Complement activation in injured patients occurs immediately and is dependent on the severity of the trauma

Fosse, Erik; Pillgram-Larsen, J; Jl, Svennevig; Nordby, Christian; Skulberg, A; Mollnes, Tom Eirik; Abdelnoor, Michel

doi:10.1016/s0020-1383(98)00113-2

Cited by 57 publications

(38 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Studies of conditions with a defined time of insult, such as major trauma 57 or cardiac arrest, 58 demonstrate an early and rapid increase in complement activation and C5a concentrations. A variety of complement activation mechanisms may be present in critical illness, including coagulation, 59 human neutrophil elastase (HNE)-mediated cleavage of IgG to form F(abЈ) portions, 60 HNE itself, 61 and systemic release and circulation of bacterial peptides.…”

Section: Discussionmentioning

confidence: 99%

C5a-mediated neutrophil dysfunction is RhoA-dependent and predicts infection in critically ill patients

Morris

Brittan

Wilkinson

et al. 2011

Blood

150

View full text Add to dashboard Cite

Critically ill patients are at heightened risk for nosocomial infections. The anaphylatoxin C5a impairs phagocytosis by neutrophils. However, the mechanisms by which this occurs and the relevance for acquisition of nosocomial infection remain undetermined. We aimed to characterize mechanisms by which C5a inhibits phagocytosis in vitro and in critically ill patients, and to define the relationship between C5a-mediated dysfunction and acquisition of nosocomial infection. In healthy human neutrophils, C5a significantly inhibited RhoA activation, preventing actin polymerization and phagocytosis. RhoA inhibition was mediated by PI3K␦. The effects on RhoA, actin, and phagocytosis were fully reversed by GM-CSF. Parallel observations were made in neutrophils from critically ill patients, that is, impaired phagocytosis was associated with inhibition of RhoA and actin polymerization, and reversed by GM-CSF. Among a cohort of 60 critically ill patients, C5a-mediated neutrophil dysfunction (as determined by reduced CD88 expression) was a strong predictor for subsequent acquisition of nosocomial infection (relative risk, 5.8; 95% confidence interval, 1.5-22; P ‫؍‬ .0007), and remained independent of time effects as assessed by survival analysis (hazard ratio, 5.0; 95% confidence interval, 1.3-8.3; P ‫؍‬ .01). In conclusion, this study provides new insight into the mechanisms underlying immunocompromise in critical illness and suggests novel avenues for therapy and prevention of nosocomial infection. (Blood. 2011;117(19):5178-5188) IntroductionThe systemic inflammatory response syndrome (SIRS) is classically characterized by profound immune activation, accompanying massive cytokinemia and organ damage. 1,2 However, SIRS is accompanied by a counter-regulatory immune suppression sometimes termed the compensatory anti-inflammatory response syndrome (CARS). 3 This relative immune suppression is considered important for effective resolution of inflammation but may extend to maladaptive counter-regulatory anti-inflammatory responses. 4,5 The consequences of impaired immune function include enhanced susceptibility to nosocomial infection 6 or death from sepsis. 7 Neutrophils are the major front-line cellular defense against bacterial pathogens, and acquired defects in neutrophil function have been identified in both animal and human sepsis 8,9 as well as sterile SIRS. 10,11 However, the mediators driving these defects, and the mechanisms involved, remain uncertain.Animal studies have implicated uncontrolled activation of the complement system in the pathogenesis of sepsis and sterile SIRS. [12][13][14] The key components mediating vasodilatation and vascular leak-the hallmarks of septic shock-are the anaphylatoxins. These are activated forms of complement factors 3 (C3a) and 5 (C5a). 14,15 Animal models of sepsis have also implicated C5a in neutrophil dysfunction. 8 Because of the rapid clearance (2-to 3-minute half life) of C5a from the circulation, measurement of plasma concentrations gives an imprecise account of neutrophil expos...

show abstract

Section: Discussionmentioning

confidence: 99%

C5a-mediated neutrophil dysfunction is RhoA-dependent and predicts infection in critically ill patients

Morris

Brittan

Wilkinson

et al. 2011

Blood

150

View full text Add to dashboard Cite

show abstract

“…13 Systemic activation of the complement system, as known from patients suffering from sepsis, severe burns or injuries, could induce autodestructive inflammatory reactions, such as adult respiratory distress syndrome (ARDS) or multiple organ failure (MOF). [14][15][16][17][18] Both types of clinical symptom complexes have been observed in the patient who died during the OTCD trial, which suggests an involvement of the complement system. In this article, we will discuss prophylactic measures which might help to control or avoid excess activation of the complement system after adenoviral gene therapy in humans.…”

Section: The Complement Systemmentioning

confidence: 91%

Complement activation by recombinant adenoviruses

et al. 2001

View full text Add to dashboard Cite

“…More recently, iTCC injected into the lateral ventricle of the CNS in rats was found to recruit intravascular PMN into the tissue and the cerebrospinal fluid and SC5b-9 purified from human serum proved to be as effective as iTCC (16). SC5b-9 is the inactive complex detected in measurable amounts in patients with septic shock (17,18), immune complex diseases (19), severe traumata (20), cardiopulmonary bypass, and other therapeutic procedure including extracorporeal circulation of blood (21).…”

mentioning

confidence: 99%

Platelet-Activating Factor and Kinin-Dependent Vascular Leakage as a Novel Functional Activity of the Soluble Terminal Complement Complex

Bossi¹,

Fischetti

Pellis³

et al. 2004

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

The infrequent occurrence of septic shock in patients with inherited deficiencies of the terminal complement components experiencing meningococcal disease led us to suspect that the terminal complement complex is involved in vascular leakage. To this end, the permeabilizing effect of the cytolytically inactive soluble terminal complement complex (SC5b-9) was tested in a Transwell system measuring the amount of fluorescein-labeled BSA (FITC-BSA) leaked through a monolayer of endothelial cells. The complex caused increased permeability to FITC-BSA after 15 min as opposed to the prompt response to bradykinin (BK). The effect of SC5b-9 was partially reduced by HOE-140 or CV-3988, two selective antagonists of BK B2 and platelet-activating factor receptors, respectively, and was completely neutralized by the mixture of the two antagonists. Also, DX-88, a specific inhibitor of kallikrein, partially inhibited the activity of SC5b-9. The permeabilizing factor(s) released after 30 min of incubation of endothelial cells with SC5b-9 caused a prompt leakage of albumin like BK. Intravital microscopy confirmed both the extravasation of circulating FITC-BSA across mesenteric microvessels 15 min after topical application of SC5b-9 and the complete neutralization by the mixture of HOE-140 and CV-3988. SC5b-9 induced opening of interendothelial junctions in mesenteric endothelium documented by transmission electron microscopy.

show abstract

Complement activation in injured patients occurs immediately and is dependent on the severity of the trauma

Cited by 57 publications

References 27 publications

C5a-mediated neutrophil dysfunction is RhoA-dependent and predicts infection in critically ill patients

C5a-mediated neutrophil dysfunction is RhoA-dependent and predicts infection in critically ill patients

Complement activation by recombinant adenoviruses

Platelet-Activating Factor and Kinin-Dependent Vascular Leakage as a Novel Functional Activity of the Soluble Terminal Complement Complex

Contact Info

Product

Resources

About