Inhibition of complement, neutrophil, and platelet activation by an anti-factor D monoclonal antibody in simulated cardiopulmonary bypass circuits

Fung, Michael; Loubser, Paul G.; Ündar, Akif; Mueller, M.; Sun, Chengyu; Sun, William N.C.; Vaughn, William K.; Fraser, Charles D.

doi:10.1067/mtc.2001.114777

Cited by 79 publications

(58 citation statements)

References 53 publications

(99 reference statements)

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“…Thus, this antibody preneutralizes C5a and thereby blocks its biologic effects before it is released. The anti-factor D antibody is highly specific for factor D of the alternative complement pathway as documented in detail previously (13,14).…”

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confidence: 82%

Complement C5a Is a Key Mediator of Meconium-Induced Neutrophil Activation

Castellheim

Pharo

Fung³

et al. 2005

Pediatr Res

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Meconium aspiration syndrome is a serious condition of the newborn characterized by pulmonary inflammation with substantial neutrophil infiltration. We recently showed that meconium is a potent activator of complement. The aim of the present study was to investigate a possible role for complement in meconiuminduced neutrophil activation. Meconium was incubated in human whole blood anticoagulated with lepirudin, a specific thrombin inhibitor that does not affect complement activation. Complement activation was detected by measuring the terminal complement complex. Neutrophil oxidative burst and changes in CD11b and L-selectin expression were measured by flow cytometry. Complement was inhibited using the MAb 166-32 and 137-26, which block factor D and neutralize C5a, respectively. Meconium markedly activated the neutrophils, as revealed by up-regulation of CD11b, accentuation of L-selectin shedding, and induction of oxidative burst. Complement inhibition using the anti-factor D antibody completely (95-100%) blocked meconium-induced changes in CD11b and L-selectin expression, whereas oxidative burst was reduced by 60 -70%. The anti-C5a antibody inhibited the neutrophil activation to the same extent as anti-factor D. The data suggest that complement activation is largely responsible for the neutrophil inflammatory responses induced by meconium in vitro and that C5a is a key mediator of this response. Abbreviations ARDS, acute respiratory distress syndrome AU, arbitrary units DHR, dihydrorhodamine LPS, lipopolysaccharide MAS, meconium aspiration syndrome MFI, median fluorescence intensity PE, phycoerythrin PMA, phorbol-12-␤-myristat-13-␣-acetate TCC, terminal SC5b-9 complement complex Meconium aspiration syndrome (MAS) may cause a profound lung inflammation similar to acute respiratory distress syndrome (ARDS). A substantial increase in neutrophils in the airways; increased levels of inflammatory cytokines, eicosanoids, superoxide anions, and endothelin-1; expression of inducible nitric oxide synthase and cyclooxygenase-2; and activation of nuclear factor-B have been described in MAS (1-8). A profound inflammatory response and the release of leukocyte cytotoxic products have an important role in initiation and propagation of lung injury in ARDS, in which neutrophils and their cytotoxic products play a crucial role (9).The complement system is a key mediator of inflammation. Complement-mediated activation of neutrophils and monocytes leads to cytokine production; release of lipid mediators and histamine; oxidative burst; and altered expression of adhesion molecules, including increased expression of CD11b and shedding, revealed as decreased expression of CD62L. We showed recently that meconium is a potent activator of the alternative complement pathway in vitro (10). To study the interaction between all participating inflammatory systems, we used an in vitro human whole-blood model that is based on the use of lepirudin, a thrombin-specific anticoagulant that does not interfere with complement activation (11). We hypot...

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mentioning

confidence: 82%

Complement C5a Is a Key Mediator of Meconium-Induced Neutrophil Activation

Castellheim

Pharo

Fung³

et al. 2005

Pediatr Res

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“…Unknown ESTs shown here but not in Table 3 tions of liver adipsin mRNA, involved ICAM-1-deficient mice on a high-fat Western diet (16) and agreed with our findings here. As the rate-limiting enzyme of alternative complement pathway activation (14), factor D is potentially a therapeutic target for reducing vascular inflammation/ lesion progression (14).…”

Section: Liver Gene Expression In Atherosclerosis-prone Micementioning

confidence: 99%

Liver gene expression associated with diet and lesion development in atherosclerosis-prone mice: induction of components of alternative complement pathway

Recinos

Carr

Bartos

et al. 2004

Physiological Genomics

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“…(18). Anti-mannosebinding lectin (MBL; mAb HYB 131-01) was purchased from Antibody Shop (Copenhagen, Denmark).…”

Section: Antibodiesmentioning

confidence: 99%

Meconium Is a Potent Activator of Complement in Human Serum and in Piglets

et al. 2004

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Meconium aspiration syndrome (MAS) is a clinical condition in the newborn infant with a significant morbidity and mortality. The complex pathophysiology of MAS, leading to both pulmonary and systemic complications, is characterized by an incompletely understood inflammatory reaction. Treatment is symptomatic, mainly limited to airway cleaning and ventilatory support. In this study, we show for the first time that meconium is a potent activator of complement, a key mediator of inflammation. In vitro, meconium activated the alternative complement pathway in human umbilical cord serum as judged by a substantial increase in the alternative pathway convertase C3bBbP. The activation proceeded through C3 (C3bc) and the terminal C5-9 pathway (terminal SC5b-9 complement complex), whereas the classical and lectin pathways were not activated (C1rs-C1-inhibitor complexes and C4bc). The lipid fraction, containing, e.g. free fatty acids, and the water fraction, containing, e.g. bile acids, contributed equally to the complement activation. A blocking antibody to factor D (alternative pathway) completely inhibited the meconium-induced complement activation, whereas blocking antibodies to mannose-binding lectin (lectin pathway) and C2 (classical and lectin pathway) had no effect. In vivo, meconium induced systemic complement activation in a piglet model of MAS, paralleling the increase in lung dysfunction. In conclusion, meconium is a potent activator of the complement system both in vitro and in vivo. Complement may be important in the pathogenesis of MAS, and specific complement inhibition might be a possible treatment approach in MAS. The aspiration of meconium-stained amniotic fluid (MSAF) in the newborn can lead to meconium aspiration syndrome (MAS), which is a clinical syndrome with significant morbidity and mortality (1). MAS might be defined as respiratory distress in an infant who is born through MSAF and whose symptoms cannot be otherwise explained (2). The pathophysiology of lung injury in MAS is complex and includes both mechanical obstruction by meconium and pronounced inflammatory responses (3). It has been postulated that other conditions, including intrauterine infection and chronic and acute asphyxia, rather than inhaled meconium, may explain the primary pathology of MAS (4). The pathophysiology of MAS (hypoxemia, pulmonary inflammation, and disturbed pulmonary vasoregulation) bears similarities with acute respiratory distress syndrome (5), the latter frequently being a manifestation of the systemic inflammatory response syndrome (SIRS) in the presence or absence of bacterial infection (6, 7).Lung inflammation by itself can lead to systemic inflammation (8). Leakage of meconium content through the alveolar wall to the lung capillaries may bring substances from meconium in direct contact with blood, leading to systemic inflammation. Furthermore, lung rupture and meconium embolism in chronic intrauterine meconium aspiration has been described (9), which may be an additional mechanism for meconium exposure to blood...

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Inhibition of complement, neutrophil, and platelet activation by an anti-factor D monoclonal antibody in simulated cardiopulmonary bypass circuits

Cited by 79 publications

References 53 publications

Complement C5a Is a Key Mediator of Meconium-Induced Neutrophil Activation

Complement C5a Is a Key Mediator of Meconium-Induced Neutrophil Activation

Liver gene expression associated with diet and lesion development in atherosclerosis-prone mice: induction of components of alternative complement pathway

Meconium Is a Potent Activator of Complement in Human Serum and in Piglets

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