Complement Activation and Complement-Dependent Inflammation by<i>Neisseria meningitidis</i>Are Independent of Lipopolysaccharide

Sprong, Tom; Møller, Anne‐Sophie W.; Bjerre, Anna; Wedege, Elisabeth; Kierulf, Peter; Meer, J.W.M. van der; Brandtzæg, Petter; Deuren, Marcel van; Mollnes, Tom Eirik

doi:10.1128/iai.72.6.3344-3349.2004

Cited by 50 publications

(34 citation statements)

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“…We therefore measured the amount of LPS in each meconium sample and included only those with pictogram levels in the batch. Although these low amounts may induce some cytokine synthesis, amount in the range of micrograms is needed for LPS to induce complement activation (54). Thus, it can virtually be excluded that LPS 246 CASTELLHEIM ET AL.…”

Section: Discussionmentioning

confidence: 99%

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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Section: Discussionmentioning

confidence: 99%

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

Castellheim

Pharo

Fung³

et al. 2005

Pediatr Res

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“…Each segment was closed end-to-end and formed small loops. The loops were rotated slowly in an incubator at 37°C for 3 h (22,23). After 3 h, plasma was separated, and proinflammatory cytokines and chemokines were analyzed.…”

Section: Methodsmentioning

confidence: 99%

Arginine Catabolic Mobile Element Is Associated With Low Antibiotic Resistance and Low Pathogenicity in Staphylococcus epidermidis From Neonates

et al. 2010

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ABSTRACT:The arginine catabolic mobile element (ACME) in Staphylococci encodes several putative virulence factors. ACME appears to have been transferred from Staphylococcus epidermidis into Staphylococcus aureus and is strongly associated with the epidemic and virulent S. aureus USA300. We sought to determine the distribution of ACME in 128 S. epidermidis blood culture isolates from neonates and to assess ACME's impact on antibiotic resistance, biofilm production, invasive capacity, and host inflammatory response. ACME was detected in 15/64 (23%) invasive blood culture isolates and 26/64 (40%) blood culture contaminants (p ϭ 0.02). ACME-positive S. epidermidis isolates displayed less antibiotic resistance (p Ͻ 0.001) and were collected from more mature neonates (p ϭ 0.001). Biofilm production was more prevalent among ACMEnegative isolates (61/87) compared with ACME positive (18/41; p ϭ 0.004). Among the 64 children considered having an invasive infection, ACME did not influence the maximum C-reactive protein level. In an in vitro whole-blood sepsis model, there were no differences in the inflammatory response between ACME-positive and ACMEnegative isolates. We conclude that ACME in S. epidermidis from neonates was associated with less antibiotic resistance and also does not seem to be associated with increased pathogenicity. (Pediatr Res 68: 237-241, 2010) S taphylococcus epidermidis is a frequent cause of late onset sepsis in preterm neonates (1,2). The major virulence factor of S. epidermidis is biofilm formation on polymer surfaces, i.e. indwelling central venous lines (3). A wide range of other putative virulence factors, e.g. surface proteins (4), phenol soluble modulins (PSM), and poly-␥-glutamic acid (3,5-7), have also been identified. However, their clinical relevance is yet to be proven.The arginine catabolic mobile element (ACME) is a genomic island in Staphylococci that may contribute to enhanced pathogenicity. It was first discovered in the community associated methicillin-resistant Staphylococcus aureus (CA-MRSA) USA300 strain and the biofilm-negative S. epidermidis strain ATCC12228 (8). ACME contains two characteristic gene clusters (the arc-operon and the opp3-operon) that are homologs of virulence determinants in other bacterial species. The arc-operon, a characteristic cluster of six genes, encodes several enzymes in the arginine deiminase catabolic pathway, a putative virulence pathway that convert L-arginine to carbon dioxide, carbamoyl ornithine, ammonia, and ATP (9,10). The opp3-operon encodes an oligopeptide permease system. Similar opp-operons in other bacterial species have a wide array of functions including pheromone transport, chemotaxis, and expression of virulence determinants (8). ACME has been divided into three allotypes (8 -11). ACME-I, first found in S. aureus USA300, possess the arc-operon and the opp3-operon. ACME-II, first found in S. epidermidis ATCC12228, consists mainly of the arc-operon. ACME-III has only the opp3-operon and lacks the arc-operon. All three allotypes have ...

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“…Although LPS is pivotal, other ligands on Gram-negative bacteria could also contribute to the pathogenesis of inflammation and sepsis. It is for instance shown that LPS-deficient N. meningitides (LPS -) can activate the complement system and induce complement mediated inflammatory effects (148). N. meningitides (LPS -) have also been shown to be able to induce large gene expression changes in human monocytes (149).…”

Section: Whole Live Escherichia Coli Bacteriamentioning

confidence: 99%