic activity and the accumulation of macrophages, suggesting that C5a, prostaglandins and leukotriene B4 are hardly involved in the Con A-induced macrophage accumulation. On the other hand, dexamethasone suppressed both the generation of chemotactic activity and the accumulation of macrophages. Taking into consideration the observation that the synthesis of macrophage chemotactic factors by mitogen-stimulated lymphocytes is inhibited by glucocorticoids, these results suggest that the macrophage chemotactic lymphokines might be involved in the accumulation of macrophages in Con A-induced peritonitis.

Animals↗
PubMed1986

The effects of the anaphylatoxins C3a and C5a on isolated mast cells from rat and man.

Of the complement peptides comprising anaphylatoxin activity, only C5a caused a very small (less than 1.5%) but statistically significant histamine release from isolated human adenoidal mast cells. C3a and the respective des-Arg-derivatives were found to be ineffective. In rat peritoneal mast cells, neither peptide caused histamine release.

Animals↗
PubMed1985

Generation of C5a and prostacyclin (PGI2) in an inflammatory response to zymosan and a reversed passive Arthus-type reaction in the peritoneal cavity of the rabbit.

Exudate fluids were removed from the rabbit peritoneal cavity 2 h after the injection of zymosan or the initiation of a reversed passive Arthus-type reaction. Inflammatory oedema was measured using Evans blue dye extravasation and the concentrations of C5a and the PGI2 metabolite, 6-oxo-PGF1 alpha, were measured by radioimmunoassay. High levels of C5a were found in these inflammatory exudates and we suggest that the extravascular generation of C5a is important in the induction of increased microvascular permeability. The presence of PGI2 may have an enhancing effect on plasma protein leakage.

Animals↗
PubMed1983

Synthesis of complement by macrophages and modulation of their functions through complement activation.

During the last decade considerable progress has been made to characterize intimate functional links between macrophages, a major cellular component of immunoinflammatory responses, and the complement system representing the major humoral mediator of inflammation. Macrophages of various species and tissue sites have been shown to synthesize and release most of the complement components providing these cells with their own "pericellular" complement system. Circumstantial evidence for the assembly of both classical and alternative pathway convertases has been adduced. An intricate network of feedback loops involving endogenous and extrinsic factors operates to adjust complement production to acute requirements, for example augmenting production in the face of accelerated turnover at sites of inflammation, and returning it to baseline levels once the inflammatory stimulus has subsided, in order to maintain a fine-tuned balance. The molecular mechanisms underlying regulation of complement synthesis by macrophages are beginning to be elucidated by use of gene technology. On the other hand, complement activation products exert a number of effects on macrophages via specific surface receptors causing internalization of offending agents, microbes, and immune complexes, promotion of intracellular killing, controlling migration behavior, inducing release of potent biologic substances such as lysosomal enzymes, arachidonic acid metabolites, and interleukin 1. In these interactions, two important humoral mediator systems of inflammation, the complement system and the arachidonic acid cascade, are functionally linked at the level of the macrophage. Stimulation of the release of immunomodulating compounds from macrophages invoke a role for complement in immune regulation. This multifaceted interplay is of particular importance considering the mobility of macrophages that allows them to gain almost unrestricted access to sites of ongoing immunoinflammatory responses. The time seems to have come to abandon the petrified thinking in socalled systems as, for instance, humoral versus cellular, specific versus unspecific, and to proceed to interlocking functions guided by physiology proper.

Anaphylatoxins↗
PubMed1989

The effect of adherence on the generation of reactive oxygen species by human neutrophilic granulocytes.

Human neutrophilic granulocytes (PMN) suspended in protein containing salt solution or adherent on protein coated nylon fibers were tested for the production of H2O2 and O2- in response to various PMN stimulants. Upon stimulation with the chemotactic factors formyl-methionyl-leucyl-phenylalanine, C5a and platelet activating factor, the non-chemotactic ionophore A23187, and the chemotaxis inhibitors tumor necrosis factor (TNF alpha) and lymphotoxin (TNF beta) adherent PMN produced considerably more reactive oxygen metabolites than suspended cells. The relative amounts of the two metabolites varied with the stimulus and its concentration, TNF alpha and TNF beta favoring H2O2 production, C5a eliciting more O2- than H2O2 and the other active stimulants being in between. Leukotriene B4 and a novel monocyte-derived chemotaxin were inactive in releasing either oxygen derivative from adherent or suspended PMN. The data indicate that attachment of PMN to endothelial cells or to connective tissue substances can strongly enhance its ability to respond to a given stimulus with the production of reactive oxygen metabolites. The findings may in part explain the "priming" phenomenon since many PMN-priming mediators increase the cells' adherence.

Calcimycin↗
PubMed1988

Anaphylatoxin-induced release of histamine from in vitro perfused guinea pig kidney.

The effect of porcine C5a des Arg and C3a, given as a bolus injection, in the isolated constant flow pump-perfused guinea-pig kidney was investigated. Only C5a des Arg showed activity which was manifested by a dose-dependent increase in perfusion pressure (PP, due to vasoconstriction) and histamine release. Although histamine release was substantial, it alone could not account for the increase in PP. The two more likely causes are a direct vasoconstrictor effect and the release of other mediators.

Anaphylatoxins↗
PubMed1983

Vascular permeability changes induced by complement-derived peptides.

The polypeptides C3a and C5a are released as protein cleavage byproducts during activation of the complement system. These substances are able to release histamine from mast cells and this has generally been thought to be the link between complement activation and increased microvascular permeability in inflammatory reactions. Recent observations of inflammatory responses in the skin suggest that there is another link, which does not involve histamine. This is potentially of more general importance since antihistamines have limited effects on the majority of inflammatory reactions. One of the complement protein fragments, C5a (with or without carboxyl terminal arginine which is necessary for histamine release), is very potent in increasing vascular permeability. However, protein leakage leading to tissue oedema in skin is difficult to detect unless an arteriolar dilator is present. There is evidence that C5a and a vasodilator prostaglandin can be generated together extravascularly in response to a microbial stimulus. Unlike histamine, C5a does not act directly on venular endothelial cells, but triggers a very rapid interaction between circulating polymorphonuclear leukocytes and venular endothelial cells which, by an unknown mechanism, results in elevated venular permeability to plasma proteins.

Animals↗
PubMed1990

Measurement of complement activation products in patients with chronic rheumatic diseases.

Measurement of the complement activation products C1s:C1-inh, C3bP and C5b-9 by ELISA in plasma samples from normals, rheumatoid arthritis (RA) and systemic lupus erythematosis (SLE) patients showed significantly elevated levels in the two patient groups (P less than 0.0001 for C1s:C1-inh, C3bP and C5b-9) compared to normals. In seropositive RA patients there were significant correlations between the levels of the three complement activation complexes and IgM-RF, IgG-RF and IgA-RF. However, IgM-RF did not interfere with any of the ELISA systems. Mean levels of C1s:C1-inh, C3bP and C5b-9 were the same in paired plasma and synovial fluids; however, C3bP levels in the paired samples did not correlate with one another by rank. Our conclusions are that: (a) elevated plasma levels of these complement activation products are detectable in rheumatic diseases; (b) plasma levels of these complement activation products are related to Rheumatoid factor (RF) levels in seropositive RA patients; and (c) IgM-RF does not influence these solid-phase ELISA procedures.

Antibodies↗