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PubMed1986

Trauma serum suppresses superoxide production by normal neutrophils.

The effect of trauma serum on superoxide production by normal neutrophils was studied in 47 serum samples from 18 patients with multiple trauma. Ten patients became septic and eight patients remained nonseptic. Incubation in trauma serum significantly suppressed superoxide production by normal neutrophils compared with incubation in normal serum: 3.6 +/- 1.44 vs 4.04 +/- 1.64 nmole of superoxide produced by 10(6) neutrophils (mean +/- SD). There was no difference in the suppressive effect between septic and nonseptic trauma serum samples. The chemiluminescence response of normal neutrophils was likewise suppressed following incubation in trauma serum compared with incubation in normal serum. The chemiluminescence response correlated with superoxide reduction of cytochrome C. In addition, the chemiluminescence response was significantly less in septic-trauma serum than in nonseptic-trauma serum. Suppressive serum was found to inhibit the neutrophil-membrane depolarization response to latex particles, as measured by flow cytometry. We conclude that trauma serum suppresses superoxide production by normal neutrophils, and that such suppression can be detected reliably using the clinically applicable technique of chemiluminescence. A normal chemiluminescence response excludes serum-mediated suppression of neutrophil superoxide production. In addition, chemiluminescence may be of value in detecting altered resistance to sepsis following injury, while superoxide determinations do not seem to be helpful in this regard. The mechanism of action of the suppressor may involve reversible inhibition of membrane depolarization necessary for the production of bactericidal oxygen species.

Adolescent↗
PubMed1986

Prostaglandin and complement interaction in clinical acute respiratory failure.

This study investigated the interaction of plasma levels of circulating prostaglandins and activated complement in clinical acute respiratory failure (ARDS). Fifty patients at risk for ARDS were followed up for up to ten days. Arterial blood gases and plasma levels of complement components C3a and C5a, thromboxane B2 (TxB), and prostaglandin 6-keto-F1 alpha (PGI) and granulocyte aggregation (GA) were measured daily. Seventeen patients (34%) developed ARDS, with mortality of 41% vs 23% for patients without ARDS. Compared with patients without ARDS, the ARDS group had significantly increased plasma C3a (1,130 +/- 750 vs 636 +/- 368 ng/mL) and granulocyte aggregation (48 +/- 10 vs 17 +/- 4 percentage of the maximum light transmission [% max T]). Plasma C5a, TxB, or PGI did not change significantly with or without ARDS. No measured variable was significantly associated with mortality. Regression analysis revealed significant correlations between GA, TxB, PGI, and arterial oxygenation. Plasma C3a and GA are increased in ARDS, suggesting systemic complement activation. A complex series of interactions between the prostaglandins, complement, and GA appears to be involved in ARDS.

Acute Disease↗
PubMed1986

Leukocyte aggregation response to quantitative plasma levels of C3a and C5a.

Granulocyte aggregation (GA) response has previously been described as a sensitive assay for complement activation in sepsis. Complement component C5a has been implicated as the plasma factor responsible for GA. The quantitative interaction of complement components C3a and C5a with GA, however, is not clearly defined. This study evaluates the relationship of GA responses to plasma levels of C5a and C3a in zymosan-activated plasma (ZAP). The C3a and C5a levels were measured by radioimmunoassay in serial dilutions of ZAP. Granulocyte aggregation responses of normal human leukocytes were determined for each ZAP dilution. The C5a levels in a 1:16 dilution of ZAP were higher than in normal plasma (22 +/- 7 vs 9 +/- 3 ng/mL), as were GA responses (24 +/- 1 vs 11 +/- 2 percentage of maximum light transmission). The C3a levels in a 1:8 dilution of ZAP are elevated above those of normal plasma (656 +/- 167 vs 411 +/- 29 ng/mL). Correlation coefficients were .9809 for C3a vs GA, .9788 for C5a vs G, and .9860 for C3a vs C5a. Complement components C3a and C5a are involved in GA in vitro. Granulocyte aggregometry can detect low levels of activated complement in ZAP but may not be specific for C5a. The relative contribution of C3a and C5a to observed GA is not clear from the data.

Cell Aggregation↗
PubMed1987

Complement-mediated neutrophil activation in sepsis- and trauma-related adult respiratory distress syndrome. Clarification with radioaerosol lung scans.

Complement-mediated neutrophil activation (CMNA) has been proposed as an important pathogenic mechanism causing acute microvascular lung injury in the adult respiratory distress syndrome (ARDS). To clarify the relationship between CMNA and evolving lung injury, we studied 26 patients with multiple trauma and sepsis within 24 hours of risk establishment for ARDS. Pulmonary alveolar-capillary permeability (PACP) was quantified as the clearance rate of a particulate radioaerosol. Seventeen patients (65%) had increased PACP (six developed ARDS) while nine (35%) had normal PACP (none developed ARDS; clearance rates of 3.4%/min and 1.5%/min, respectively). These patients, regardless of evidence of early lung injury, had elevated plasma C3adesArg levels and neutrophil chemotactic desensitization to C5a/C5adesArg. Plasma C3adesArg levels correlated weakly, but significantly, with PACP. Thus, CMNA may be a necessary, but not a sufficient, pathogenic mechanism in the evolution of ARDS.

Adult↗
PubMed1988

Terminal complement complexes and anaphylatoxins in septic and ischemic patients.

Terminal complement complex (TCC) and anaphylatoxin formation in 18 patients with sepsis and 20 patients with acute limb ischemia were studied before the start of treatment and seven days later. The septic or ischemic patients had elevated levels of plasma TCC before start of therapy. In successfully treated patients these concentrations were within the normal range one week later. Similarly, the plasma anaphylatoxin level was increased before therapy and returned to the normal range within seven days. Escherichia coli incubated in vitro in fresh human serum at body temperature started formation of TCC in a dose-related manner. As complement will induce cellular lysis via TCC and edema via anaphylatoxins, anemia and impaired respiration in these patients may be influenced by increased concentrations of terminal complement complexes and of C3a and C5a.

Aged↗
PubMed1988

Effects of cardiopulmonary bypass on pulmonary leukostasis and complement activation.

We measured white blood cell counts and complement component (C3a, C4a, and C5a) and prostacyclin levels, and studied lung biopsy specimens, in 16 patients undergoing cardiopulmonary bypass and compared them with four patients undergoing other pulmonary procedures. Bypass caused no significant elevation in peripheral venous white blood cell counts. Higher counts were present in the right atrium compared with the left atrium. Patients who underwent bypass had elevated complement component and prostacyclin concentrations before operation and these levels increased further during operation. Trapping of polymorphonuclear leukocytes occurred in pulmonary alveolar capillaries and venules after bypass. We conclude that bypass activates complement components primarily of the alternative pathway and leads to increased blood prostacyclin levels. These changes are accompanied by polymorphonuclear leukocyte accumulation in the lungs and may be important in initiation of the adult respiratory distress syndrome in these patients.

6-Ketoprostaglandin F1 alpha↗
PubMed1984

Migration of porcine endothelial and smooth muscle cells in response to platelet-associated factors.

A NeuroProbe multiwell microchemotaxis assembly has been used to study the migration of porcine aortic endothelial and smooth muscle cells in vitro in response to serum factors. Whole pig serum was found to be chemokinetic for endothelial cells but not smooth muscle cells. Chemokinetic activity was higher in platelet-enriched, plasma-derived serum (PDS) than in platelet-free PDS. The supernatant from washed, lysed pig platelets also showed chemokinetic activity both for endothelial and smooth muscle cells. Chromatography on Sephadex G-200 showed that the lysate contained a number of activities that act independently on the two cell types. The chemokinetic activity that we have detected appears to be distinct from the chemotactic effect of platelet-derived growth factor and platelet factor 4 on the basis of insensitivity to protamine sulfate and molecular size. The role of these platelet factors in pathological changes in vascular structure is currently under study.

Animals↗
PubMed1985

Elevated C3 anaphylatoxin levels in synovial fluids from patients with rheumatoid arthritis.

Because cleavage products of the third component of complement augment inflammation and may contribute to arthritis, we used a competitive inhibition radioimmunoassay to measure levels of the low molecular weight cleavage products of the third component of complement, C3a and C3adesArg, in 72 synovial fluid samples. Mean levels of C3a/C3adesArg were more than sevenfold higher in 41 patients who had rheumatoid arthritis than in 15 patients who had degenerative joint disease or 5 patients who had traumatic arthritis. Striking elevations were also present in 2 patients who had acute gouty arthritis. A calculation of the fraction of intraarticular C3 cleaved showed that the patients with rheumatoid arthritis had a mean C3 cleavage of 11.6 +/- 11.0%, which was significantly higher than values of less than 1.5% for patients with degenerative joint disease or traumatic arthritis. In rheumatoid arthritis and gouty arthritis, specific immunoassay identified substantial quantities of the initial C3 cleavage fragments.

Arthritis, Rheumatoid↗
PubMed1986

Complement activation during systemic lupus erythematosus. C3a and C5a anaphylatoxins circulate during exacerbations of disease.

To determine whether activated complement components appear in the circulation of patients with systemic lupus erythematosus (SLE), we measured C5a and C3a by radioimmunoassay. Mean C5a concentration in the plasma of acutely ill SLE patients was 46.0 ng/ml, compared with 17.1 ng/ml in normal controls (P less than 0.01). Mean C3a concentration in patients with severe disease was 526 ng/ml, compared with 134 ng/ml in controls (P less than 0.01). In patients with moderately active SLE, the mean C3a concentration, but not the mean C5a concentration, was also elevated. In addition, C3a was elevated in 15 or 21 patients with active SLE, whereas low levels of C3 or C4 were noted in only 7 of these 21 patients. We conclude that the measurement of complement-derived anaphylatoxins may be useful in the management of patients with SLE. In addition, we suggest that these circulating mediators may contribute to the pathogenesis of vascular injury in patients with the disease.

Complement Activation↗
PubMed1988

Increased levels of plasma anaphylatoxins in systemic lupus erythematosus predict flares of the disease and may elicit vascular injury in lupus cerebritis.

We measured levels of complement anaphylatoxin split products, C3a and C5a, in the circulation of patients with systemic lupus erythematosus (SLE). In 23 SLE patients who were followed serially, the mean C3a value was 179 ng/ml during stable disease and 550 ng/ml during a disease flare. In 10 patients, C3a levels predicted disease activity, with the C3a value rising from a mean of 183 ng/ml at a time of stable disease to a mean of 242 ng/ml 1-2 months prior to a clinical exacerbation of disease. The mean C3a level in 5 patients with acute dysfunction of the central nervous system (CNS) was 1,297 ng/ml, which is significantly higher than that observed in patients with active disease but without CNS involvement (P less than 0.01). C5a levels were also significantly elevated in 4 patients with acute CNS disease. Pathologic specimens from 2 patients who died during an acute lupus flare revealed neutrophils occluding the cerebral and intestinal vessels. Fluorescein angiography in a patient with CNS lupus revealed vasoocclusive retinopathy. In 5 of 7 SLE patients who were pregnant, C3a levels were elevated, with a group mean value of 310 ng/ml. There was a negative correlation (r = -0.59) between C3a and C3 levels in pregnant patients with SLE, and this finding is consistent with complement activation as the cause of decreasing C3 levels. We suggest that serial measurements of C3a can predict flares of disease in lupus patients and can demonstrate complement activation during pregnancy in women with SLE. In addition, release of C3a and C5a (mediators of inflammation) into the circulation may elicit vascular injury, particularly in patients with lupus cerebritis.

Anaphylatoxins↗
PubMed1987

The ischaemic leg as a source of complement activation.

Complement activation before and after surgical resection was studied in 40 patients with ischaemic legs (17 with acute and 23 with chronic ischaemia). Plasma anaphylatoxin concentrations (C3a and C5a) and anaphylatoxin inhibitor (AI) activity were studied pre-operatively, and 1 h, 24 h and 1 week postoperatively. Increased plasma anaphylatoxin concentrations were found pre-operatively. Anaphylatoxin levels in plasma had returned to normal one week postoperatively. Patients with acute ischaemia had higher plasma C3a and C5a pre-operatively and during the first 24 h postoperatively than patients with chronic ischaemia. Anaphylatoxins increase vascular permeability, smooth muscle contraction and histamine release from mast cells. Their enhanced activity might be one of the explanations for respiratory, hepatic and renal insufficiency before surgical resection in patients with extensive ischaemia.

Aged↗
PubMed1985

The selective localization of B lymphocytes in the spleen and the role of complement receptors.

The role of complement receptors on the localization of T and B cells in the spleen of mice was studied using short-term homing experiments in cobra venom factor (CoF)-treated animals. The localization ratio of B and T cells in the spleen of CoF-treated mice decreased significantly compared to control recipients. No changes could be found in the relative distribution of resident T and B cells in the spleen or other lymphoid organs of CoF-treated animals and when their spleen or lymph node cells were transferred, the localization pattern was normal. When cells were incubated in serum prior to transfer a disturbed localization ratio in the spleen of untreated recipients was observed. This was due to a blockade of complement receptors as determined by the inability of the incubated cells to form EAC rosettes. No blockade of EAC rosettes and no changes in localization ratios upon transfer could be observed when the cells were incubated in functionally C3-depleted serum. The results suggest a role for the complement-receptor on B cells in the initial localization in the spleen, whereas no influence upon the selective localization in high endothelial venules-bearing organs was found.

Animals↗
PubMed1987

Modulation of neutrophil expression of C3b receptors (CR1) by soluble monomeric human C3b.

Upon incubation at 37 degrees C with purified human C3b (500 micrograms/ml), polymorphonuclear neutrophils (PMN) were found to express up to 50% more C3b receptors (CR1) than PMN incubated with buffer alone. This up-regulation of CR1, assessed by the binding of radiolabeled CR1-specific monoclonal antibody, was dependent on the dose of C3b, occurred within 10-20 min and was stable for at least 90 min. PMN incubated with C3b also demonstrated enhanced CR1-dependent binding functions, such as EC3b rosette formation and phagocytosis of EIgGC3b particles. C3b at a concentration of 500 micrograms/ml induced up to 90% increase in the attachment or the phagocytic index. However, CR1 remained unable to promote phagocytosis of EC3b intermediates. Fc receptor-mediated functions were unaffected by the treatment with C3b. The active factor was characterized as monomeric C3b and, in particular, shown to be distinct from C5a. C3b purified by anion-exchange fast protein liquid chromatography on a Mono Q column or eluted from a monoclonal anti-C3b-Sepharose retained its modulating activity, while native C3 or C3 fragments such as iC3b, C3c or C3d,g were ineffective.

Antibodies, Monoclonal↗
PubMed1991

Chronic experimental autoimmune encephalomyelitis induced by the 89-101 myelin basic protein peptide in B10RIII (H-2r) mice.

Development of experimental allergic encephalomyelitis (EAE) in the SJL (H-2s) mice is associated with a T cell-dependent autoimmune response to the C-terminal part of the myelin basic protein (MBP). In this study the influence of both H-2 and non-H-2 genetic background on EAE induced with the MBP89-101 peptide is described. Analysis of different H-2q haplotype strains, B10G, B10Q, SWR and NFR/N, showed that the B10 background is relatively resistant to disease induction. Both SWR and NFR/N were susceptible to EAE showing that the H-2q haplotype is permissive for EAE development induced with MBP89-101 and that the T cell receptor (TcR) haplotype or complement C5 deficiency exert no significant influence on disease susceptibility. In a series of H-2-congenic strains on the B10 background only B10RIII (H-2r) mice were susceptible to EAE. The B10RIII mice developed a severe EAE with early onset and chronic progressive or relapsing course of disease. In addition, B10RIII mice treated with Freund's complete adjuvant and pertussis toxin alone showed an early monophasic disease. The clinical observations were confirmed by immunohistopathologic analysis of the central nervous system. In these studies, we also applied antibodies to different TcR V beta elements which showed no specific limitation of the used TcR among infiltrating T cells in the target tissue in any of the strains. It is concluded that an MBP peptide-specific disease can be induced in three different haplotypes and it is possible that shared structures between the As, Aq and Ar molecules are of importance for the trigger of encephalitogenic T cells with different TcR V elements. The presently described chronic EAE model induced in the B10RIII mice will be of value as a model for multiple sclerosis.

Adjuvants, Immunologic↗
PubMedDate not supplied

Elevation of chemotactic factor inactivator in alcoholic liver disease.

Defective regulation of neutrophil chemotaxis occurs in patients with alcoholic liver disease. One potent mediator of neutrophil chemotaxis is the complement-derived neutrophil chemoattractant, C5a, which can be inhibited by a serum protein, chemotactic factor inactivator. We hypothesized that chemotactic factor inactivator elevation might, in part, explain the defective neutrophil chemotaxis seen in patients with alcoholic hepatitis. To test this hypothesis, sera were collected from 22 patients with alcoholic hepatitis and 9 normal controls, and evaluated for the antigenic presence of chemotactic factor inactivator using an ELISA test. Chemotactic factor inactivator levels were found to be markedly elevated in patients with alcoholic hepatitis (162 +/- 24 micrograms per ml) compared to normals (60 +/- 3 micrograms per ml, p less than 0.01). Subdividing the hepatitis patients revealed that the elevation of chemotactic factor inactivator was found to be greatest in those patients with mild alcoholic hepatitis (prothrombin time within normal limits and bilirubin less than or equal to 5 mg per dl, 256 +/- 44 micrograms per ml, p less than 0.001), while the group with the severest hepatic dysfunction (prolonged prothrombin time and bilirubin greater than 5 mg per dl) did not differ significantly from controls (71 +/- 11 micrograms/ml, p less than 0.2). Importantly, the inhibition of C5a-induced chemotactic activity by partially purified chemotactic factor inactivator correlated with antigenic amounts of chemotactic factor inactivator in serum (r = 0.63, p less than 0.05). The C5a inhibitory activity in sera obtained from patients with alcoholic hepatitis coprecipitated with chemotactic factor inactivator when serum was precipitated by ammonium sulfate precipitation (45 to 64% saturation).(ABSTRACT TRUNCATED AT 250 WORDS)

Aminopeptidases↗
PubMed1985

Effect of leukocyte activation on the formation of heterotypic tumor-cell aggregates in vitro.

Walker tumor cell (1 x 10(6) cells/ml) were incubated at 37 degrees C in a stirred cuvette with rat peritoneal exudate cells (9 x 10(6) cells/ml) with or without the synthetic leukocyte chemo-attractant fMLP (2 x 10(6) M) or biologically active concentrations of the major endogenous chemo-attractant, C5a. Aggregation, induced by the chemo-attractants, was detected after 3 min by a platelet aggregometer and by studying cytocentrifuge preparations. The response was amplified in the presence of cytochalasin B (5 micrograms/ml). Tumor cells could be identified in the aggregates by their morphology or by autoradiography after labeling with 3H-thymidine. Although tumor cells were incorporated into the leukocyte aggregates, there was no appreciable change in the number of aggregates formed between tumor cells themselves. Levine III human breast tumor cells (1 x 10(6)/ml) in heparinized human blood were incorporated into leukocyte aggregates within 30 min of adding 50 U cobra venom factor to activate complement. Aggregation correlated with a decrease in complement hemolytic activity (CH50). The aggregation reaction was not cytotoxic to tumor cells when evaluated by Trypan blue exclusion or by 51Cr release. We conclude that local tumor cells can be incorporated into aggregates formed when leukocytes are stimulated by chemo-attractants. We postulate that intravascular activation of neutrophils might affect the localization of circulating tumor cells by incorporating them into microembolic cell aggregates and by causing damage to the pulmonary endothelium.

Animals↗
PubMed1988

Serotherapy of cancer: cellular changes in primary rat mammary carcinomas after infusion of syngeneic sera absorbed with protein A-Sepharose.

Serotherapy and plasma therapy have proved to be effective in the treatment of diverse neoplasms. The mechanisms of the tumoricidal or growth-inhibitory effects are unknown. We previously reported that activation of the alternative pathway of complement in absorbed sera correlated with the presence of anti-tumor activity. Complement components generated during absorption may serve as the initial mediators of cytotoxicity; for example, C5a may function in its role as a chemo-attractant. To further investigate the anti-tumor mechanisms, we undertook a series of sequential histological studies of in vivo changes in tumors following i.v. serotherapy. We found diffuse inflammatory cellular infiltrates in the interstitial compartments of primary mammary carcinomas of rats within 3-4 hr of administration of protein A-Sepharose absorbed syngeneic serum. The number of inflammatory cells was significantly higher in tumors from treated rats: total infiltrating cells (p = 0.002), eosinophils (p = 0.001), neutrophils (p = 0.001), macrophages (p = 0.001), lymphocytes (p = 0.004) and plasma cells (p = 0.001). Also, the mitotic index of tumor cells was significantly lower 4 hr after serotherapy when compared with that of untreated rat tumor cells. C3 in tumor tissue was decreased at 4 hr following serotherapy. Fibrosis was present in tumor nodules with retarded growth 5 weeks after the start of serotherapy. Localization of the infiltrating cells to tumor interstitial compartments prevents direct contact between inflammatory cells and neoplastic cells, making it unlikely that direct cell-cell killing occurs. Indirect cell killing within the tumor bed apparently occurs through several mechanisms involving interactions between serotherapy-initiated humoral mediators and inflammatory cells. The resulting anti-tumor effects include microvascular injury leading to localized ischemia, tumor infarction, and fibroblastic reactions obstructing tumor invasion and growth.

Animals↗