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PubMed1983

C5a and antigen-induced tracheal contraction: effect of a combination of an antihistamine and cyclo-oxygenase inhibitors.

Our previous studies with C5a, a cleavage product of the fifth component of complement, have shown that the antihistamine diphenhydramine and the cyclo-oxygenase inhibitor aspirin do not inhibit the C5a-induced contraction of isolated guinea pig trachea (Regal, Eastman & Pickering, 1980; Regal & Pickering, 1981). We investigated the effect of cyclo-oxygenase inhibitors in the presence of diphenhydramine to determine if cyclo-oxygenase products were contributing to the contraction beyond any effect they might have on histamine release. A combination of a cyclo-oxygenase inhibitor and diphenhydramine caused a delay in onset and decrease in magnitude and duration of the C5a-induced contraction. Indomethacin itself also caused a slight inhibition. In contrast, a combination of aspirin and diphenhydramine did not inhibit the initial portion of antigen-induced tracheal contraction any more than diphenhydramine alone and enhanced the later portion just as aspirin alone. Cross tachyphylaxis experiments demonstrated that antigen pretreatment significantly inhibited a subsequent C5a-induced tracheal contraction, though C5a pretreatment did not affect a subsequent antigen-induced contraction. Thus, cyclo-oxygenase products do contribute to C5a-induced tracheal contraction, and histamine participation in the presence of cyclo-oxygenase inhibitors is suggested. Our studies demonstrate the dissimilarities of C5a and antigen-induced contraction as regards inhibition by aspirin plus diphenhydramine, yet suggest common pathways leading to the contractile response as evidenced by cross tachyphylaxis experiments.

Animals↗
PubMed1987

Influence of lysophospholipids and PAF on the oxidative burst of PMNL.

Lysophosphatidylcholine (LC), platelet activating factor (PAF) and its precursor lysophosphatidalcholine (LP) enhance O-2-release by polymorphonuclear leucocytes (PMNL) triggered by PMA whereas lysophospholipids with other polar headgroups fail to do so. The generation of these lysophosphatidylcholine-like molecules appears to represent an essential step in the activation of the oxidative burst of the PMNL triggered by PMA since inhibition of phospholipase A2 (PLA2) by p-bromophenacylbromide (BB) or mepacrine results in an inhibition of the O-2 release. This inhibition seems to be due to the reduced generation of the phospholipids studied as it could be reversed by LP. In addition, stimulation of the oxidative burst of the PMNL by the chemotactic stimuli, N-formyl-methionyl-leucylphenylalanine (FMLP), and the complement fragment C5a could also be significantly enhanced by LP as shown by chemiluminescence. However, the response to the phagocytic stimulus, opsonized zymosan (Zx), is not affected by LP. These data provide evidence for the participation of phospholipid metabolism in the initiation of the oxidative burst of PMNL induced by the soluble monomeric stimuli PMA, FMLP and C5a.

Acetophenones↗
PubMed1989

Treatment of malignant ascites and pleurisy by a streptococcal preparation OK-432 with fresh frozen plasma--a mechanism of polymorphonuclear leukocyte (PMN) accumulation.

A single injection of a streptococcal preparation, OK-432, with fresh frozen plasma (FFP) (or fresh human serum) into the peritoneal or pleural cavity for the treatment of malignant ascites or pleurisy resulted in a complete reduction of ascitic fluid or pleural effusion in 5 out of 11 patients. FFP was used a further source of complement for the effective accumulation of antitumor polymorphonuclear leukocytes (PMNs) by complement-derived chemotactic factors in the cavity. C5a increased in the fluids 3-9 h after the injection and preceded a massive increase in PMNs. C1 inhibitor (C1INH) and C3b inactivator (C3bINA) decreased in several cases 6 h after the treatment. Chemotactic arachidonic acid metabolites, thromboxane B2(TXB2) as a characteristics of TXA2, and leukotriene B4(LTB4) also increased at the same time even in cases where C5a changed only minimally, and may play a role in accumulating antitumor PMNs in the cavity.

Adult↗
PubMed1993

The B chain, but not the A chain, of Ricinus communis activates human complement.

Complement activation properties of ricin holotoxin, its A or B chain were assessed in two enzyme immunoassays (EIA). One was specific for C3 activation products and the other detected the terminal SC5b-9 complement complex (TCC) and thus determined activation of the initial and terminal part of the complement pathways, respectively. Ricin and its A and B chains were incubated with normal human serum or EDTA-serum. It was found that ricin B chain activated both the initial and terminal complement pathways in a time- and concentration-dependent fashion, whereas the A chain and the holotoxin did not.

Complement Activation↗
PubMed1988

The use of high field NMR to determine homogeneity in a preparation of human C5a produced by Escherichia coli.

The polypeptide backbone of human C5a was prepared by recombinant DNA techniques. Standard biochemical analysis guided the protein separation to give a sample of C5a which was deemed homogeneous. However, nuclear magnetic resonance (NMR) studies showed the material to be significantly heterogeneous. Reanalysis by high performance liquid chromatography (HPLC) corroborated the NMR results. Further separation by HPLC and analysis by NMR spectroscopy guided the isolation of rC5a to greater than 92% purity. NMR analysis, immunochemical and biological evaluation of the impurities showed them to be C5a structural variants. These results indicate that conventional methods of protein chemistry can fail to reveal heterogeneity in recombinant proteins, and in some circumstances NMR spectroscopy can aid in their purification.

Chromatography, High Pressure Liquid↗
PubMed1987

Anaphylotoxin levels following thermal injury.

Following thermal injury, anaphylotoxins (C3a and C5a) are generated by complement activity. We measured C3a and C5a levels serially in 18 seriously burned patients (mean burn size = 37.9 per cent body surface area) over the initial 3 weeks following injury. Values for C3a were significantly increased when compared with normal controls, with maximum levels during the second week, while C5a levels were slightly elevated initially. These levels did not correlate with the extent of tissue injury, the development of septic complications or the clinical outcome. However, it appears likely that C3a and C5a may be responsible for some of the pathophysiological alterations observed following thermal injury.

Adult↗
PubMed1987

Biochemical investigations after burning injury: complement system, protease-antiprotease balance and acute-phase reactants.

Seventeen burned patients were investigated--Group I (n=10) with a mean burned area expressed as unit burn standard (UBS) of 69 +/- 24 and Group II (n = 7) with a mean UBS of 23 +/- 8. Blood samples were collected immediately after admission, 6-12 h after injury, during the morning and evening of day 1, and then daily for 2 weeks. This prospective study demonstrated complement activation in vivo in all burned patients, measured by C3d/C3 ratio index which was not related to the extent of the burned surface. A significant protease-antiprotease imbalance, correlated to the severity of burns, was found, leukocyte elastase was increased throughout the observation period, alpha 2-macroglobulin drastically decreased in severely burned patients, and alpha 1-proteinase inhibitor promptly decreased below the normal level in patients with more than 40 UBS. Finally, there was a delayed but then persistent acute-phase reactant protein response involving C-reactive protein, haptoglobin and alpha 1-acid glycoprotein, the concentrations of which reached a plateau on days 6 or 7.

Acute-Phase Proteins↗
PubMed1986

High-level expression of a gene encoding the human complement factor C5a in Escherichia coli.

The synthetic C5a gene was initially found to be expressed poorly in Escherichia coli. We undertook studies to determine the reasons for poor expression and to increase expression. The work was focused on the role of the mRNA structure in C5a expression and stability of its product in E. coli. We present data on the effects of varying the sequence at the 5' end of mRNA as well as different ribosome-binding sites on expression. Evaluation of the stability of C5a showed rapid degradation of C5a in wild-type E. coli (half-life 3-5 min). Screening of several protease-deficient strains of E. coli showed that C5a was much more stable in an htpR strain carrying a mutation in the sigma subunit of RNA polymerase that is specific for heat shock promoters. The mutation is associated with a proteolytic deficiency. The half-life of C5a was increased to 20 min. By manipulating the expression vector, the regulatory region for the C5a gene, the host strain, growth conditions and methods for recovering the protein, C5a levels were increased 300-fold over previously reported amounts to about 3% of total cellular protein.

Base Sequence↗
PubMed1984

Complement, granulocytes, and shock lung.

Intravascular leukostasis in the pulmonary microvasculature is a cardinal early histologic finding in patients with shock lung. Identical leukostasis is also observed in patients undergoing extracorporeal hemodialysis with cellophane membrane dialyzers, and it has been documented that the accumulation of granulocyte plugs in the lung is mediated by complement activation triggered by dialyzer cellophane. The C5a-desarg so generated causes peripheral blood granulocytes to aggregate, and the aggregates so formed embolize to the lung, where they cause occlusion of the microvasculature and increased capillary leakage, manifested by interstitial and alveolar edema. In vitro studies suggest that this endothelial damage is mediated by hydrogen peroxide from the adherent granulocytes. Most importantly, a close correlation has been found between the presence of C5a-desarg in plasma and the subsequent onset of shock lung in patients after trauma, burns, and sepsis. As exemplified by hemodialysis leukopenia, C5a-desarg-mediated pulmonary leukostasis is a self-limiting process because of selective down-regulation of granulocyte receptors for C5a-desarg--a mechanism that primarily limits the lung damage associated with intravascular complement activation.

Animals↗
PubMed1985

Oxygen radicals in complement and neutrophil-mediated acute lung injury.

The development of experimental acute lung injury following systemic complement activation is closely related to availability of blood neutrophils. Although tissue-destructive neutrophil-derived proteinases may play a supportive role in acute pulmonary injury, it appears that oxygen radical constitute the major neutrophil product responsible for acute damage of lung tissues and cells. Intravascular activation of neutrophils by the chemotactic complement peptide C5a is related to the generation of superoxide anion. Dismutation of superoxide to hydrogen peroxide and its iron-mediated conversion to hydroxyl radical appear to constitute in vivo events that ultimately lead to acute lung microvascular injury.

Animals↗
PubMed1988

Host factors in the resistance of newborn mice to K1 Escherichia coli infection.

It is not clear which factors are responsible for the deficient resistance of human neonates to K1 E. coli sepsis and meningitis. To evaluate the relative importance of different defense mechanisms against bacterial invasion, we have analyzed the sensitivity of newborn mice with known immune deficiencies to infection after oral challenge with virulent K1 E. coli. T and B lymphocyte and complement (C5) defects had no significant effect on natural resistance. In contrast, both endotoxin-hyporesponsive mouse strains tested were highly sensitive. This susceptibility to infection was strongly age dependent. Infant endotoxin-hyporesponsive mice were killed by i.p. injection of less than ten virulent K1 E. coli cells. In contrast, endotoxin-responsive animals and F1 hybrids derived from crosses between endotoxin-responsive and hyporesponsive mice survived an injection with up to 10(4) bacteria. Mutants of a virulent 018:K1 E. coli strain defective in the synthesis of the capsular polysaccharide or the O-antigen of lipopolysaccharide were avirulent as were 01:K1 bacteria, which are under-represented among E. coli isolates from neonatal meningitis. Endotoxin-hyporesponsive mice were protected from lethal bacterial challenge by monoclonal IgG specific for the O-antigen of the challenge strain or by human recombinant interleukin 1. A fulminant bacterial multiplication in the bloodstream of endotoxin-hyporesponsive mice was observed after i.v. injection of 100 virulent K1 E. coli cells. Persistent bacteremia with 10(5) to 10(6) bacteria per ml of blood resulted in death of the animals one to two days after challenge. In the bloodstream of endotoxin-responsive mice the bacteria proliferated to a comparable extent within the first 6 h after challenge. Thereafter they were rapidly cleared from the circulation and the animals recovered from the infection.

Animals↗
PubMed1989

Chemotactic factor generation and cell accumulation in acute lung injury induced by endotracheal acid instillation.

We studied the time course of chemotactic factor generation and inflammatory cell accumulation in the rabbit aspiration pneumonia model. Two major potent chemotactic factors, leukotriene B4 (LTB4) and C5a, in bronchoalveolar lavage fluid (BALF) were measured by radioimmunoassay, and cell analysis was also done. The level of LTB4 increased only in the early phase (2-6 h) after endotracheal acid instillation. The level of C5a increased gradually almost in parallel with the total protein level in BALF, and reached a maximum at 24 h. Neutrophil accumulation occurred early and reached a maximum at 24 h. In contrast, the number of alveolar macrophages increased from days 1 to 7. These findings suggest that the increases in LTB4 and C5a are responsible for accumulation of neutrophils and that C5a may be an important chemotactic factor for alveolar macrophage.

Animals↗
PubMed1988

Complement activation in cardiopulmonary bypass, with special reference to anaphylatoxin production in membrane and bubble oxygenators.

Complement activation by cardiopulmonary bypass (CPB) was studied in 82 patients divided into membrane (MOG) and bubble oxygenator groups (BOG). The influence of primed homologous to circulating autologous blood volume (H/A) ratio was also evaluated. C4a increased very slowly during CPB in both groups, maintaining slightly higher levels in the BOG than in the MOG, with the exception of a marked initial rise in the BOG with a high H/A ratio (greater than or equal to 20%). Anaphylatoxin C3a levels increased more steeply in the BOG than in the MOG. An obvious rise in anaphylatoxin C5a production was observed in the BOG alone. The influence of high H/A ratio perfusion on complement activation was milder in the MOG than in the BOG. In 20 monkeys (Macaca fascicularis), continuous intraaortic infusion with bubbled autologous blood increased C4a and C3a levels, while autologous blood extracorporeally contacted with nylon increased C3a levels alone. In vitro studies revealed that human immunoglobulin fractions denatured by oxygen bubbling produced C4a, C3a, and C5a in a dose-dependent manner, although human albumin treated identically as human immunoglobulin did not produce these complements. It was thus inferred that (1) during CPB, complement is predominantly activated via the classical pathway in the BOG and via the alternative pathway in the MOG; (2) higher anaphylatoxin levels in the BOG than in the MOG are related to mode and grade of blood trauma; (3) anaphylatoxin level differences in both groups tend to increase with high H/A perfusion; and (4) immunoglobulin-free sera may reduced classical pathway activation.

Animals↗
PubMed1983

5-L-hydroxy-6,8,11,14-eicosatetraenoate potentiates the human neutrophil degranulating action of platelet-activating factor.

Platelet-activating factor (AAGPC) and two of its structural analogues degranulated human neutrophils with respective potencies that were increased up to 100 to 1000-fold by 16 nM to 5 microM of 5-L-hydroxyeicosatetraenoate (5-L-HETE). 5-rac-HETE had similar actions but 8-rac-HETE was without effect. Furthermore, 5-L-HETE did not influence the degranulating actions of C5a, A23187 or a formalated oligopeptide chemotactic factor and none of the HETEs, by themselves, caused degranulation. Thus, 5-L-HETE and AAGPC selectively interact to induce degranulation. Since these products rapidly form in stimulated PMNs, they may serve as potentiator and agonist, respectively, to transduce biological signals into cell function.

Arachidonic Acids↗
PubMed1987

Lack of correlation between calcium mobilization and respiratory burst activation induced by chemotactic factors in rabbit polymorphonuclear leukocytes.

Low concentrations of FMLP, partially purified rabbit C5a, leukotriene B4 and platelet activating factor induced a rapid rise of intracellular free Ca2+ in rabbit polymorphonuclear leukocytes. However, the four factors differed markedly in their ability to activate the respiratory burst. The peptides FMLP and C5a induced a single, strong chemiluminescence response whereas the lipids leukotriene B4 and platelet activating factor induced a markedly less intense response with a two-peak profile. Respiratory burst activation by the peptides was dependent on extracellular Ca2+ whereas the lipids required both Mg2+ and Ca2+. The results indicate that mobilization of intracellular Ca2+ is insufficient by itself to induce respiratory burst activation and that the intracellular pathways leading to activation differ depending on the nature of the stimulus.

Animals↗
PubMed1987

Oscillatory motion in human neutrophils responding to chemotactic stimuli.

Human neutrophils treated with the secretion inhibitor 17-hydroxywortmannin were stimulated with fMLP, C5a, PAF or LTB4, and the ensuing shape change was studied. The cells rapidly extended lamellipodia and showed regular oscillatory behaviour. The oscillations were observed in both light transmission and 90 degrees light scattering, had the same frequency in each case, and disappeared within 30-50 seconds. Light scattering theory suggests that they reflect rhythmic changes in the shape and/or size of the chemotactically stimulated cells, possibly related to crawling or swimming movements associated with migration.

Androstadienes↗
PubMed1987

Synthesis of a new photoreactive C5a analog that permits identification of the ligand binding component of the granulocyte C5a receptor.

Human C5a is a complement derived inflammatory mediator that binds to specific receptors that are found in the granulocyte plasma membrane. A new photoreactive C5a analog, that can be radiolabeled in the aryl azide moiety, has been synthesized by coupling p-azidosalicyl-2-mercapto-N-ethylamide-2'-thiopyridine disulfide to a partially reduced form of C5a. This unique analog (ASAMEA-SC5a) specifically bound to the granulocyte C5a receptor with an apparent Kd of 1.8 nM, a value that is comparable to that of the native ligand. Photoactivation resulted in crosslinking of this probe to the granulocyte C5a receptor. Subsequent reductions of the complex produced a radiolabeled C5a receptor, or a subunit of this receptor that had an apparent molecular weight of 47,000 Daltons on SDS-PAGE.

Affinity Labels↗