title: Alternative Pathway Inhibition by Exogenous Factor H Fails to Attenuate Inflammation and Vascular Leakage in Experimental Pneumococcal Sepsis in Mice.
abstract: Streptococcus pneumoniae is a common cause of sepsis. Effective complement activation is an important component of host defence against invading pathogens, whilst excessive complement activation has been associated with endothelial dysfunction and organ damage. The alternative pathway amplification loop is important for the enhancement of complement activation. Factor H is a key negative regulator of the alternative pathway amplification loop and contributes to tight control of complement activation. We assessed the effect of inhibition of the alternative pathway on sepsis associated inflammation and disease severity using human factor H treatment in a clinically relevant mice model of pneumococcal sepsis. Mice were infected intravenously with live Streptococcus pneumoniae. At the first clinical signs of infection, 17 hours post-infection, mice were treated with ceftriaxone antibiotic. At the same time purified human factor H or in controls PBS was administered. Treatment with human factor H did not attenuate disease scores, serum pro-inflammatory cytokines, or vascular permeability and did not significantly affect C3 and C3a production at 26 h post-infection. Therefore, we conclude that inhibition of the alternative complement pathway by exogenous human factor H fails to attenuate inflammation and vascular leakage at a clinically relevant intervention time point in pneumococcal sepsis in mice.
authors.affiliation: Laboratory of Pediatric Infectious Diseases, Department of Pediatrics, Radboud Institute for Molecular Life Sciences, Radboudumc, Nijmegen, The Netherlands.
authors.forename: Erika
authors.initials: E
authors.lastname: van der Maten
authors.affiliation: Laboratory of Pediatric Infectious Diseases, Department of Pediatrics, Radboud Institute for Molecular Life Sciences, Radboudumc, Nijmegen, The Netherlands.
authors.forename: Saskia
authors.initials: S
authors.lastname: van Selm
authors.affiliation: Laboratory of Pediatric Infectious Diseases, Department of Pediatrics, Radboud Institute for Molecular Life Sciences, Radboudumc, Nijmegen, The Netherlands.
authors.forename: Jeroen D
authors.initials: JD
authors.lastname: Langereis
authors.affiliation: Laboratory of Pediatric Infectious Diseases, Department of Pediatrics, Radboud Institute for Molecular Life Sciences, Radboudumc, Nijmegen, The Netherlands.
authors.forename: Hester J
authors.initials: HJ
authors.lastname: Bootsma
authors.affiliation: Laboratory of Pediatric Infectious Diseases, Department of Pediatrics, Radboud Institute for Molecular Life Sciences, Radboudumc, Nijmegen, The Netherlands.
authors.forename: Fred J H
authors.initials: FJ
authors.lastname: van Opzeeland
authors.affiliation: Laboratory of Pediatric Infectious Diseases, Department of Pediatrics, Radboud Institute for Molecular Life Sciences, Radboudumc, Nijmegen, The Netherlands.
authors.forename: Ronald
authors.initials: R
authors.lastname: de Groot
authors.affiliation: Laboratory of Pediatric Infectious Diseases, Department of Pediatrics, Radboud Institute for Molecular Life Sciences, Radboudumc, Nijmegen, The Netherlands.
authors.forename: Marien I
authors.initials: MI
authors.lastname: de Jonge
authors.affiliation: Laboratory of Pediatric Infectious Diseases, Department of Pediatrics, Radboud Institute for Molecular Life Sciences, Radboudumc, Nijmegen, The Netherlands.|Pediatric Infectious Diseases and Immunology, Department of Pediatrics, Radboudumc, Nijmegen, The Netherlands.
authors.forename: Michiel
authors.initials: M
authors.lastname: van der Flier
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000627:therapeutic use*; D002199:Capillary Permeability / Q000187:drug effects*; D002443:Ceftriaxone / Q000627:therapeutic use*; D017242:Complement Factor H / Q000627:therapeutic use; D016207:Cytokines / Q000097:blood / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D011008:Pneumococcal Infections / Q000097:blood / Q000150:complications / Q000188:drug therapy* / Q000276:immunology; D018805:Sepsis / Q000097:blood / Q000150:complications / Q000188:drug therapy* / Q000276:immunology; D013296:Streptococcus pneumoniae / Q000187:drug effects* / Q000276:immunology
chemical_list: D000900:Anti-Bacterial Agents; C493495:CFH protein, human; D016207:Cytokines; D002443:Ceftriaxone; D017242:Complement Factor H