Dialysate temperature and complement activation.
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Cellulose↗
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Quantitation of membrane biocompatibility.
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Biocompatible Materials↗
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↗
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↗
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↗
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↗
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↗
C5a decreases regional coronary blood flow and myocardial function in pigs: implications for a granulocyte mechanism.
Granulocytes cause some of the pathophysiological effects associated with the capillary no-reflow phenomenon during ischemia and in ischemia-reperfusion injury. However, no study has examined the consequences of in vivo granulocyte activation during normal perfusion pressures. In this study, we examined the effects of intracoronary administration of the complement component C5a, which is known to be a potent granulocyte activating factor. Nine open-chest, anesthetized pigs were instrumented to monitor regional coronary blood flow and segment shortening, left ventricular dP/dt, heart rate, and pulmonary artery and aortic blood pressures and to sample arterial and regional coronary venous blood for oxygen content and complete blood counts. Intracoronary infusion of human or porcine C5a in doses ranging from 10 to 500 ng produced a significant reduction in regional coronary blood flow and myocardial function. Although perfusion pressure and heart rate remained constant, venous oxygen content fell, indicating an imbalance between myocardial oxygen supply and demand. In addition, the arteriovenous difference of white blood cells was increased significantly after anaphylatoxin infusion, indicating intravascular trapping in the myocardium. Granulocytes accounted entirely for the differences in leukocyte counts because no significant changes in platelet, lymphocyte, or hematocrit levels were observed. Injection of vehicle alone did not alter any of the monitored variables.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Complement activation and membrane lipids in lung vascular injury.
Intravascular complement activation induces a rapid neutropenia and transient hypotension in laboratory animals such as rabbits. Injection of purified C5a causes similar hemodynamic events, and the hematologic changes suggest involvement of components such as polymorphonuclear leukocyte (PMN) and mediators including vasoamines and prostanoids. The anaphylatoxin-induced hypotension coincided with an increase in central venous pressure (CVP), decreased cardiac output (CO), increased plasma prostanoid levels, and neutropenia. These phenomena were repeatable in the animals when C5a was administered as a bolus 45 min after the initial treatment. Animals pretreated with indomethacin failed to exhibit the hypotensive response to C5a but still exhibited the transient neutropenia. Indomethacin effectively eliminated prostanoid release into plasma as expected. Administration of H2, but not H1, histamine-receptor antagonists reduced both C5a-induced hypotension and prostanoid release, suggesting that histamine may contribute to the C5a response in rabbits. Animals rendered neutropenic with nitrogen mustard prior to C5a challenge respond normally to C5a infusion (i.e., elevated prostanoid release and hypotension). The mechanism that we proposed for C5a-induced hypotension requires vascular smooth muscle contraction to be predominant over peripheral vasodilation in affecting cardiac output. Neutropenia occurs as a parallel event to hypotension but seemingly has little influence on the hemodynamic response. Prostacyclin (PGI2) levels were elevated in C5a-treated animals, and this lipid mediator contributes to hypotension by enhancing peripheral vasodilation. Because plasma TGxB2, levels were also elevated and central venous pressure increased as cardiac output decreased in treatment animals, we concluded that thromboxane-dependent pulmonary vasoconstriction contributes significantly to the C5a hypotensive response.
Animals↗
Accentuated formation of the terminal C5b-9 complement complex in patient plasma precedes development of the adult respiratory distress syndrome.
Extensive studies have been conducted to determine the pathogenesis of the adult respiratory distress syndrome (ARDS) by investigating the role of complement, a mediator of inflammation. Complement activation products have been detected in blood samples from patients during ARDS. However, the individual complement components that have been assessed only indicated generalized inflammation, and none could unequivocally discriminate the onset of this acute inflammatory lung injury. In this two-year prospective study of 87 septic patients, 22 of whom developed ARDS (25%), we determined complement activation by quantifying the terminal complement complex (TCC), C5b-9. The TCC is a stable complement by-product formed following activation of either the classical or alternative pathways. Our results show that plasma TCC concentrations increased an average of 110% (p = 0.002) two days prior to the onset of ARDS and also transiently increased an average of 45% (p = 0.01) immediately preceding its resolution. Furthermore, plasma TCC concentrations were a more sensitive measure of this acute inflammatory lung injury than levels of C3a desarginine, C4a desarginine, C5a desarginine, and total hemolytic complement activity. We conclude that a temporal association exists between accentuated formation of plasma TCC and the development and also resolution of septic ARDS. Therefore, we suggest that researchers include plasma TCC concentrations in clinical studies when they could use a potential early indicator for ARDS.
Complement Activation↗
Absence of inflammatory lung injury in rabbits challenged intravascularly with complement-derived chemotactic factors.
Systemic activation of the complement system results in the generation of chemotactic factors that have been suggested to play a role in the pathogenesis of inflammatory pulmonary diseases such as the adult respiratory distress syndrome. This led us to ask whether systemic complement activation by cobra venom factor (CVF) or intravascularly administered zymosan-activated rabbit plasma (ZAP) or rabbit C5a would result in lung injury. As had been described previously for CVF and ZAP, intravenously administered rabbit C5a also caused an acute neutropenia along with sequestration of neutrophils within the pulmonary vasculature. However, no significant lung inflammation as measured by neutrophil emigration or increased vascular permeability occurred with any of the three stimuli. Only when these agents were combined with anesthesia, surgical manipulation, and intubation did significant neutrophil emigration into alveoli occur, but again without any change in vascular permeability. After administration of ZAP, a decrease in dynamic compliance and an increase in pulmonary resistance as well as a transient period of hypoxemia occurred that was not observed after CVF or rabbit C5a treatment. Thus, our studies suggest that changes in lung function after ZAP instillation may not represent changes from complement activation alone in that they are not reproduced with CVF or rabbit C5a. We conclude that complement activation, as an isolated event, may be an insufficient insult in the lung to produce significant lung injury.
Airway Resistance↗
Procoagulant activity of rabbit alveolar macrophages.
Alveolar macrophages are thought to participate in the clearance of fibrin from the injured lung, but their ability to facilitate the conversion of fibrinogen to fibrin (procoagulant activity) has not been described. In order to characterize their procoagulant properties, unstimulated alveolar macrophages obtained from normal rabbits were tested for their ability to accelerate the coagulation of plasma in a one-stage clotting assay. Compared with control assays containing no macrophages (coagulation times greater than 500 s), intact cells (10(6)/ml) were shown to display procoagulant activity (coagulation time, 153.6 +/- 11.3 s mean +/- SEM). Cell lysis caused further procoagulant activity to be expressed (125.6 +/- 11.8 s). Alveolar macrophages that were stimulated in vitro with bacterial lipopolysaccharide (LPS) or the purified complement fragments C5a and C5a des Arg caused further significant (p less than 0.002) reductions in coagulation times (intact cells, 71 to 76 s; lysed cells, 27 to 32 s), representing 5- to 6-fold and 30- to 40-fold increases in the procoagulant activity of intact and lysed cells, respectively. The generation of this material was independent of the presence of lymphocytes. The procoagulant material was identified as a cell-associated tissue thromboplastin, acting via the extrinsic coagulation pathway. These findings show that alveolar macrophages have procoagulant activity that is markedly augmented by LPS and complement fragments. This suggests that alveolar macrophages may contribute to intra-alveolar fibrin deposition in vivo.
Animals↗
Biologically active products of complement and acute lung injury in patients with the sepsis syndrome.
To determine if biologically active products of complement appear during sepsis and to establish the relationship of these components to the respiratory and hemodynamic complications of sepsis, we measured C5a des Arg and C3a des Arg (radioimmunoassay), neutrophil chemotaxis, and neutrophil-aggregating activity in plasma obtained from 40 patients at the time sepsis was suspected clinically. Levels of C3a des Arg and C5a des Arg were elevated in 35 and 38 patients, respectively, and in all 25 with positive blood cultures. Highest C5a des Arg levels occurred in patients with hypotension (less than 90 mmHg) and/or acidemia. The C5a des Arg concentrations were significantly higher in patients with than in those without neutrophil-chemotactic activity. Neutrophil-aggregating activity was less sensitive an index of complement activation, as it was positive in only 8 patients and correlated poorly with C5a des Arg and C3a des Arg values. Using a composite scoring system to quantify sepsis-related pulmonary abnormalities, we found that neither biologic nor immunologic assays of complement activation products correlated with the initial severity nor predicted the development or worsening of associated acute lung injury.
Bacterial Infections↗
Alveolar macrophage function and inflammatory stimuli in smokers with and without obstructive lung disease.
To explore possible cofactors in the development of chronic obstructive pulmonary disease (COPD) in smokers, we performed bronchoalveolar lavage in 6 smokers with normal pulmonary function, 6 smokers with COPD (FEV1/FVC less than or equal to 65%) matched for smoking history and age, and 9 age-matched nonsmoking control subjects. Elastase release by macrophages from smokers with COPD was significantly higher (p less than 0.016) than was elastase release by macrophages from normal smokers. There were no differences between chemoattractiveness of alveolar macrophage supernatants for one person's polymorphonuclear leukocytes among the groups of smokers and there was no detectable C5/C5a in these supernatants (limit of detection of C5a greater than 1 ng/ml). There were no significant differences in numbers or species of bacteria in aerobically and anaerobically cultured bronchial brushings. There was no difference in alveolar macrophage superoxide anion release with particulate or membrane-perturbing stimuli for the smokers. Alveolar macrophages from the 3 groups of subjects had similar limited microbicidal ability for the obligate intracellular protozoan, Toxoplasma gondii, and similar numbers of elastase receptors and affinity for elastase.
Adult↗
Time course of chemotactic factor generation and the corresponding macrophage response to asbestos inhalation.
Inhalation of asbestos fibers causes a progressive fibrotic lung disease in humans and animals. Pulmonary macrophages are associated with asbestos exposure and have been implicated as significant mediators of the pathogenic process. In previous studies, we showed that macrophages are attracted to sites of asbestos fiber deposition, i.e., alveolar duct bifurcations. We also showed that macrophages accumulated at these sites as the result of asbestos-induced activation of complement proteins on alveolar surfaces, consequently producing C5a, a chemotactic factor for macrophages. In the present study, we have demonstrated the time course of chemotactic factor generation and the corresponding macrophage response in vivo. A complement-dependent chemotactic factor for macrophages was activated during a 3-h exposure to asbestos and reached maximal activity by 3 h postexposure. Macrophage accumulation followed and reached a maximal amount by 24 h postexposure. Rats decomplemented with cobra venom factor exhibited a significant reduction in macrophage accumulation, but the macrophage response ensued when serum complement returned to normal. Approximately 30% of the macrophages lavaged from complement-normal, asbestos-exposed animals contained fibers, whereas only half as many macrophages from decomplemented rats contained asbestos. A small but significant increase in lavaged lung protein was measured in asbestos-exposed animals. Evidence supports the concept that complement proteins on alveolar surfaces are derived from normal transudation of serum components from the pulmonary vasculature. Increased serum transudation could provide a source of alveolar complement that sustains the generation of a chemotactic factor for macrophages.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Airways hyperreactivity and inflammation produced by aerosolization of human C5A des arg.
The premise of this study was that complement fragments would lead to granulocyte infiltration and to associated changes in airways reactivity. Inflammation was induced in large airways (greater than 1.0 mm) by aerosolization of the complement chemotactic factor, C5a des arg, which was isolated from activated human serum. Pulmonary function (resistance, compliance, and lung volume) and histamine reactivity were assessed at 4 and at 48 h after C5a des arg or a saline sham aerosol. Four hours after exposure to C5a des arg, the animals exhibited evidence of significant bronchoconstriction and hyperinflation. In addition, an increased responsiveness to histamine was demonstrated, which was not correlated with the degree of bronchospasm. By 48 h, these alterations were partially or completely resolved. Histologic examination and quantitation demonstrated significant accumulation of neutrophils, which was limited to airways 0.5 mm in or larger. Saline-treated animals also demonstrated a neutrophil infiltration, but significantly less than those treated with C5a des arg. However, these animals did not demonstrate hyperreactivity to histamine, and there was little change in baseline mechanical function. The mild inflammation associated in the saline control animals was demonstrated to be a result of intubation of the airways. Granulocyte dependence of the effects of C5a des arg was partially established by abrogation of these effects when the animals were rendered granulocytopenic with nitrogen mustard. We conclude that the physiologic responses of the airways to C5a des arg were largely granulocyte dependent. However, since granulocyte accumulation could occur without airways dysfunction, it is suggested that cell activation is an important step in producing neutrophil-associated airways hyperresponsiveness.
Aerosols↗
Activation of the complement system in the adult respiratory distress syndrome.
The adult respiratory distress syndrome (ARDS) is an acute pulmonary disorder characterized by the accumulation of neutrophils within the lower respiratory tract. Because activation of the complement system can generate C5a, a potent neutrophil chemoattractant, complement activation was assessed in both serum and bronchoalveolar lavage fluid obtained from 10 patients with ARDS and compared with that from normal control subjects. Crossed immunoelectrophoresis was used to determine activation of the complement components C3 and properdin factor B (PFB), and radioimmunoassay was used to determine the presence of C5a. Complement activation was not detected either in the plasma or in the lung epithelial lining fluid of the control subjects. In contrast, evidence of C3 activation was found in the plasma of 50% of the patients with ARDS when initially studied; likewise, C3 activation, PFB activation, and C5a could all be detected in the epithelial lining fluid of all patients with ARDS with a single exception. Follow-up bronchoalveolar lavages revealed decreased amounts of C3 activation and C5a 2 to 7 days after the onset of ARDS, and the complement activation had resolved when the patients with ARDS had completely recovered. To determine if the C5a in bronchoalveolar lavage fluid could be responsible for the influx of neutrophils observed in ARDS, epithelial lining fluids obtained from both normal control subjects and from patients with ARDS were fractionated by molecular sieve chromatography. Two distinct fractions of chemotactic activity were found in the ARDS bronchoalveolar lavage fluid.(ABSTRACT TRUNCATED AT 250 WORDS)
Body Fluids↗
Complement lysis of human erythrocytes. Differeing susceptibility of two types of paroxysmal nocturnal hemoglobinuria cells to C5b-9.
Although enhanced sensitivity of erythrocytes to complement-mediated lysis is a hallmark of paroxysmal nocturnal hemoglobinuria (PNH), subpopulations of erythrocytes in such patients vary significantly in this respect. One PNH erythrocyte subpopulation (termed type III) comprises exquisitely sensitive cells, whereas type II PNH erythrocytes are intermediate in complement sensitivity between PNH type III and normal human erythrocytes. Differences in the action of the terminal complement components that would account for the differing lytic behavior of types II and III PNH erythrocytes have been proposed but not directly demonstrated. The present studies, making use of carefully selected cases with pure populations of type II or type III erythrocytes, confirm a prior observation that antibody-coated PNH erythrocytes of both types II and III display comparably supranormal C3 binding in whole human serum. However, when lysis was induced by the isolated C5b-9 membrane attack mechanism, bypassing the requirement for C3 binding, only type III PNH cells exhibited greater than normal lysis. This finding suggests that type III PNH erythrocytes have an additional membrane abnormality not present in type II cells. Thus, the differing lytic behavior of these two cell types in whole serum may reflect the additive effects on type III cells of both exaggerated C3 binding and enhanced sensitivity to C5b-9, whereas the more moderate lysis of type II PNH cells may be determined mainly or entirely by the earlier-acting mechanism producing augmented C3 binding. The failure of guinea pig C8 and C9, as opposed to human C8 and C9, to reveal the true lytic sensitivity of PNH-III E in our earlier study is illustrated, and its implications briefly discussed.
Animals↗