title: The role of the complement cascade in endotoxin-induced septic encephalopathy.
abstract: The complement system normally eliminates bacteria and has a protective effect. However, in an inflammatory setting such as sepsis, an exaggerated or insufficient activation of this cascade can have deleterious effect through the activation of glial cells, secretion of proinflammatory cytokines and generation of other toxic products. The aim of the present study was to investigate the role of the complement cascade in septic encephalopathy, through the passive injection of endotoxin/lipopolysaccharide (LPS) into mice overexpressing the potent complement inhibitor, CR1-related y (Crry-tg). Increased gliosis occurred in brains of endotoxemic mice. Concomitant with this, there was a significant rise in mRNA expression of GFAP, CD45 and proinflammatory molecules, TLR4, TNF-alpha and NO, in these brains. Consistent with the capacity of these inflammatory mediators, there was increased apoptosis as determined by DNA fragmentation and TUNEL staining on LPS treatment, which occurred through the Akt pathway. In addition, there was increased water content in brain, similar to cerebral edema observed in sepsis. Relative to wild-type mice, complement-inhibited mice had an attenuated inflammatory response, decreased edema and reduced apoptosis. Therefore, we demonstrate for the first time that the complement cascade appears to be one of the key players that cause brain pathology in an endotoxemic setting and therefore is a viable therapeutic target.
authors.affiliation: Department of Medicine, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Jacob
authors.forename: Lauren K
authors.initials: LK
authors.lastname: Hensley
authors.forename: Bryan D
authors.initials: BD
authors.lastname: Safratowich
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Quigg
authors.forename: Jessy J
authors.initials: JJ
authors.lastname: Alexander
mesh_terms: D000818:Animals; D017209:Apoptosis; D001927:Brain Diseases / Q000209:etiology / Q000276:immunology* / Q000473:pathology; D001929:Brain Edema / Q000209:etiology / Q000276:immunology; D003167:Complement Activation; D020287:In Situ Nick-End Labeling; D017493:Leukocyte Common Antigens / Q000096:biosynthesis; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D009569:Nitric Oxide / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011951:Receptors, Complement / Q000235:genetics / Q000378:metabolism; D017463:Receptors, Complement 3b; D018805:Sepsis / Q000209:etiology / Q000276:immunology* / Q000473:pathology; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: C081470:Cr1l protein, mouse; D008070:Lipopolysaccharides; D011951:Receptors, Complement; D017463:Receptors, Complement 3b; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D051057:Proto-Oncogene Proteins c-akt; D017493:Leukocyte Common Antigens; C516770:Ptprc protein, mouse