title: Increased C5a receptor expression in sepsis.
abstract: Excessive production of the complement activation product C5a appears to be harmful during the development of sepsis in rodents. Little is known about the role of the C5a receptor (C5aR) and its presence in different organs during sepsis. Using the cecal ligation/puncture (CLP) model in mice, we show here that C5aR immunoreactivity was strikingly increased in lung, liver, kidney, and heart early in sepsis in both control and neutrophil-depleted mice. C5aR mRNA expression in these organs was also significantly increased during sepsis. Immunohistochemical analysis revealed patterns of increased C5aR expression in parenchymal cells in all four organs following CLP. Mice injected at the start of CLP with a blocking IgG to C5aR (alphaC5aR) showed dramatically improved survival when compared with animals receiving nonspecific IgG, as did mice injected with alphaC5a. In alphaC5aR-treated mice, serum levels of IL-6 and TNF-alpha and bacterial counts in various organs were significantly reduced during CLP when compared with control CLP animals. These studies demonstrate for the first time that C5aR is upregulated in lung, liver, kidney, and heart during the early phases of sepsis and that blockade of C5aR is highly protective from the lethal outcome of sepsis.
authors.affiliation: Department of Pathology, University of Michigan Medical School, 1301 Catherine Road, Ann Arbor, MI 48109, USA.
authors.forename: Niels C
authors.initials: NC
authors.lastname: Riedemann
authors.forename: Ren-Feng
authors.initials: RF
authors.lastname: Guo
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Neff
authors.forename: Ines J
authors.initials: IJ
authors.lastname: Laudes
authors.forename: Katie A
authors.initials: KA
authors.lastname: Keller
authors.forename: Vidya J
authors.initials: VJ
authors.lastname: Sarma
authors.forename: Maciej M
authors.initials: MM
authors.lastname: Markiewski
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Mastellos
authors.forename: Christoph W
authors.initials: CW
authors.lastname: Strey
authors.forename: Carl L
authors.initials: CL
authors.lastname: Pierson
authors.forename: John D
authors.initials: JD
authors.lastname: Lambris
authors.forename: Firas S
authors.initials: FS
authors.lastname: Zetoune
authors.forename: Peter A
authors.initials: PA
authors.lastname: Ward
mesh_terms: D000818:Animals; D000906:Antibodies / Q000008:administration & dosage; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D007150:Immunohistochemistry; D007668:Kidney / Q000276:immunology; D008099:Liver / Q000276:immunology; D008168:Lung / Q000276:immunology; D008212:Lymphocyte Depletion; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009206:Myocardium / Q000276:immunology; D009504:Neutrophils / Q000276:immunology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D044087:Receptor, Anaphylatoxin C5a; D011951:Receptors, Complement / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D018805:Sepsis / Q000235:genetics / Q000276:immunology* / Q000517:prevention & control; D014018:Tissue Distribution; D015854:Up-Regulation
chemical_list: D000906:Antibodies; D015703:Antigens, CD; D012333:RNA, Messenger; D044087:Receptor, Anaphylatoxin C5a; D011951:Receptors, Complement