Complement and the damaging effects of cardiopulmonary bypass.
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Anaphylatoxins↗
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Complement ligand-receptor interactions that mediate biological responses.
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Animals↗
Chemoattractant receptors on phagocytic cells.
Chemoattractant receptors on leukocytes can trigger a number of cellular responses, including the cytoskeletal reorganization, changes in cell shape, directed motility, lysosomal enzyme secretion, and activation of the respiratory burst. The dose of chemoattractants required to induce motility-related functions is generally at least ten-fold smaller than the dose required to initiate secretory and respiratory burst activities. This finding and other pharmacological evidence clearly indicate that the two types of functions (i.e. motility and secretion) are regulated differently and can be divergently modified by drugs. The affinity of the oligopeptide chemoattractant receptor on polymorphonuclear leukocytes and macrophages is heterogeneous and dynamically regulated by guanine nucleotides and prior agonist exposure. High- and low-affinity forms of the oligopeptide receptor have been identified by direct binding studies. Our data suggest that low doses of agonists can initiate interconversion of low- and high-affinity states of that portion of chemoattractant receptors regulated by guanine nucleotides. On the other hand, high doses of agonists sufficient to induce chemotactic desensitization, lysosomal enzyme secretion, and the respiratory burst lead to the formation of a new population of high-affinity receptors. These binding sites are insensitive to the effects of guanine nucleotides and appear to be rapidly internalized. Transmethylation reactions mediated by S-adenosyl methionine are required for the activation of a phospholipase and release of arachidonate from leukocytes by chemotactic factors. We suggest that release of arachidonate from membrane phospholipid activates and translocates a cytosolic but loosely membrane-associated protein kinase C into the membrane and that this kinase participates in stimulus-response coupling of chemoattractant receptors.
Animals↗
Infections and hypocomplementemia.
The complement system, phagocytic leukocytes, and antibodies constitute the "department of defense" in the battle against infections caused by pyogenic microorganisms. Complement components are capable of directly killing (by lysis) certain susceptible bacteria and are the source of chemotactic peptides and heat-labile opsonin, which facilitate recognition and killing of microbes by phagocytic cells. When these vital functions are compromised, as in individuals with inherited deficiencies of complement components, the result is unusual susceptibility to severe infections.
Complement Activation↗
Inherited complement component abnormalities.
Inherited deficiencies of early complement components are frequently associated with immune/rheumatic disorders and recurrent (Neisserial) infection with deficiency of late complement components. The genetic complexity of complement components is further demonstrated by electrophoretic allotypy and analysis of DNA restriction fragment length polymorphisms.
Adult↗
Endotoxemia and neutrophil activation in vivo.
There is a growing body of data to suggest that marginated granulocytes mediate much of the pulmonary damage observed during endotoxemia. The mechanism(s) by which endotoxemia initiates neutrophil margination and cytotoxicity remain either controversial or unknown. The objectives of this study were 1) to determine the temporal relationship between endotoxin-induced decreases in mean arterial pressure and circulating neutrophils, 2) to monitor neutrophil activation in vivo by measuring myeloperoxidase (MPO) activity in the plasma and lymph, and 3) to assess the interaction between endotoxin and complement in activation of neutrophilic oxidative metabolism in vitro. We found that a bolus injection of endotoxin causes a concurrent decrease in both mean arterial pressure and circulating neutrophils at 2 min postinfusion. Blood pressure recovered to approximately 70% of control values by 180 min, whereas circulating neutrophils remain depressed at 20% of control values for the entire experimental period. Using MPO as a marker for neutrophil activation, we found that infusion of endotoxin produces a dramatic increase in plasma and lymph MPO activity, suggesting activation of neutrophilic metabolism in vivo. In vitro data showed that both endotoxin and plasma were required for optimal neutrophilic degranulation and superoxide formation. We conclude that 1) the appearance of MPO in the plasma (or lymph) may be a useful neutrophil marker for neutrophil activation in vivo and may prove useful in following the course of neutrophil-mediated tissue injury during endotoxemia, and 2) endotoxin-activated complement (C5a) activates neutrophils to produce cytotoxic oxidants.
Animals↗
Bronchial epithelial cells release chemotactic activity for lymphocytes.
Lymphocytes can frequently be observed in association with bronchial tissues. One mechanism that might account for this association is that bronchial epithelial cells might release chemotactic factors for lymphocytes. To test this hypothesis, bovine bronchial epithelial cells were cultured in serum-free media, and the supernatant fluids were harvested and evaluated for lymphocyte chemotactic activity using a blind-well chamber technique. Media alone attracted few lymphocytes (12 +/- 2 cells/high power field), but in contrast, there was a significant increase in the number of cells attracted by supernatant fluids obtained from bronchial epithelial cell cultures (40 +/- 6 cells/high power field, P = 0.002). The activity was dose dependent and was demonstrated to be chemotactic activity by checkerboard analysis. Partial characterization of the activity revealed it was not extractable into ethyl acetate but was partially inactivated by trypsin and heat (100 degrees C, 15 min). The responding cells were predominantly T-helper lymphocytes as shown by monoclonal antibody staining, with a smaller proportion being B-lymphocytes. Molecular sieve column chromatography revealed multiple peaks of lymphocyte chemotactic activity, with three of the peaks preferentially attracting T-helper lymphocytes and one of the peaks preferentially attracting B-lymphocytes. These data demonstrate that bronchial epithelial cells can release chemotactic factors for lymphocytes and suggest that bronchial epithelial cells may modulate their local population of immune effector cells.
Animals↗
Relation between complement activation and susceptibility to decompression sickness.
The consequences of complement activation and the symptoms of decompression sickness are similar. Consequently, the relation between the sensitivity of individuals to complement activation by air bubbles and their susceptibility to decompression sickness has been examined. Plasma samples from 34 individuals were incubated with air bubbles, and the concentration of the fluid phase metabolites of complement activation C3a, C4a, and C5a were measured with radioimmunoassays. It was found that both the anaphylatoxins C3a and C5a were produced by the presence of air bubbles but that the anaphylatoxin C4a was not. This finding indicates that air bubbles activate the complement system by the alternate pathway. One group of individuals was found to be particularly sensitive to complement activation by this pathway. They produced 3.3 times more C3a and 5.3 times more C5a in their plasma samples incubated with air bubbles as did the other group. Sixteen individuals were subjected to a series of pressure profiles that were severe enough to produce bubbles in their circulatory system that could be detected by Doppler ultrasonic monitoring. The group of individuals that had been identified as being more sensitive to complement activation by the alternate pathway was also found to be more susceptible to decompression sickness.
Adult↗
Role of the complement anaphylatoxins in inflammation and hypersensitivity reactions in the lung.
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Anaphylatoxins↗
Density changes in leukocytes following hemodialysis or exposure to chemotactic factors.
Analysis of standard Ficoll-Hypaque separation profiles of peripheral WBC from patients undergoing hemodialysis (HD) demonstrated that dialysis caused a marked alteration in the number of cells found at both the interface between the Ficoll-Hypaque and plasma which normally contains mononuclear cells and the cell pellet which normally contains granulocytes. By 30 min into dialysis, there was a 175% increase in white blood cells in the mononuclear band with a corresponding decrease in the number of cells obtained from the cell pellet. When peripheral blood samples from normal donors were pumped through various types of hemodialyzers, a shift in the cell separation profiles similar to that of patients undergoing HD was observed. Differential analysis of the cells obtained from both the interface between the Ficoll-Hypaque and plasma and the cell pellet showed that by 30 min into dialysis, the 'mononuclear' band contained 40-50% polymorphonuclear neutrophils (PMN). To ascertain whether the cell separation changes were possibly due to C5a generation resulting from complement activation by the HD membrane, whole blood was incubated with the purified chemotactic factors C5a, C5ades arg, and formyl-methionyl-leucyl-phenylalanine. This resulted in similar alterations in PMN densities. This study demonstrates that both in vivo and in vitro exposure of human peripheral blood to HD membranes as well as the chemotactic factors C5a, C5ades arg, and formyl-methionyl-leucyl-phenylalanine results in density changes in PMN.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Effects of complement activation by hemodialysis membranes.
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Animals↗
Anaphylatoxin C5a generation and dialysis-induced leukopenia with different hemodialyzer membranes.
Leukocyte counts and plasma C5a anaphylatoxin levels were studied during hemodialysis in patients using Cuprophan, polycarbonate and polyacrylonitrile membrane dialyzers. Cuprophan induced a marked leukopenia with significant plasma C5a generation. Polycarbonate promoted the same trend of changes in both parameters but significantly less pronounced, while polyacrylonitrile did not affect leukocyte counts nor plasma C5a levels. These data suggest that complement-derived C5a generation may be an important factor in the mechanism of hemodialysis-induced leukopenia.
Acrylic Resins↗
Biocompatibility of a new polycarbonate dialysis membrane.
The present report summarizes our experience with a new polycarbonate (PC)-based dialysis membrane (Gambro Lundia PRO-5) compared with a cuprophan (CP)-based membrane (Gambro Lundia 10-5N). Platelet count decreased during dialysis with CP, but was unchanged with PC membranes. Platelet injury, reflected by decreased platelet aggregation and increase in plasma beta-thromboglobulin, occurred equally with both membranes. Complement activation (C3d and C5a), leukopenia and release of granulocyte-derived elastase was more extensive with CP than with PC membranes. The new membrane represents an improvement of biocompatibility with respect to the complement-leukocyte system, whereas the effect on platelets resembles the injury caused by CP membranes.
Adenosine Diphosphate↗
Performance and biocompatibility of a new hemodialysis membrane.
Performance studies and investigations of the biocompatibility of a new hemodialysis membrane were conducted in patients being chronically hemodialyzed. The investigated polycarbonate membrane revealed a very satisfying performance with regard to clearance values and the ultrafiltration rate. The biocompatibility studies showed a significant leukopenia and an increase of C5a, platelet factor 4 and granulocyte elastase. Thrombocytes and C3d remained unchanged. Long-term studies have to confirm whether or not the new membrane is more biocompatible, a suggestion which could be advanced, as no febrile episodes were observed during any treatment, a finding which is not typical for Cuprophan hemodialysis.
Biocompatible Materials↗
Biocompatibility of artificial organs: an overview.
Papers that are presented in this symposium on biocompatibility of foreign surfaces used in artificial organs are commented upon and set in an overall context of the biocompatibility of foreign surfaces to blood. A working formulation of the events comprising lack of biocompatibility of hemodialysis membranes to the complement system is given as a possible model to which other foreign surfaces may be compared.
Animals↗
Biocompatibility of different hemodialysis and plasmapheresis membranes.
The biocompatibility of different membranes was assessed by measuring changes in different white blood cell counts, PGE2 concentrations, thromboplastin activity, production of anaphylatoxins and clinical parameters during treatment. The in vivo recorded complement activation was compared with in vitro experiments. Hemodialysis (HD) treatment was performed with 5 different membranes. Plasmapheresis was run with cellulose diacetate membranes in single (SMF) and double (DMF) membrane filtration and with a new polycarbonate membrane in SMF. The polysulfone membrane was found to be the most, and the cuprophane membrane the least biocompatible membrane in HD. However, large individual differences from one HD patient to the other were found. In contrast to the cellulose diacetate membrane, the polycarbonate membrane apparently activated no complement along the blood-membrane interface during plasmapheresis, but activated large amounts within the membrane matrix. High blood concentrations of C5a were promptly cleared in the body, while high concentrations of C3a seemed to block the removal of this substance from the blood compartment. Even when the patients had high blood concentrations of anaphylatoxins throughout the plasmapheresis treatments using cellulose diacetate membranes and when a significant activation of PGE2 was found in patient plasma, no activation of thromboplastin was recorded on the surface circulating monocytes.
Biocompatible Materials↗
Analysis of density changes and chemotactic receptors of leukocytes from chronic hemodialysis and peritoneal dialysis patients.
Analysis of standard Ficoll-Hypaque (density = 1.077 g/ml) separation profiles of peripheral white blood cells (WBC) from patients undergoing hemodialysis (HD) demonstrated that dialysis caused a marked decrease in the density of polymorphonuclear leukocytes (PMN) resulting in about 50% of these cells separating with the mononuclear cells. In vitro exposure of normal control peripheral blood to HD membranes as well as to the purified chemotactic factors C5a, C5ades-Arg, and formyl-Met-Leu-Phe (fMLP) also resulted in PMN density changes which altered the Ficoll-Hypaque separation profiles of WBC. Therefore, these results imply that C5a generation, resulting from complement activation by the HD membrane, induced the density changes in the PMN from HD patients. Further studies using flow cytometry and fluorescein-labeled chemotactic factors (C5a, formyl-Met-Leu-Phe-Lys [fMLPL] and casein) indicated that HD patients had a significant reduction in the ability of their PMN and monocytes to bind C5a. This contrasted with the findings of no significant difference in the percentage or fluorescence intensity of HD patients' PMN or monocytes binding casein or fMLPL. Functional studies to analyze chemotactic-factor-mediated responses indicated that there was a decreased ability of HD patients' PMN and monocytes to generate superoxide anion, produce H2O2 and release myeloperoxidase in response to both C5a and fMLP. Additional studies evaluated the binding of chemotactic factors to PMN and monocytes from normal blood following passage through a hemodialyzer and from patients undergoing HD. Analysis of receptor binding by control cells passed through the dialyzer showed that there was a progressive decrease in the percentage of C5a-receptor-positive PMN and monocytes but no change with casein or fMLPL. In contrast, peripheral PMN and monocytes from chronic renal failure patients on HD showed no difference in C5a, casein or fMLPL receptors during the course of HD as compared to the predialysis period. This appears to be attributable to a difference in the regulation of the C5a that is generated as a result of the dialysis-membrane-induced activation of the complement system. Although C5a has been shown to be continuously generated during the course of HD, these patients show no modulation of their C5a receptors during the course of HD or when their whole blood is exposed to dialysis membrane fibers. These findings suggest that there are mechanisms functioning in chronically dialyzed patients to protect them from the effects of excessive C5a generation during HD.(ABSTRACT TRUNCATED AT 400 WORDS)
Cell Separation↗