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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↗
PubMed2004

The role of the complement system in ischemia-reperfusion injury.

Ischemia-reperfusion (I/R) injury is a common clinical event with the potential to seriously affect, and sometimes kill, the patient. Interruption of blood supply causes ischemia, which rapidly damages metabolically active tissues. Paradoxically, restoration of blood flow to the ischemic tissues initiates a cascade of pathology that leads to additional cell or tissue injury. I/R is a potent inducer of complement activation that results in the production of a number of inflammatory mediators. The use of specific inhibitors to block complement activation has been shown to prevent local tissue injury after I/R. Clinical and experimental studies in gut, kidney, limb, and liver have shown that I/R results in local activation of the complement system and leads to the production of the complement factors C3a, C5a, and the membrane attack complex. The novel inhibitors of complement products may find wide clinical application because there are no effective drug therapies currently available to treat I/R injuries.

Animals↗
PubMed1985

Multifunctional inhibition by anthralin in nonstimulated and chemotactic factor stimulated human neutrophils.

Treatment of human polymorphonuclear leukocytes (PMN) with anthralin (0.2-50 micrograms/ml) results in dose-dependent inhibition of nondirected as well as directed migration (chemotaxis) against the synthetic tripeptide N-formyl-methionyl-leucyl-phenylalanine (FMLP), the complement fragment C5a and leukotriene B4. Polymorphonuclear leukocytes (PMN) pretreated with anthralin at concentrations which inhibit cell motility also show a dose-dependent inhibition of superoxide anion generation. In contrast to anthralin two derivatives (danthrone and anthralin dimer) were ineffective. Specific binding of [3H]FMLP to neutrophil membrane receptors was impaired by anthralin at concentrations 5-10 fold higher than those which were inhibitory for cell function. Release of beta-glucuronidase from azurophilic (lysosomal) granules provoked by various chemotaxins in the presence of cytochalasin B was not affected by anthralin over a wide range of concentrations. Also there were no signs of cytotoxicity e.g., leakage of cytoplasmatic lactate dehydrogenase (LDH) caused by anthralin, These data indicate that neutrophil functions may become substantially altered by anthralin. The effective dosages correspond to concentrations obtained in vivo after local application. Danthrone as well as anthralin dimer, known to be clinically ineffective, showed no effects upon PMN function. It is suggested that anthralin via a free radical mechanism alters sensitive sites at or in the cellular membrane including receptors.

Anthracenes↗
PubMed1985

Transient absence of C5a-specific neutrophil function in inflammatory disorders of the skin.

Chemotactic migration, production of superoxide anion (O2-), and the release of beta-glucuronidase from azurophilic granules were determined in polymorphonuclear leukocytes (PMN) from 135 patients with infectious (e.g., pyoderma, acne conglobata, erysipelas) as well as noninfectious (psoriasis) skin diseases. Purified C5a and the formylated tripeptide FMLP were used as stimuli. In addition, longitudinal profiles of PMN activities were performed at daily intervals in several patients. There was a complete absence of PMN responses (chemotaxis, O2--production, and enzyme release) specifically induced by C5a in 25 patients suffering from various inflammatory diseases of the skin. In these patients PMN responsiveness for the tripeptide FMLP was either normal or increased. The C5a-dependent defect of PMN was transient and correlated with disease activity. When normal PMN were incubated with sera from C5a-defective patients, no inherent stimulatory or inhibitory activities compared to control sera were seen. Pretreatment of normal PMN in vitro with various concentrations of C5a failed to completely deactivate PMN without affecting FMLP dependent functions. These observations demonstrate the presence of a functional defect in circulating PMN during acute cutaneous inflammation. The in vitro experiments suggest transient blocking of C5a-dependent PMN functions by a cell-bound factor which seems not to be C5a or C5adesarg.

Acne Vulgaris↗
PubMed1989

Analysis of the interaction of human C5a and C5a des Arg with human monocytes and neutrophils: flow cytometric and chemotaxis studies.

C5a and C5a des Arg are potent complement-derived mediators that bind receptors on peripheral blood leukocytes and tissue-specific cellular elements to elicit and amplify inflammatory and immunomodulatory reactions. To study the interactions of C5a and C5a des Arg with these cells, fluorescein conjugates of these ligands were prepared by a new technique and their binding to monocytes, neutrophils, platelets, and endothelial cells was studied with flow cytometry. Fluoresceinated C5a produced neutrophil myeloperoxidase release and chemotaxis and also bound rabbit anti-C5a antibody much like native anaphylatoxin; likewise, fluoresceinated C5a des Arg demonstrated retention of biologic and antigenic activities. Both fluorescein-conjugated C5a and C5a des Arg bound to monocytes and neutrophils in a concentration-dependent, saturable, and homogeneous manner, but 10- to 15-fold higher concentrations of C5a des Arg were required to attain saturable binding of these leukocytes. Ligand binding was specifically inhibited by native purified human C5a in a concentration-dependent manner, while it was unaffected by C3a or N-formyl-methionyl-leucyl-phenylalanine-lysine. There was no evidence of a C5a receptor-negative subpopulation of monocytes or neutrophils. Moreover, comparative binding experiments with leukocytes from multiple normal volunteers showed that a greater percentage of monocytes than neutrophils bound C5a at less than saturable concentrations of ligand (P less than 0.05, 0.5 to 5.0 nM). A representative half-maximal binding of fluorescein-conjugated C5a (C5a des Arg) binding to monocytes and neutrophils was 1.2 nM (30 nM) and 2.6 nM (68 nM), respectively. In contrast, fluorescein-conjugated C5a did not specifically bind to human platelets or umbilical vein endothelial cells.

Blood Platelets↗
PubMed1984

Activation of the alternative complement pathway by Fonsecaea pedrosoi.

Human sera were examined for evidence of complement activation by Fonsecaea pedrosoi. The serum that had been incubated with F. pedrosoi showed immunoelectrophoretic C3 conversion and generation of C5a, as measured by radioimmunoassay. C3 conversion and C5a generation did not occur in serum chelated with EDTA, or in serum heated to 56 degrees C for 30 min. Serum depleted of the heat (50 degrees C X 30 min)-labile factor B was also deficient in C3 conversion and C5a generation. Complement activation was not affected when the classical pathway was blocked by Mg++-EGTA. These studies indicate that F. pedrosoi can activate the complement system via the alternative pathway, with the resultant development of C5a.

Chromoblastomycosis↗
PubMed1986

Trichophyton mentagrophytes spores differ from mycelia in their ability to induce pustules and activate complement.

To determine whether the morphology of dermatophytes plays a role in the clinical manifestation of dermatophytosis, we isolated spores and mycelia from colonies of killed Trichophyton mentagrophytes and tested their ability to induce gross and microscopic cutaneous changes when applied to guinea pig skin. The skin of normal guinea pigs failed to develop any cutaneous changes after inoculation with either dead spores or mycelia. In contrast, guinea pigs that had recovered from a T. mentagrophytes infection reacted to topically applied spores by producing pustules but failed to develop pustules either grossly or microscopically when inoculated with mycelia. Because differences in the activation of C' and the subsequent generation of the polymorphonuclear leukocyte (PMN) chemoattractant, C5a, might account for our in vivo findings, we measured the amount of C5a activated in vitro when serum was incubated with equivalent amounts of spores or mycelia. Spores consistently activated more C' to C5a than mycelia, although each could activate serum C'. The results support previous studies that show a direct correlation between the clinical manifestations of a dermatophytic infection and the development of immunity against the dermatophyte. Furthermore, the data suggest that a dermatophyte's predominant morphology during an infection may play a critical role in producing pustules by activating C' and chemoattracting PMNs into the fungus-laden stratum corneum.

Animals↗
PubMed1987

Patients with bone marrow failure demonstrate decreased cutaneous reactivity to human C5a.

In vivo studies have shown that human C5a, a potent complement-derived anaphylatoxin and chemoattractant, produces immediate inflammatory reactions following intradermal injection in human skin. At concentrations within its potential physiologic range, intradermal injection of C5a elicits immediate wheal and flare reactions, increased vascular permeability, mast cell degranulation, and neutrophil-rich infiltrates. To assess the relative contribution of interacting cellular elements to C5a-induced inflammation in normal human skin, purified human C5a was tested intradermally in 8 patients with bone marrow failure (BMF). Reactions to C5a in patients with BMF were compared with responses at identical test sites in healthy volunteers and other patients with cutaneous disorders. Patients with BMF demonstrated significantly less wheal and flare reactivity following intradermal injection of C5a than controls (p less than 0.05 and less than 0.02, respectively). In these studies, patients with the greatest cytopenia generally showed the least cutaneous reactivity to human C5a. Biopsies of C5a test sites in patients with BMF revealed an absence of leukocytes in marked contrast to neutrophil-rich infiltrates observed at test sites in healthy volunteers. Avidin-fluorescent and/or Giemsa staining of skin biopsies revealed no difference between the number of dermal mast cells in patients with BMF and samples of normal human skin. In addition, skin test studies with histamine (2 micrograms) and morphine (5 micrograms) performed to assess cutaneous vascular and mast cell responsiveness in patients with BMF, normal volunteers and controls with rhinitis revealed no significant differences in cutaneous reactivity to these pharmacologic agents. These in vivo studies demonstrate that patients with BMF specifically exhibit decreased cutaneous reactivity to human C5a and suggest that neutrophils make an important and an immediate contribution to inflammatory responses elicited by this anaphylatoxin.

Adolescent↗
PubMed1987

Methotrexate inhibits the human C5a-induced skin response in patients with psoriasis.

In this study we examined the effects of intradermal injections of human complement split product C5a in 10 patients with psoriasis in long-term treatment with methotrexate (MTX). The C5a was injected at the end of the weekly MTX cycle just before the intake of the first MTX dose and 3 h after the second of the 3 doses. The C5a-induced skin response was evaluated by measuring the diameter of the wheal and the area of the flare and by erythema index (EI), which was determined objectively by reflectance spectrophotometry. In all patients the skin response was significantly depressed when C5a was injected after MTX intake. The decrease of wheal, flare, and EI averaged 61.6%, 71.1%, and 57.5%, respectively, when all parameters were obtained at maximal skin response. The in vitro chemotaxis of peripheral blood neutrophils and monocytes from the patients toward C5a was markedly inhibited after intake of MTX (p less than 0.01). The skin biopsies obtained after C5a injection before intake of MTX revealed a perivascular inflammatory infiltrate and considerable dermal edema. After MTX intake the number of infiltrating leukocytes and the degree of dermal edema was markedly reduced. This study indicates that MTX is a potent inhibitor of C5a-induced skin inflammation, and that this inhibition may be caused by a direct effect on circulating neutrophils and monocytes. The results obtained in this work support the idea that anti-inflammatory effects of MTX may be partially responsible for its antipsoriatic effect.

Adolescent↗
PubMed1986

Identification of C5ades arg and an anionic neutrophil-activating peptide (ANAP) in psoriatic scales.

Scales from patients with nonpustular psoriasis were investigated for the presence of peptides capable of activating functional activities in human polymorphonuclear leukocytes (PMNL). Two compounds with similar molecular weight (12,500 and 15,000) were isolated which markedly stimulated PMNL functional activities including chemotaxis, generation of superoxide radical anion (O-2), and liberation of beta-glucuronidase as a marker enzyme. As revealed by ion-exchange and subsequent radioimmunoassay followed by chromatofocusing, one peptide proved to be the desarginated form of the complement split product C5ades arg. No C5a was detectable. As a second psoriatic scale chemotaxin we isolated an anionic neutrophil-activating peptide (ANAP) which shows a single isoelectric point at pH 6.8. This peptide shares some of the characteristics of epidermal cell-derived thymocyte-activating factor and interleukin 1 and, as shown by deactivation experiments, it cross-reacts with a monocyte-derived cytokine. The 2 newly described neutrophil-activating peptides (C5ades arg and ANAP) may play an important role in the psoriatic tissue reaction.

Cell Movement↗
PubMed1989

Stratum corneum activation of complement through the antibody-independent alternative pathway.

We provide evidence that stratum corneum (SC) activates complement through the alternative pathway to generate C5a anaphylatoxin. By immunofluorescence studies it was shown that in addition to circulating IgG autoantibody, there were anti-SC antibodies of IgM and IgA classes in the sera from normal individuals. However, all the titers were significantly lower than the level of C3 deposition between corneocytes. By contrast, no C1q deposition occurred. Immunoelectrophoretically the orthokeratotic SC homogenates were found to induce the conversion of C3 from native C3 to C3b in fresh human serum even when the classic pathway was blocked by Ca2+-chelation. Enzyme immunoassay showed that factor B split product, Bb, was generated by the SC homogenates in the Ca2+-chelated serum. Radioimmunoassay for C5a also demonstrated that the SC homogenates could generate C5a anaphylatoxin in serum to an extent similar to that in non-treated serum when restricted to the alternative pathway activation; neutrophil chemotactic activity was generated in Ca2+-chelated serum at levels comparable to that generated in non-treated fresh serum. We separated the SC samples into a cornified envelope and soluble and keratin fractions. The cornified envelope was more effective in activating complement. This activity resided in heat-stable and non-lipid substances of corneocytes. Our hypothesis is that when the SC comes in contact with serum, it activates complement mainly through the alternative pathway to induce chemotactic C5a anaphylatoxin. Hence, inflammation in normal individuals after a traumatic injury to the skin or rupture of acne comedones, or epidermal cysts and possibly the formation of subcorneal sterile pustules noted in several dermatoses are explainable through this mechanism.

Adult↗