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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↗
PubMed1993

Restricted ability of group B streptococcal C5a-ase to inactivate C5a prepared from different animal species.

Most strains of group B streptococci (GBS) elaborate a cell surface-associated enzyme that rapidly inactivates the human complement-derived chemoattractants C5a and C5adesarg by cleaving the His-Lys bond at positions 67 and 68 in the C5a molecule. We have suggested that rapid inactivation of C5a and C5adesarg by this enzyme, called C5a-ase, can hinder the inflammatory response at sites of GBS infection. We tested the ability of GBS C5a-ase to inactivate C5a preparations from various animal species to determine the proper species for studying the role of GBS C5a-ase in the pathogenesis of GBS infections. Exposure of C5a preparations from humans, monkeys, and cows to GBS caused inhibition of C5a functional activity as measured by the ability of C5a to stimulate human polymorphonuclear leukocyte (PMN) adherence and human PMN chemotaxis. Bovine PMN chemotaxis to bovine C5a was also abolished after exposure of bovine C5a to GBS. In contrast, mouse, rat, guinea pig, rabbit, pig, and sheep C5a preparations retained full functional activity after exposure to GBS as measured by chemotaxis of human PMNs, PMNs from the same animal species, or both. These data suggest that there are structural differences between C5a proteins from different species which alter their susceptibility to GBS C5a-ase and indicate that most commonly used animal models of human GBS infection are inadequate for detection of a contribution of GBS C5a-ase to GBS virulence.

Amino Acid Sequence↗
PubMed1988

Different sensitivities of the responses of human neutrophils stimulated with immune complex and C5a anaphylatoxin to pertussis toxin.

When stimulated with immune complex or C5a anaphylatoxin, human neutrophils undergo an increase in the concentration of intracellular Ca2+ [( Ca2+]i) that precedes the onset of superoxide (O2-) production. The extracellular Ca2+ is required for the O2- production of neutrophils stimulated by C5a, but is only partially required for those by immune complex. The addition of pertussis toxin to neutrophils does not inhibit the rise in [Ca2+]i and O2- production induced by immune complex but does inhibit those induced by C5a. These results suggest that a different sequence of reaction is involved by different stimulants, the anaphylatoxin and immune complex.

Antigen-Antibody Complex↗
PubMed1987

In vivo Streptococcus pyogenes C5a peptidase activity: analysis using transposon- and nitrosoguanidine-induced mutants.

The streptococcal C5a peptidase removes a six-amino-acid fragment from human C5a and thereby inactivates this chemotaxin. We used transposon and chemical mutagenesis to generate mutants of Streptococcus pyogenes that did not produce C5a peptidase. These mutants showed no alteration in expression of capsule, M protein, streptolysins O and S, or pyrogenic exotoxin C. Serial passage of a peptidase-producing strain in vivo resulted in a 100-fold increase in production of C5a peptidase. The presence of C5a peptidase delayed the accumulation of polymorphonuclear leukocytes (PMNLs) in the peritoneal cavities of mice after intraperitoneal challenge. However, there was no difference in virulence (as evaluated by LD50) between strains that produced and those that lacked C5a peptidase. Although C5a peptidase is expressed on the cell surface, antibody to this enzyme did not opsonize streptococci for phagocytosis in vitro. These studies show that C5a peptidase alters the normal host inflammatory response by delaying the accumulation of PMNLs at the foci of streptococcal infection.

Adhesins, Bacterial↗
PubMed1987

Inhibition of human neutrophil chemotaxis by the protein kinase inhibitor, 1-(5-isoquinolinesulfonyl) piperazine.

The protein kinase inhibitor, 1-(5-isoquinolinesulfonyl) piperazine (C-I), inhibits superoxide release from human neutrophils (PMN) stimulated with phorbol myristate acetate or synthetic diacylglycerol, without inhibiting superoxide release from PMN stimulated with the chemoattractants C5a or N-formyl-methionyl-leucyl-phenylalanine (f-Met-Leu-Phe). In this study, we investigated the effect of C-I on human PMN chemotaxis to C5a, f-Met-Leu-Phe, leukotriene B4 (LTB4), and fluoresceinated N-formyl-methionyl-leucyl-phenylalanine-lysine (f-Met-Leu-Phe-Lys-FITC). PMN, preincubated for 5 min at 37 degrees C with 0 to 200 microM C-I, were tested for their migratory responses to the chemoattractants. C-I (greater than or equal to 1 microM) significantly inhibited PMN chemotaxis to f-Met-Leu-Phe, f-Met-Leu-Phe-Lys-FITC, and C5a without affecting random migration. Maximal inhibition of chemotaxis to these attractants occurred with greater than or equal to 50 microM C-I, at which chemotaxis was inhibited by 80 to 95%. The C-I inhibition was reversible. In contrast, 200 microM C-I did not inhibit the number of PMN migrating to LTB4, although, the leading front of PMN migration to LTB4 was inhibited by C-I. C-I inhibited PMN orientation to C5a and f-Met-Leu-Phe without affecting orientation to LTB4. C-I did not inhibit the binding of radiolabeled f-Met-Leu-Phe or f-Met-Leu-Phe-Lys-FITC to PMN. These findings suggest that the chemotactic responses of PMN to f-Met-Leu-Phe and C5a involve a protein kinase-dependent reaction which is inhibited by C-I.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1999

Roles for C-X-C chemokines and C5a in lung injury after hindlimb ischemia-reperfusion.

We evaluated the roles of the C-X-C chemokines cytokine-induced neutrophil chemoattractant (CINC) and macrophage inflammatory protein-2 (MIP-2) as well as the complement activation product C5a in development of lung injury after hindlimb ischemia-reperfusion in rats. During reperfusion, CD11b and CD18, but not CD11a, were upregulated on neutrophils [bronchoalveolar lavage (BAL) and blood] and lung macrophages. BAL levels of CINC and MIP-2 were increased during the ischemic and reperfusion periods. Treatment with either anti-CINC or anti-MIP-2 IgG significantly reduced lung vascular permeability and decreased lung myeloperoxidase content by 93 and 68%, respectively (P < 0.05). During the same period, there were significant increases in serum C5a-related neutrophil chemotactic activity. Treatment with anti-C5a decreased lung vascular permeability, lung myeloperoxidase, and BAL CINC by 51, 58, and 23%, respectively (P < 0.05). The data suggest that the C-X-C chemokines CINC and MIP-2 as well as the complement activation product C5a are required for lung neutrophil recruitment and full induction of lung injury after hindlimb ischemia-reperfusion in rats.

Animals↗
PubMed1991

Chemotaxis of germinal center B cells in response to C5a.

An infiltrate of B cells and plasma cells is characteristic of certain chronic inflammatory lesions. However, mechanisms involved in the local accumulation of these cells have not been established. Efforts to demonstrate that B cells from normal animals can migrate in response to inflammation-induced chemoattractants have been inconclusive. The objective of this study was to determine if murine germinal center (GC) B cells could respond chemotactically to a C5a gradient. On successive days after secondary immunization, draining lymph nodes were harvested and the activated GC B cells isolated. These GC B cells were placed in modified Boyden chambers, incubated for 3 h and the distance the leading front of cells migrated through the filters was determined. The results show that GC B cells migrated to factors in zymosan- and lipopolysaccharide-activated serum. The migratory response demonstrated distinct kinetics. Cells isolated between 2 to 4 days after secondary immunization migrated, whereas cells isolated at day 0 and beyond day 6 did not. Checkerboard analysis revealed that the migratory response was attributable to both chemokinesis and chemotaxis. Anti-C5 inhibited the migration of day-3 GC B cells implicating C5 in the migration mechanism. Studies using recombinant C5a established that this C5 fragment was chemotactically active. In conclusion, GC B cells generally were not chemotactically active. However, at a particular stage of maturation B cells in the GC become responsive to C5a as a chemotactic agent. Thus, B cells from normal animals may respond chemotactically, and C5a may play a role in recruitment of recently activated B cells into inflammatory sites.

Animals↗
PubMed1991

The deficient migration in vitro of lung macrophages from newborn rats normalizes after three days of maturation in situ.

Because there are functional deficiencies in neonatal phagocytes, we investigated age-dependent differences in the directed migration of rat pulmonary macrophages (PM). Directed migration of PMs from newborn (less than 24 h old) rats towards partially purified rat C5a was lower than that of PMs from adults, but reached adult levels by the third post-natal day. Calculation of the dose of C5a resulting in a half-maximal migratory response (ED-50) revealed that the ED-50s for all age groups studied were similar. These results suggest that responding PMs at all times after birth have comparable sensitivity to C5a, but that a lower percentage of newborn PMs migrate toward this factor because of defects in either signal transduction or cell motility.

Aging↗
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

Intracellular or extracellular calcium can be used to trigger C5a-stimulated enzyme secretion from rabbit neutrophils.

The ability of C5a to stimulate lysosomal enzyme release and 45Ca2+ efflux from rabbit neutrophils was studied. C5a stimulated beta-glucuronidase release from cytochalasin B-treated neutrophils either in the presence or absence of extracellular calcium. Depletion of cell calcium by pretreatment with the calcium ionophore A23187 blocked both the ability of C5a to elicit enzyme release in the absence of extracellular calcium and its ability to stimulate 45Ca2+ efflux. Both actions were dose-dependent over the same concentration range (10(-8)-10(-6) M ionophore A23187). In contrast, ionophore pretreatment had no effect on C5a-stimulated enzyme release in the presence of extracellular calcium. These results suggest that (a) release of cell calcium is required for enzyme secretion in the absence of extracellular calcium, and (b) C5a can trigger near-maximal enzyme release by using calcium from either of two sources: the extracellular space or an intracellular site.

Animals↗
PubMed2002

Anti-c5a ameliorates coagulation/fibrinolytic protein changes in a rat model of sepsis.

Sepsis and trauma are the two most common causes of disseminated intravascular coagulation and multiple organ dysfunction syndrome. Both disseminated intravascular coagulation and the systemic inflammatory response syndrome often lead to multiple organ dysfunction syndrome. The current studies have evaluated the relationship between the anaphylatoxin, C5a, and changes in the coagulation/fibrinolytic systems during the cecal ligation and puncture (CLP) model of sepsis in rats. CLP animals treated with anti-C5a had a much improved number of survivors (63%) compared to rats treated with pre-immune IgG (31%). In CLP rats treated with pre-immune IgG there was clearly increased procoagulant activity with prolongation of the activated partial thromboplastin time and prothrombin time, reduced platelet counts, and increased levels of plasma fibrinogen. Evidence for thrombin formation was indicated by early consumption of factor VII:C, subsequent consumption of factors XI:C and IX:C and anti-thrombin and increased levels of the thrombin-anti-thrombin complex and D-dimer. Limited activation of fibrinolysis was indicated by reduced plasma levels of plasminogen and increased levels of tissue plasminogen activator and plasminogen activator inhibitor. Most of these parameters were reversed in CLP rats that had been treated with anti-C5a. Production of C5a during sepsis may directly or indirectly cause hemostatic defects that can be reduced by blockade of C5a.

Animals↗
PubMed2003

Differences in the involvement of prostanoids from Kupffer cells in the mediation of anaphylatoxin C5a-, zymosan-, and lipopolysaccharide-dependent hepatic glucose output and flow reduction.

Various inflammatory stimuli such as anaphylatoxin C5a, zymosan, and lipopolysaccharides (LPSs) have been reported both to enhance glucose output in the perfused rat liver and to induce prostanoid (ie, prostaglandin and thromboxane) release from Kupffer cells, the resident liver macrophages. Because prostanoids can enhance glucose output from hepatocytes, it was the aim of this study to compare the possible roles of prostanoids released after C5a, zymosan, and LPS in the mediation of hepatic glucose output. In perfused livers both C5a and zymosan immediately enhanced glucose output, reduced flow, and induced prostanoid overflow into the hepatic vein, but with different quantities and kinetics. Only the C5a-induced but not the zymosan-induced effects were abrogated by inhibitors of prostanoid signaling as the prostanoid synthesis inhibitor indomethacin and the thromboxane receptor antagonist daltroban. In contrast to C5a and zymosan, LPS had no effect on glucose output, flow rate, or prostanoid overflow. In isolated Kupffer cells, C5a and zymosan induced maximal release of prostaglandins D(2) and E(2) and of thromboxane A(2) within a period of 0 to 2 minutes and 5 to 15 minutes, respectively. In pulse-chase experiments, maximal prostanoid release was already observed after 2 minutes of continuous stimulation with C5a, but only after 10 to 15 minutes of continuous stimulation with zymosan. LPS-dependent prostanoid release was not seen before 1 hour. Thus, even though C5a, zymosan, and LPS induced prostanoid release from Kupffer cells, only C5a quickly regulated hepatic glucose metabolism in a prostanoid-dependent manner (due to the kinetics and quantities of prostanoids released).

Animals↗
PubMed1994

Effect of in vivo desensitization to leukotriene B4 on eosinophil infiltration in response to C5a in guinea-pig skin.

1. The effect of in vivo desensitization to leukotriene B4 (LTB4) on eosinophil infiltration in response to recombinant C5a was examined in guinea-pig skin. 2. LTB4 (10-300 ng) and C5a (1-10 micrograms) caused a dose-dependent increase in the levels of eosinophil peroxidase activity (a measure of eosinophil infiltration) 4 h after injection into guinea-pig skin. Leukotriene B4 and C5a were approximately equipotent on a molar basis. Platelet activating factor (0.01-10 micrograms) also caused eosinophil accumulation but was much less active than LTB4 or C5a. 3. 20-Hydroxy-LTB4 caused a dose-dependent desensitization of eosinophil responses to LTB4 (ED50 = 1.6 micrograms kg-1, s.c.) and partially reduced responses to C5a. At a dose of 20-hydroxy-LTB4 (10 micrograms) which inhibited responses to LTB4 completely, responses to C5a were reduced by 56.5 +/- 1.8% (n = 5). The structurally related metabolite of 20-hydroxy-LTB4, 20-carboxy-LTB4, which does not cause desensitization to the effects of LTB4, did not inhibit eosinophil infiltration in response to C5a. 4. The LTB4 receptor antagonist, SC-41,930 (10 mg kg-1, p.o.), also inhibited eosinophil accumulation in response to C5a by 63.0 +/- 3.9% (n = 5) at a dose which inhibited responses to LTB4 by 86.5 +/- 1.9% (n = 5). 5. These data indicate that eosinophil infiltration in response to C5a may, in part, be mediated by the generation of secondary chemotactic factors such as LTB4.

Amitrole↗
PubMed1999

C5a suppresses the production of IL-12 by IFN-gamma-primed and lipopolysaccharide-challenged human monocytes.

IL-12 is a key mediator of the immune response, skewing T lymphocytes toward a type 1 cytokine pattern. Priming with IFN-gamma or GM-CSF is required for expression of IL-12p70 by cells in which IL-12 is inducible by bacterial products such as LPS. We here show for the first time that the production of bioactive IL-12 by human monocytes can be significantly suppressed by C5a if applied to IFN-gamma-primed monocytes before LPS stimulation. There was a dose-dependent suppression by IL-12 (p70) on the levels of intracellular cytokine production and cytokine secretion. mRNA studies consistently showed a reduction of IL-12p40 and IL-12p35 expression by stimulation in the presence of C5a. The results of several different experimental approaches suggest that IL-12 down-regulation was not due to endogenous IL-10, IL-4, or PGE2 production induced by C5a. Moreover, stimulation of IFN-gamma-primed monocytes with C5a did not lead to a down-regulation of the CD14 Ag, which is an LPS receptor. These findings show that the anaphylatoxin C5a has the capacity to directly interact with the complex regulation of IL-12.

Adjuvants, Immunologic↗
PubMed2003

[Detection of C5a receptor expressions on human epiretinal membranes and cultured RPE cells by immunohistochemical staining].

AIM: To observe the expression and distribution of C5a receptor(C5aR) on epiretinal membranes (ERM) tissue from patients with proliferative retreous body-retina (PVR) lesion and cultured retinal pigmentary epithelial (RPE) cells. METHODS: The C5aR expressions on ERM tissue and cultured RPE cells were detected by ABC immunohistochemical staining with mouse anti-human C5aR mcAbs. RESULTS: Expression of C5aR was found in ERM tissue and on cultured RPE cells as well as macrophages. CONCLUSION: As a pro-inflammatory factor, binding of C5a to C5aR on RPE cells may play an important role in the development of PVR.

Animals↗
PubMed1986

Presence of chemotactic peptides other than C5a anaphylatoxin in scales of psoriasis and sterile pustular dermatoses.

A unique leukocyte chemotactic factor of around 12 kD molecular weight has been suggested to be responsible for the mechanisms involved in transepidermal migration of leukocytes observed in psoriasis and related sterile pustular dermatoses. Although we confirmed with radioimmunoassay the presence of a C5-cleavage product in the chemotactic fractions from psoriatic scale extract eluted by gel filtration HPLC, the neutrophil chemotactic activity demonstrated in the peak fraction was only partially inhibited by rabbit antiserum to human C5a, whereas that noted in the peak fraction, prepared from zymosan activated serum, was totally abrogated by the same treatment. Similarly the chemotactic fraction prepared from the scale extracts of other related pustular dermatoses were only partially inhibited with anti-C5a antiserum. These findings suggest that chemotactic peptides other than C5a also play a role in the transepidermal migration of leukocytes in these dermatoses.

Animals↗
PubMed1989

Rabbit leukocytes activated by C5a des Arg and N-formyl-methionyl-leucyl-phenylalanine promote endothelial prostacyclin production. Evidence for a role of hydrogen peroxide.

Prostacyclin (PGI2) production by an intact endothelial cell layer on the surface of isolated rabbit aortas was investigated in the presence of chemoattractants (C5a des Arg, FMLP, LTB4, PAF) and autologous blood leukocytes. Leukocytes themselves did not produce detectable amounts of PGI2, nor did they alter basal endothelial PGI2 formation. In the absence of leukocytes, C5a des Arg (but not FMLP, LTB4 or PAF) produced a direct and dose-dependent stimulation of PGI2 release from endothelial cells. This effect was greatly enhanced when C5a des Arg and leukocytes were incubated together on the endothelium. Similar results were obtained on co-incubation of endothelium and leukocytes with FMLP and to a lesser extent with LTB4 and PAF. Experiments with superoxide dismutase and catalase suggest that release of H2O2 may partly explain the stimulatory activity of leukocytes in the presence of chemoattractants. The effect of aspirin treatment of the endothelial cells in enhancing leukocyte adherence induced by C5a des Arg suggests that local PGI2 production by vascular endothelium may provide a natural defence mechanism by attenuating cell-cell interactions.

Animals↗