title: Tissue factor-dependent coagulation is preferentially up-regulated within arterial branching areas in a baboon model of Escherichia coli sepsis.
abstract: Endothelium plays a critical role in the pathobiology of sepsis by integrating systemic host responses and local rheological stimuli. We studied the differential expression and activation of tissue factor (TF)-dependent coagulation on linear versus branched arterial segments in a baboon sepsis model. Animals were injected intravenously with lethal doses of Escherichia coli or saline and sacrificed after 2 to 8 hours. Whole-mount arterial segments were stained for TF, TF-pathway inhibitor (TFPI), factor VII (FVII), and markers for endothelial cells (ECs), leukocytes, and platelets, followed by confocal microscopy and image analysis. In septic animals, TF localized preferentially at branches, EC surface, leukocytes, and platelet aggregates and accumulated in large amounts in the subendothelial space. FVII strongly co-localized with TF on ECs and leukocytes but less so with subendothelial TF. TFPI co-localized with TF and FVII on endothelium and leukocytes but not in the subendothelial space. Focal TF increases correlated with fibrin deposition and increased endothelial permeability to plasma proteins. Biochemical analysis confirmed that aortas of septic baboons expressed more TF mRNA and protein than controls. Branched segments contained higher TF protein levels and coagulant activity than equivalent linear areas. These data suggest that site-dependent endothelial heterogeneity and rheological factors contribute to focal procoagulant responses to E. coli.
authors.affiliation: Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, 825 NE 13 St., Oklahoma City, OK 73104, USA.
authors.forename: Cristina
authors.initials: C
authors.lastname: Lupu
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Westmuckett
authors.forename: Glenn
authors.initials: G
authors.lastname: Peer
authors.forename: Lacramioara
authors.initials: L
authors.lastname: Ivanciu
authors.forename: Hua
authors.initials: H
authors.lastname: Zhu
authors.forename: Fletcher B
authors.initials: FB
authors.lastname: Taylor
authors.forename: Florea
authors.initials: F
authors.lastname: Lupu
mesh_terms: D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000648:ultrastructure; D001158:Arteries / Q000033:anatomy & histology / Q000378:metabolism* / Q000648:ultrastructure; D015415:Biomarkers / Q000097:blood; D001777:Blood Coagulation; D001792:Blood Platelets / Q000378:metabolism; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism; D004927:Escherichia coli Infections / Q000378:metabolism*; D005167:Factor VII / Q000378:metabolism; D007091:Image Processing, Computer-Assisted; D007962:Leukocytes / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity; D008074:Lipoproteins / Q000378:metabolism; D018613:Microscopy, Confocal; D008954:Models, Biological; D010215:Papio; D012333:RNA, Messenger / Q000378:metabolism; D012772:Shock, Septic / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D013925:Thromboplastin / Q000235:genetics / Q000378:metabolism* / Q000648:ultrastructure; D015854:Up-Regulation
chemical_list: D015415:Biomarkers; D008070:Lipopolysaccharides; D008074:Lipoproteins; D012333:RNA, Messenger; C051928:lipoprotein-associated coagulation inhibitor; D005167:Factor VII; D013925:Thromboplastin