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PubMed1980

Host factors in the formation of abscesses.

The role of host factors in the formation of subcutaneous abscesses due to Bacteroides fragilis or Staphylococcus aureus was investigated in athymic nude mice, mice deficient in the fifth component of complement (C5D), and mice pretreated with cobra venom factor (CVF). CVF-treated mice, inoculated with B. fragilis, had abscesses 62% larger than those of control mice at day 4 (P < 0.01), but no significant difference was observed when S. aureus was used. Athymic nude mice had significantly smaller abscesses than control animals at both days 4 and 7 after inoculation with either organism. There were no differences in abscess size or in the accumulation of neutrophils at day 4 when C5D mice were compared with control animals for either organism. The results suggested that the activity of the alternative complement pathway may influence abscess size and that chemotactic factors other than the fifth component of complement can supervene in C5D mice to produce encapsulated abscesses. The absence of thymic factors did not prevent containment of abscesses.

Abscess↗
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↗
PubMed2000

Evidence for activation of the alternate complement pathway in patients with juvenile rheumatoid arthritis.

OBJECTIVE: Complement activation has been shown to occur in patients with juvenile rheumatoid arthritis (JRA). Since the two pathways of complement are activated by different stimuli (the alternate pathway by microbial products and IgA, and the classical pathway by immune complexes), we decided to study the relative contribution of the two pathways of complement activation in patients with JRA. METHODS: In 56 patients with JRA, plasma levels of C3 and C4 were measured by turbidimetric assays, and those of C4d, factor Bb and sC5-9 complex by solid-phase enzyme immunoassays. Levels beyond the mean +/- 2 S.D. of normal were considered abnormal. RESULTS: Plasma C3 and C4 levels were decreased in one patient each. The C4d values were increased in 17 patients, whereas levels of factor Bb were elevated in 42 patients and levels of sC5-9 complex were elevated in 51 patients. The values of factor Bb and sC5-9 had a linear correlation (r = 0.75), but there was no significant correlation between C4d and sC5-9 levels (r = 0.36). CONCLUSION: Complement activation in JRA is initiated predominantly by the alternate pathway and culminates in the formation of terminal membrane attack complex.

Adolescent↗
PubMed1979

Immunopathological mechanisms in rheumatoid arthritis at the dual interface of the synovial membrane: the joint cavity and the pannus.

The significance of immune responses is examined in relation to clinicopathological changes in the rheumatoid joint and the concept of a dual site of action is developed. In the joint cavity interaction between immune complexes and complement is central to the phenomena observed, which depend on the generation of chemotactic factors and the ingress of polymorphs. Other chemical mediators--e.g. prostaglandins and lymphokines--are envisaged as playing a secondary or augmentory role. At the pannus-cartilage (and bone) junction the possibility is considered that changes are due to activation of a variety of cell types which results in enzymatic degradation of collagen in cartilage, osteolastic activity in bone and prostaglandin-induced depletion of bone. The production of migration inhibition factors by rheumatoid membranes is examined and some evidence in support of their lymphokine nature is found by gel filtration; their role as cell activators is considered.

Antigen-Antibody Complex↗
PubMed1987

C5a as a mediator of cutaneous inflammation.

C5a is an 11,000-dalton fragment of the fifth component of complement with potent anaphylatoxic and leukocyte chemotactic activities. Because C5a may play an important role in selected skin disorders as well as in systemic diseases with cutaneous manifestations, we have studied the clinical and histologic alterations produced by the intradermal injection of this potent soluble mediator of inflammation in human skin in vivo. These studies have outlined the biologic properties of human C5a within the context of cells resident in the skin, the cutaneous microvasculature, and interacting cellular elements of peripheral blood.

Anaphylatoxins↗
PubMedDate not supplied

Clinical applications of complement measurements in rheumatic diseases.

There is now convincing evidence that the complement system is involved in the pathogenesis of at least some of the manifestations of human rheumatic diseases. Complement measurements in serum and/or pathologic fluids from patients with these disorders not only reflect this involvement but also may provide important clues regarding the activity and extent of the disease processes. Future studies should provide additional information concerning the usefulness of such measurements for predicting the outcome of specific therapeutic regimens, and perhaps also be the basis for the evolution of new and more rational forms of therapy.

Antigen-Antibody Reactions↗
PubMed1987

C5a and thromboxane generation associated with pulmonary vaso- and broncho-constriction during protamine reversal of heparin.

The authors conducted a study in humans to determine the mediators associated with acute pulmonary vaso- and broncho-constriction occurring episodically with protamine reversal of heparin anticoagulation. Of 48 adult patients investigated prospectively after termination of cardiopulmonary bypass, two presented a sudden increase of airway pressure, acute pulmonary hypertension, and systemic hypotension 1-3 min after right atrial protamine injection. In these two subjects, plasma levels of C5a increased from 0.7 and 2.2 to 9.8 and 9.9 ng/ml, respectively, and thromboxane B2 increased from 0.26 and 0.34 to 7.5 and 16.2 ng/ml 1 minute after drug injection. A third subject not identified prospectively had an identical reaction and mediator profile (C5a, 10.2 ng/ml; TxB2, 18.6 ng/ml at 1 min). The plasma levels of these mediators were unchanged in the remaining patients (C5a, 0.7 +/- 1.1 [x +/- S.D.] to 0.6 +/- 0.9 ng/ml; TxB2, 0.16 +/- 0.12 to 0.15 +/- 0.07 ng/ml). Plasma histamine was not involved in this type of reaction, but increased from 0.7-10.4 ng/ml in a fourth patient who became hypotensive without acute pulmonary hypertension, bronchoconstriction, or elevation of C5a or TxB2. The authors' data indicate that the generation of high plasma levels of C5a anaphylatoxins and thromboxane is associated with pulmonary vaso- and broncho-constriction induced by protamine reversal of heparin in humans.

Adult↗
PubMed2002

Neutrophil adhesion molecule expression and serum concentration of soluble adhesion molecules during and after pediatric cardiovascular surgery with or without cardiopulmonary bypass.

BACKGROUND: Increased neutrophil activation by cardiopulmonary bypass (CPB) during cardiovascular surgery is thought to be responsible for postoperative complications. In children, the contribution of cardiovascular surgery alone to this response is not well-characterized. METHODS: Children undergoing surgery with CPB (CPB group, n = 35) and without CPB (control, n = 22) were studied (age, 3-17 yr). Blood was drawn 24 h preoperatively before medication, after anesthesia, after connection to CPB, at reperfusion, 4 h to 2 days after surgery, at discharge, and months after surgery. Neutrophil antigen expression and serum concentration of adhesion molecules, interleukin 8, and C5a (fragment of C5 complement) were analyzed by flow cytometry and enzyme-linked immunosorbent assay, respectively. RESULTS: With and without CPB, anesthesia and surgery induced decreased LFA-1 (CD11a-CD18), Mac-1 (CD11b-CD18), CD45, and CD54 (intercellular adhesion molecule 1) surface expression and sICAM-1 serum concentrations (all P < 0.001). sL-selectin serum concentration decreased with CPB (P < 0.001) but was not significantly altered in the control. In contrast, CD62L expression increased during CPB (P < 0.001). The time course of all analyzed markers was not significantly different between CPB and control, with the exception of sL-selectin (P = 0.017). One-day preoperative baseline values were reached days to months after surgery. Interleukin 8 and C5a serum concentrations increased after surgery in both the CPB group and the control group. CONCLUSIONS: Pediatric cardiovascular surgery leads to reduced adhesiveness and activity of circulating neutrophils. This reduction is more pronounced and sustained with CPB. These data may be useful in the assessment of novel therapeutic strategies.

Adolescent↗
PubMed1984

Regulation of neutrophil migratory function in burn injury by complement activation products.

Polymorphonuclear neutrophils were isolated from patients with burn injury and random mobility, chemotaxis in response to C5adesArg (as agarose-activated control serum) and to N-formyl-methionyl-leucyl-phenylalanine (F-Met-Leu-Phe) were assessed. For a group of eight patients identified as not experiencing systemic infection, all three neutrophil migratory functions were observed to fall below control levels, beginning 4 to 6 days following burn injury, and to return to control levels after 21 to 30 days of hospitalization. Over this time the chemotactic differential (distance chemotactic migration-distance random migration) for F-Met-Leu-Phe remained positive, while the chemotactic differential for activated serum became nil after postburn day 4. This temporal, specific loss of a chemotactic response to activated serum was associated with rises in immunoreactive plasma C3a and C5a. This pattern of loss of chemotactic function was associated with a selective loss of C5a but not F-Met-Leu-Phe binding activity. These results demonstrate that burn injury can alter neutrophil migratory functions generally, and specifically depress chemotactic responsiveness to activated serum. The mechanism of the latter phenomenon appears to be related to desensitization of circulating neutrophils to C5a due to complement activation.

Adolescent↗
PubMed1988

The effects of complement activation during cardiopulmonary bypass. Attenuation by hypothermia, heparin, and hemodilution.

Complement activation was examined prospectively in 100 cardiopulmonary bypass (CPB) patients. Plasma C3a desArg (C3a) increased (cannulation: 234 +/- 33 ng/mL; 20 minutes on CPB: 622 +/- 51; 2 hours after CPB: 1143 +/- 109, p less than 0.0001). C3a at 2 hours was higher in the 13 patients requiring mechanical ventilation for longer than 1 day (1023 +/- 274) than in the 67 without respiratory complication (568 +/- 45, p less than 0.004). Five more patients were studied for neutrophil activation to confirm that a biologic effect of complement activation occurs during CPB; in these five patients C3a increased to 317% of baseline after 10 minutes on CPB with a corresponding rise in neutrophil cell surface receptors for the complement opsonin C3b (as measured by indirect immunofluorescence) to 168% (p less than 0.05). Both increases were sustained at 30 minutes. Temperature, dilution, and heparin were studied as variables relevant to CPB. Exposure of normal neutrophils to C5a in vitro caused an increase in C3b receptors which was dependent on temperature (0 specific fluorescence at 0 C, 30 at 25 C, 180 at 30 C, and 275 at 37 C). Generation of C3a and C5a in normal serum by zymosan was also temperature-dependent (ng/mL C5a generated: 0.7 at 25 C, 200 at 30 C, and 897 at 37 C; ng/mL C3a generated: 546 at 25 C, 10,872 at 30 C, and 65,667 at 37 C). Serum dilution to 33% decreased ng/mL C5a generated in the same system from 200 to 76 with no effect on C3a. Addition of heparin to 20 U/mL decreased ng/mL C3a generated from 10,872 to 913 and C5a from 200 to 8. Thus, hypothermia, dilution, and heparin protect CPB patients from complement activation by reducing both generation of C3a/C5a and the subsequent cellular response of neutrophil activation.

Cardiopulmonary Bypass↗
PubMed1985

Quantitative analysis of polymorphonuclear leukocyte superoxide anion generation in critically ill children.

Apart from its well-known bactericidal action, superoxide anion produced by activated polymorphonuclear leukocytes is believed to be involved in pathophysiology of diffuse capillary leak syndromes, e.g., adult respiratory distress syndrome and septic shock. Neutrophil NADPH oxidoreductase, the superoxide anion synthetase, was assayed in blood samples from a variety of critically ill children. Neutrophils from patients with evidence of diffuse capillary leak syndrome had significantly depressed enzyme specific activity as compared to neutrophils from healthy controls or intensive care patients without evidence of diffuse capillary leak. These data along with additional in vitro findings support the contention that previously activated granulocytes may be refractory to subsequent activation, and that such behavior may represent an intrinsic defense mechanism to minimize inflammatory amplification autoinjury.

Adolescent↗
PubMed1986

The effect of trauma on serum C3 activation and its correlation with injury severity score in man.

The sera of 12 patients with mechanical trauma were studied to determine C3 levels and activation. The injury severity score (ISS) was then related to serum C3 levels and activation. It was found that in the immediate postinjury period, serum C3 activation occurred in cases where ISS was greater than or equal to 12. The mean ISS of patients with complement activation was 25.2. In comparison, in patients with nonactivation of complement, the mean ISS was 9.5 (p less than 0.05). Serum C3 levels were inversely related to ISS. The mean serum C3 level of patients with ISS greater than or equal to 12 was 73.3 mg% and mean serum C3 level with ISS less than 12 was 109.4 mg%. This difference was again statistically significant (p less than 0.05). There is indication that complement depletion occurs in the immediate postinjury period in moderate to severe injury (ISS greater than or equal to 12). This finding could explain, in part, the immunosuppressive effect of trauma and can be used as a marker to predict possible septic complications.

Adult↗
PubMed1988

Complement and the severity of pulmonary failure.

Complement-induced granulocyte aggregation is suspected as a cause of the adult respiratory distress syndrome. Quantifying the lung damage in these patients is difficult, and complement levels combined with clinical parameters of oxygenation might help define the severity of pulmonary deterioration. Forty-five high-risk patients, selected by arterial blood gas criteria, had their pulmonary insult related to C3a and C5a levels. Patients were stratified by pulmonary shunt, alveolar-arterial oxygen gradient, and radiographic findings into two categories of severity: pulmonary dysfunction, a milder insult, and ARDS, a major aberration in pulmonary function. The clinical assignment of a diagnostic category required at least 96 hours of monitoring. During this 96-hour period, multiple complement levels were obtained. These complement levels were then compared in pulmonary dysfunction and ARDS patients. ARDS patients had significantly higher C3a and C5a values after the patients were selected as high risk. These results suggest that the amount of complement activated in patients with incipient respiratory failure correlates with the severity of eventual pulmonary insult. The use of arterial blood gases and C3a and C5a levels should allow better and earlier definition of patients at risk for ARDS.

Adult↗
PubMed2001

Complement activation products in plasma after heart transplantation in humans.

BACKGROUND: Complement activation has recently been implicated as a contributing factor to early and late allograft dysfunction in cardiac transplantation. The current study was designed to determine whether measurement of plasma complement fragments C4d and SC5b-9 would be useful in detecting acute rejection or accelerated graft atherosclerosis (AGA) in cardiac allograft recipients. METHODS: We measured complement activation products, C4d (classical pathway) and SC5b-9 (terminal pathway), at the time of routine endomyocardial biopsy in heart transplant recipients. Ten patients in the immediate posttransplantation period (0-100 days) and 19 patients more than 6 months after transplantation were studied. RESULTS: No correlation was found between plasma levels of complement activation fragments and the presence of biopsy-proven acute allograft rejection or AGA (assessed by coronary angiography). However, plasma C4d and SC5b-9 were significantly elevated in 9 of 10 and 7 of 10 patients, respectively, in the immediate posttransplantation period. This was followed by progressive decrease in the levels of C4d and SC5b-9 fragments during the first 4-6 weeks after transplantation. CONCLUSION: We conclude that measuring plasma levels of fragments C4d and SC5b-9 is not a useful noninvasive method for detecting acute rejection or AGA after heart transplantation. However, this study provides further evidence that early complement activation after heart transplantation may play a pathogenic role in allograft injury.

Complement Activation↗