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PubMed1988

Human C5a induces a substantial histamine release in human basophils but not in tissue mast cells.

The histamine-releasing effect of human C5a was compared with that of concanavalin A in blood basophils and isolated adenoidal mast cells from the same donors. In basophils, C5a (10 ng/ml) induced a significant histamine release (7.5 +/- 2.1%, corrected value). In isolated adenoidal mast cells C5a had only a marginal effect (2% histamine release), although the cells responded markedly to concanavalin A stimulation (about 13% release). The results support the view that the heterogeneity of mast cells and basophils is also reflected in the expression of anaphylatoxin receptors on their surface.

Adenoids↗
PubMed1988

C5a-induced bronchoconstriction: absence of a role of circulating white blood cells and platelets.

C5a causes an intense bronchoconstriction when injected intravenously into the guinea pig. The present study was designed to determine if circulating white blood cells or platelets were important target cells for the induction of bronchoconstriction on intravenous injection of C5a. To accomplish this, we examined the effect of C5a on numbers of circulating cells as well as the effect of depletion of various circulating cell populations on C5a-induced bronchoconstriction. Intravenous injection of C5a caused a precipitous drop in circulating granulocytes which preceded the maximum bronchoconstrictor response. The levels of circulating platelets and mononuclear cells were unchanged by intravenous injection of C5a. Depletion of either white blood cells or platelets did not significantly alter either the maximum bronchoconstrictor response to C5a or the time course of the response. Thus, these studies suggest that C5a-induced bronchoconstriction in the guinea pig is not dependent on an interaction of C5a with circulating white blood cells or platelets.

Airway Resistance↗
PubMed1988

The significance of complement activation in the pathogenesis of hypersensitivity pneumonitis: sequential changes of complement components and chemotactic activities in bronchoalveolar lavage fluids.

Hypersensitivity pneumonitis (HP) is believed to be induced by immunological mechanisms, the details of which remain to be clarified. While a role for cellular immunity is accepted in the pathogenesis of HP, several clinical observations also suggest a role for immune-complex-mediated lung injury. We have previously demonstrated the presence of chemotactic factors for polymorphonuclear cells (PMNs) in bronchoalveolar lavage (BAL) fluids of acutely ill patients with the summer type of HP found in Japan. The present study correlated chemotactic factors for PMNs with the level of C5a des Arg in BAL fluids obtained from patients with summer type HP. Furthermore, this study demonstrated that PMNs were increased in BAL fluids obtained after 2 days of avoidance of exposure to the presumptive causative agent. The percentage of PMNs in the BAL increased in proportion to the activity of the chemotactic factors. Finally, leukotriene B4 was not detected in concentrated BAL or supernatant fluids of cultured macrophages. These results suggest that complement activation in the respiratory tract may occur as the early event in the pathogenesis of HP.

Alveolitis, Extrinsic Allergic↗
PubMed1983

C5a-induced histamine release. Species specificity.

C5a has long been known to cause histamine release from isolated perfused guinea pig lung, isolated human basophils, rat and guinea pig mast cells, and guinea pig skin. The purpose of the present study was to compare the ability of guinea pig C5a to cause histamine release from lung fragments of dog, rabbit and rat with that released from guinea pig lung fragments. In addition, C5a-induced histamine release from the skin of the guinea pig, rabbit, and rat was investigated by examining antihistamine inhibition of C5a-induced vascular permeability changes. Guinea pig C5a caused a concentration-related release of histamine from guinea pig lung fragments with only minimal amounts of histamine being released from dog, rat, and rabbit lung fragments over the same concentration range. Guinea pig C5a also caused increased vascular permeability in guinea pig skin which was markedly inhibited by H1 antagonists. In rabbit skin, guinea pig C5a increased vascular permeability in the presence of PGE2 but the vascular leakage was unaffected by antihistamines. Rat skin was virtually unresponsive to C5a with or without PGE2. This data emphasize the differences between reactivity of species to C5a and the danger of extrapolating results obtained in one animal species to models employed with another species.

Animals↗
PubMed1989

Decreased releasability of basophils from patients with cold urticaria after cold exposure.

Histamine release from peripheral blood basophils challenged with C5a, f-met-peptides and calcium ionophore was studied in patients with cold urticaria before and after exposure to low environmental temperatures. Compared to healthy controls, stimulated mediator release before cold exposure was increased in 7 of 11 patients. When challenged by cold exposure mediator release from in vitro-stimulated basophils was decreased. This decrease was more pronounced after stimulation with receptor-mediated stimuli (e.g. C5a) as compared to receptor-unrelated stimuli, e.g. calcium ionophore. In 4 of 11 patients stimulated mediator release before cold exposure was moderately increased. Also after cold exposure only a weak decrease of stimulated histamine release was seen. Levels of activated complement components (C3a) before and after cold exposure failed to provide evidence for complement activation in vivo. Also the number of circulating basophils as well as their cellular histamine content remained normal after cold exposure. The results show that in these patients release of histamine is altered before and after cold exposure. These changes in basophil responsiveness are not due to complement activation in vivo.

Basophils↗
PubMed1989

Effect of the late complement components C5b-9 and of platelet-derived growth factor on the prostaglandin release of human synovial fibroblast-like cells.

We examined the prostaglandin E (PGE) synthesis of cultured adherent synovial fibroblast-like cells (SFC) from patients with osteoarthritis (OA) in the noninflammatory state as well as with rheumatoid arthritis (RA). In cells from RA patients the spontaneous PGE release was generally higher compared to that of OA patients, but decreased fast with time in culture. After cell passage, similar PGE baseline levels were seen in cells of the two patient groups. The cells could then be stimulated by the terminal complement components C5b-9 or C5b-8. PGE synthesis was also stimulated by the platelet-derived growth factor (PDGF), interleukin-1 (IL-1), or lipopolysaccharide (LPS). The amount of PGE synthesis after incubation with PDGF, LPS and IL-1 was comparable to that released after C5b-9. Thus, like other inflammatory mediators C5b-9 and PDGF trigger the increased PGE production by SFC and thus may participate in the development of synovial inflammation and contribute to the pathogenesis of RA.

Arthritis, Rheumatoid↗
PubMed1996

S-protein/vitronectin interaction with the C5b and the C8 of the complement membrane attack complex.

S-protein/vitronectin participates in the regulation of complement-mediated lysis by incorporating into the membrane attack complex C5b-9. Subsequently, soluble SC5b-7 and SC5b-9 macromolecules are not inserted into the membrane lipid bilayer nor induce lytic pore formation. Using a dot blot binding assay, it was determined that soluble S-protein/vitronectin interacted with immobilized C5b and C8 among the five separately immobilized components (C5b, C6, C7, C8, C9) of the membrane attack complex. Those interactions imply a new model of the formation of the complement membrane attack complex and its regulation by S-protein/vitronectin.

Animals↗
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↗
PubMed1987

The properties of human C5a anaphylatoxin. The significance of C5a formation during hemodialysis.

Human C5a anaphylatoxin is a potent bioactive molecule that possesses both spasmogenic and leukocyte-related properties. As such, it normally serves as a local mediator of the acute inflammatory response. Additionally, C5a, through its actions of mononuclear phagocytes, may act to bridge the gap in the acute-chronic inflammatory continuum. While these properties are critical to normal host defense mechanisms, it is now apparent that this anaphylatoxin and/or its des-Arg74 derivative, may exert significant systemic effects that are manifest as cardiopulmonary abnormalities and intravascular activation of granulocytes. Knowledge of these properties is critically important for understanding the clinical sequelae exhibited by patients undergoing extracorporeal circulation since we now know that both hemodialysis and cardiopulmonary bypass [28-30] procedures promote intravascular complement activation and C5a formation. Viewed in this context, it seems reasonable to postulate that many of the immediate and delayed responses to extracorporeal circulation might be mediated by C5a formed in the extracorporeal circuit (table IV). For example, it is now recognized that a few particularly susceptible patients display adverse reactions during the initial phases of hemodialysis. The symptoms of this so-called 'first-use syndrome' may range from severe urticaria and angioedema to life-threatening bronchospasm, hypotension, and cardiopulmonary collapse. Some investigators have presented data which suggest that complement-derived products may be causative of these symptoms in some patients [31]. While this hypothesis remains to be confirmed, present evidence clearly demonstrates that C5a alone may produce many of the observed phenomena. In addition to the acute effects produced by C5a, both our own basic studies and the clinical investigations presented by others at this conference suggest that the long-term effects of repeated C5a exposure in the dialyzed patient may be considerable. Thus, there has been a great deal of interest in the role of complement-derived mediators as initiators of leukocyte degranulation and toxic oxygen radical production and an exploration of the significance of these events in the eventual development of chronic pulmonary fibrosis in the dialyzed patient. Similarly, the effects of repeated exposure to IL-1 that has been postulated to occur as a result of C5a triggering of monocytes during dialysis is currently an active area of investigation.(ABSTRACT TRUNCATED AT 400 WORDS)

Anaphylatoxins↗
PubMed1986

Biochemistry and biology of anaphylatoxins.

The molecular architecture of anaphylatoxins has been explored on several levels. Primary, secondary and tertiary structural parameters that dictate function of the C3a, C4a and C5a molecules are being elucidated with the aid of comparative sequence analyses, physical measurements and organic syntheses. Although C3a, C4a and C5a are biologically distinct mediators, as defined by their unique receptor systems, a common genetic origin is apparent from conserved features in their primary structures. Evidence is now available which suggests that similarities in the folding pattern of the anaphylatoxins may dictate a concensus conformation for each factor. We have learned from synthetic peptide studies that the binding (e.g. effector) site in anaphylatoxin molecules exists as a linear sequence contained in the C-terminal portion of the polypeptide. What is also evident is that a preferred conformation is defined for the binding site requiring a proper side chain orientation for optimal bioactivity. It is proposed that folding of the native structure stabilizes this conformation at the binding site. The binding site in C3a contains the essential residues LGLAR folded in an irregular or pseudo-beta-turn and stabilized by an adjacent alpha-helical segment. It is proposed that the alpha-helical segment influences orientation of the side chain residues in the 'binding site'. A similar model is evolving for C5a based on synthetic C5a peptides that express both spasmogenic and chemotactic activities. This helix turn model promises to be representative of an essential structural feature that determines anaphylatoxin activity. We believe that these models contribute significantly to our understanding of the molecular relationships between structure and function for these humoral mediators of inflammation.

Amino Acid Sequence↗
PubMed1986

Immunopharmacology of anaphylatoxin-induced bronchoconstrictor responses.

The complement anaphylatoxin peptides, C3a and C5a, are potential mediators of immediate hypersensitivity reactions, eliciting many of the same actions on isolated tissue and cell preparations as specific antigen. Instilled intratracheally in experimental animals, the peptides induce acute bronchospasms and are sometimes lethal. In vitro, they cause dose-dependent contraction of isolated lung tissue preparations, a response which correlates well with bronchospasms observed in vivo, and our current understanding of the cellular and molecular mechanisms of this action are reviewed here. C5a and its catabolic derivative, C5ades Arg, stimulate contraction of isolated guinea pig lung parenchymal strips in part by production of leukotrienes that constitute SRS-A, and by release of histamine. Leukotrienes in turn release thromboxane from lung tissue, and evidence indicates that at least part of the spasmogenic activity of these peptidolipids is mediated by this effect. C3a is considerably less potent than C5a in contracting lung tissues and appears to act primarily by causing the release of spasmogenic cyclooxygenase metabolites. Both peptides may additionally have direct action on contractile cells within the tissue. Platelet-activating factor (PAF), an unusual phospholipid mediator released from inflammatory cells stimulated with C5a and other agents, also contracts isolated lung parenchymal tissues. PAF stimulates release of significant quantities of thromboxane from guinea pig lung; however, indomethacin does not block contractile responses of the tissue. Recent evidence indicates that PAF may act on parasympathetic neurons in lung to release endogenous acetylcholine, and this action may be a major component of tissue responses to this mediator. Thus the complement anaphylatoxins stimulate release of many of the same mediators from lung tissues as are released by antigen challenge of sensitized tissue, and may, therefore, play an important role in the pathogenesis of allergic bronchospasms.

Anaphylatoxins↗
PubMed1986

Anaphylatoxin formation in extracorporeal circuits.

Anaphylatoxin radioimmunoassay techniques have been employed to define both the temporal profile and the amount of complement activation taking place in two different types of extracorporeal circuits. Prospective studies of patients undergoing both maintenance hemodialysis and cardiopulmonary bypass provided essentially similar findings. In both cases, plasma C3a antigen levels proved to be the most accurate and sensitive indicator of intravascular complement activation. By contrast, plasma C5a levels varied little during the period of extracorporeal circulation. Instead, this anaphylatoxin retained considerable biologic activity in vivo as evidenced by its ability to promote granulocyte activation and transient granulocytopenia which was displayed by patients in both groups. Plasma levels of C4a antigen were not elevated during the period of extracorporeal circulation, suggesting that alternative pathway mechanisms were predominantly responsible for the complement activation taking place in both hemodialyzers and bypass oxygenators. However, classical pathway activation events could be documented when protamine sulfate was administered to heparinized patients after cardiopulmonary bypass. In this instance, elevated plasma levels of both C4a and C3a antigens were observed. Prospective studies also suggested that complement activation could be associated with the development of both acute and delayed clinical sequelae. Available data support the hypothesis that C5a anaphylatoxin might be the primary mediator of these undesirable effects of extracorporeal circulation. These types of investigations have contributed significantly to our understanding of the role of the anaphylatoxins in human disease and may be directly applied to facilitate design of more biocompatible medical devices.

Anaphylatoxins↗
PubMed1986

Anaphylatoxins: possible roles in disease.

Anaphylatoxins, in particular C3a and C5a, have various biological activities which suggest a role as mediators of inflammatory reactions: they cause contraction of smooth muscle, histamine release, increase in capillary permeability, adhesion of leukocytes to vascular endothelium, leukocyte chemotaxis, and aggregation of platelets and leukocytes. Most of these effects are supported by the cooperation of other mediators, in particular arachidonic acid derivatives which may be produced by anaphylatoxin-stimulated cells, e.g. leukocytes or endothelium. In vivo effects of the complement peptides depend very much on the site of their generation: intravascular release in the general circulation leads to adverse symptoms such as adult respiratory distress syndrome and shock lung, mainly due to leukocyte activation, aggregation and their accumulation in lung vessels. Intravascular release may be induced by certain drugs, and by contact of blood with the surfaces of bypass or dialysis apparatus. Induction of local inflammatory and defense reactions requires release of anaphylatoxins in tissue spaces. Tissue fluid differs quantitatively from blood plasma in its concentration of complement components. This raises some problems of how efficient concentrations of C3a and C5a can be attained at the site of a lesion to generate a chemotactic gradient capable of attracting blood leukocytes.

Anaphylatoxins↗
PubMed1986

Comparative structural anatomy of the complement anaphylatoxin proteins C3a, C4a and C5a.

The anaphylatoxins are a family of proteins produced during the course of complement activation as the result of cleavage by specific serine proteases. These proteins are involved in a variety of biological functions, including inflammation. Comparative modeling techniques have been used to produce structures for C4a and C5a from the crystal structure of C3a. All three structures have conserved interior residues but very different external side chains and surface shapes and properties. Comparison of the anaphylatoxin structures and of the sequence conservation among different species suggests possible locations for their receptor binding sites and for their specificity residues which permit regulated proteolytic cleavage from precursor.

Amino Acid Sequence↗