title: Complement component 5 promotes lethal thrombosis.
abstract: Extracellular histones promote platelet aggregation and thrombosis; this is followed by induction of coagulation disorder, which results in exhaustion of coagulation factors. Complement component 5 (C5) is known to be associated with platelet aggregation and coagulation system activation. To date, the pathological mechanism underlying liver injury has remained unclear. Here, we investigated whether C5 promotes liver injury associated with histone-induced lethal thrombosis. C5-sufficient and C5-deficient mice received single tail vein injections of purified, unfractionated histones obtained from calf thymus (45-75 μg/g). Subsequently, the mice were monitored for survival for up to 72 h. Based on the survival data, the 45 μg/g dose was used for analysis of blood cell count, liver function, blood coagulation ability, and promotion of platelet aggregation and platelet/leukocyte aggregate (PLA) production by extracellular histones. C5-deficient mice were protected from lethal thrombosis and had milder thrombocytopenia, consumptive coagulopathy, and liver injury with embolism and lower PLA production than C5-sufficient mice. These results indicate that C5 is associated with coagulation disorders, PLA production, and embolism-induced liver injury. In conclusion, C5 promotes liver injury associated with histone-induced lethal thrombosis.
authors.affiliation: Department of Analytical Pharmacology, Meijo University, Nagoya, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Mizuno
authors.affiliation: Department of Analytical Pharmacology, Meijo University, Nagoya, Japan.
authors.forename: Kengo
authors.initials: K
authors.lastname: Yoshioka
authors.affiliation: Department of Renal Replacement Therapy, Nagoya University, Nagoya, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Mizuno
authors.affiliation: Department of Enviromental Sciences, Meijo University, Nagoya, Japan.|Yokohama Brain and spine Center, Yokohama, Japan.
authors.forename: Mie
authors.initials: M
authors.lastname: Shimizu
authors.affiliation: Department of Analytical Pharmacology, Meijo University, Nagoya, Japan.
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Nagano
authors.affiliation: Department of Drug Delivery Research, Meijo University, Nagoya, Japan.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Okuda
authors.affiliation: Department of Nephrology, Nagoya University, Nagoya, Japan.
authors.forename: Naotake
authors.initials: N
authors.lastname: Tsuboi
authors.affiliation: Department of Nephrology, Nagoya University, Nagoya, Japan.
authors.forename: Shoichi
authors.initials: S
authors.lastname: Maruyama
authors.affiliation: Department of Analytical Pharmacology, Meijo University, Nagoya, Japan.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Nagamatsu
authors.affiliation: Department of Immunology, Nagoya City University, Nagoya, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Imai
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D003182:Complement C5 / Q000378:metabolism*; D006657:Histones / Q000494:pharmacology; D007962:Leukocytes / Q000187:drug effects / Q000378:metabolism; D017093:Liver Failure / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D010974:Platelet Aggregation; D013927:Thrombosis / Q000150:complications / Q000378:metabolism* / Q000473:pathology
chemical_list: D003182:Complement C5; D006657:Histones