Harmful molecular mechanisms in sepsis

Rittirsch, Daniel; Flierl, Michael A.; Ward, Peter A.

doi:10.1038/nri2402

Cited by 1,074 publications

(991 citation statements)

References 121 publications

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“…There is a concensus in the scientific community that systemic inflammation induced by the host's response to DAMPs, PAMPs on invading pathogens and alarmins on damaged tissue are harmful and contribute to the development of severe sepsis and septic shock (202). The findings in this Thesis suggest that inhibition of CD14/TLR4/MD-2 and complement should be regarded as an early treatment approach in sepsis.…”

Section: New Treatments In Sepsis and Possible Clinical Application Omentioning

confidence: 95%

“…The many disappointments of anti-inflammatory therapies in sepsis have led some researchers to ask the question if mortality in sepsis is not derived from an uncontrolled proinflammatory response (202). However, the complex interplay between the many pathogenic mediators, probably impossible to dampen with single target approaches, might be the main reason for the failures (198,203).…”

Section: New Treatments In Sepsis and Possible Clinical Application Omentioning

confidence: 99%

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Candidate inhibitors of porcine complement

Thorgersen¹,

Ghebremariam²,

Thurman³

et al. 2007

Molecular Immunology

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Section: New Treatments In Sepsis and Possible Clinical Application Omentioning

confidence: 95%

Section: New Treatments In Sepsis and Possible Clinical Application Omentioning

confidence: 99%

Candidate inhibitors of porcine complement

Thorgersen¹,

Ghebremariam²,

Thurman³

et al. 2007

Molecular Immunology

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“…Human complement is the first barrier of innate immunity and kills infectious agents when they try to invade the bloodstream (26). To do this, it attacks anything that is not self.…”

Section: Discussionmentioning

confidence: 99%

Solution Structure of the Factor H-binding Protein, a Survival Factor and Protective Antigen of Neisseria meningitidis

Cantini

Veggi

Dragonetti

et al. 2009

Journal of Biological Chemistry

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Factor H-binding protein is a 27-kDa lipoprotein of Neisseria meningitidis discovered while screening the bacterial genome for vaccine candidates. In addition to being an important component of a vaccine against meningococcus in late stage of development, the protein is essential for pathogenesis because it allows the bacterium to survive and grow in human blood by binding the human complement factor H. We recently reported the solution structure of the C-terminal domain of factor H-binding protein, which contains the immunodominant epitopes. In the present study, we report the structure of the full-length molecule, determined by nuclear magnetic resonance spectroscopy. The protein is composed of two independent barrels connected by a short link. Mapping the residues recognized by monoclonal antibodies with bactericidal or factor H binding inhibition properties allowed us to predict the sites involved in the function of the protein. The structure therefore provides the basis for designing improved vaccine molecules.

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“…This variant of sepsis occurs in ∼15% of diagnosed patients. Sepsis is accompanied by robust activation of the coagulation (3,4) and the complement (5) systems, triggered both by the pathogen itself and by damaged tissue. Whereas local and controlled activation of these pathways can promote host defense against pathogens, excessive or uncontrolled systemic activation is harmful (5,6).…”

mentioning

confidence: 99%

Inhibition of complement C5 protects against organ failure and reduces mortality in a baboon model of Escherichia coli sepsis

Keshari

Silasi‐Mansat

Popescu

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Bacterial sepsis triggers robust activation of the complement system with subsequent generation of anaphylatoxins (C3a, C5a) and the terminal complement complex (TCC) that together contribute to organ failure and death. Here we tested the effect of RA101295, a 2-kDa macrocyclic peptide inhibitor of C5 cleavage, using in vitro whole-blood assays and an in vivo baboon model of Escherichia coli sepsis. RA101295 strongly inhibited E. coli-induced complement activation both in vitro and in vivo by blocking the generation of C5a and the soluble form of TCC, sC5b-9. RA101295 reduced the E. coliinduced "oxidative burst," as well as leukocyte activation, without affecting host phagocytosis of E. coli. RA101295 treatment reduced plasma LPS content in E. coli-challenged baboons, implying reduced complement-mediated bacteriolysis, whereas treated animals showed slightly improved bacterial clearance during the bacteremic stage compared with controls. Treatment with RA101295 also improved consumptive coagulopathy and preserved endothelial anticoagulant and vascular barrier functions. RA101295 abolished sepsis-induced surges in proinflammatory cytokines and attenuated systemic circulatory and febrile responses, likely reflecting decreased systemic levels of LPS and C5a. Overall, RA101295 treatment was associated with significant organ protection and markedly reduced mortality compared with nontreated controls (four of five animals survived in a 100% lethal model). We therefore conclude that inhibition of C5 cleavage during the bacteremic stage of sepsis could be an important therapeutic approach to prevent sepsis-induced inflammation, consumptive coagulopathy, and subsequent organ failure and death. complement | coagulation | sepsis | Escherichia coli | organ failure

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Harmful molecular mechanisms in sepsis

Cited by 1,074 publications

References 121 publications

Candidate inhibitors of porcine complement

Candidate inhibitors of porcine complement

Solution Structure of the Factor H-binding Protein, a Survival Factor and Protective Antigen of Neisseria meningitidis

Inhibition of complement C5 protects against organ failure and reduces mortality in a baboon model of Escherichia coli sepsis

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