title: Toll-like receptor 4 regulates platelet function and contributes to coagulation abnormality and organ injury in hemorrhagic shock and resuscitation.
abstract: BACKGROUND
  Growing evidence indicates that the presence of toll-like receptor 4 (TLR4) on platelets is a key regulator of platelet number and function. Platelets exposed to TLR4 agonists may serve to activate other cells such as neutrophils and endothelial cells in sepsis and other inflammatory conditions. The functional significance of platelet TLR4 in hemorrhagic shock (HS), however, remains unexplored.
  
  
  RESULTS
  Using thromboelastography and platelet aggregometry, we demonstrate that platelet function is impaired in a mouse model of HS with resuscitation. Further analysis using cellular-specific TLR4 deletion in mice revealed that platelet TLR4 is essential for platelet activation and function in HS with resuscitation and that platelet TLR4 regulates the development of coagulopathy after hemorrhage and resuscitation. Transfusion of TLR4-negative platelets into mice resulted in protection from coagulopathy and restored platelet function. Additionally, platelet-specific TLR4 knockout mice were protected from lung and liver injury and exhibited a marked reduction in systemic inflammation as measured by circulating interleukin-6 after HS with resuscitation.
  
  
  CONCLUSIONS
  We demonstrate for the first time that platelet TLR4 is an essential mediator of the inflammatory response as well as platelet activation and function in HS and resuscitation.
authors.affiliation: From the Department of Surgery, University of Pittsburgh, PA (N.D., G.C., R.H., P.A.L., T.R.B., M.D.N.); Department of Anesthesiology, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, People's Republic of China (N.D.); Department of Anesthesiology, Shanghai Tenth People's Hospital, Tongji University, School of Medicine, Shanghai, People's Republic of China (G.C.); and Division of Pediatric Surgery, Department of Surgery, Children's Hospital of Pittsburgh of UPMC, PA (C.P.S., D.J.H.).
authors.forename: Ning
authors.initials: N
authors.lastname: Ding
authors.affiliation: From the Department of Surgery, University of Pittsburgh, PA (N.D., G.C., R.H., P.A.L., T.R.B., M.D.N.); Department of Anesthesiology, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, People's Republic of China (N.D.); Department of Anesthesiology, Shanghai Tenth People's Hospital, Tongji University, School of Medicine, Shanghai, People's Republic of China (G.C.); and Division of Pediatric Surgery, Department of Surgery, Children's Hospital of Pittsburgh of UPMC, PA (C.P.S., D.J.H.).
authors.forename: Guoqiang
authors.initials: G
authors.lastname: Chen
authors.affiliation: From the Department of Surgery, University of Pittsburgh, PA (N.D., G.C., R.H., P.A.L., T.R.B., M.D.N.); Department of Anesthesiology, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, People's Republic of China (N.D.); Department of Anesthesiology, Shanghai Tenth People's Hospital, Tongji University, School of Medicine, Shanghai, People's Republic of China (G.C.); and Division of Pediatric Surgery, Department of Surgery, Children's Hospital of Pittsburgh of UPMC, PA (C.P.S., D.J.H.).
authors.forename: Rosemary
authors.initials: R
authors.lastname: Hoffman
authors.affiliation: From the Department of Surgery, University of Pittsburgh, PA (N.D., G.C., R.H., P.A.L., T.R.B., M.D.N.); Department of Anesthesiology, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, People's Republic of China (N.D.); Department of Anesthesiology, Shanghai Tenth People's Hospital, Tongji University, School of Medicine, Shanghai, People's Republic of China (G.C.); and Division of Pediatric Surgery, Department of Surgery, Children's Hospital of Pittsburgh of UPMC, PA (C.P.S., D.J.H.).
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Loughran
authors.affiliation: From the Department of Surgery, University of Pittsburgh, PA (N.D., G.C., R.H., P.A.L., T.R.B., M.D.N.); Department of Anesthesiology, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, People's Republic of China (N.D.); Department of Anesthesiology, Shanghai Tenth People's Hospital, Tongji University, School of Medicine, Shanghai, People's Republic of China (G.C.); and Division of Pediatric Surgery, Department of Surgery, Children's Hospital of Pittsburgh of UPMC, PA (C.P.S., D.J.H.).
authors.forename: Chhinder P
authors.initials: CP
authors.lastname: Sodhi
authors.affiliation: From the Department of Surgery, University of Pittsburgh, PA (N.D., G.C., R.H., P.A.L., T.R.B., M.D.N.); Department of Anesthesiology, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, People's Republic of China (N.D.); Department of Anesthesiology, Shanghai Tenth People's Hospital, Tongji University, School of Medicine, Shanghai, People's Republic of China (G.C.); and Division of Pediatric Surgery, Department of Surgery, Children's Hospital of Pittsburgh of UPMC, PA (C.P.S., D.J.H.).
authors.forename: David J
authors.initials: DJ
authors.lastname: Hackam
authors.affiliation: From the Department of Surgery, University of Pittsburgh, PA (N.D., G.C., R.H., P.A.L., T.R.B., M.D.N.); Department of Anesthesiology, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, People's Republic of China (N.D.); Department of Anesthesiology, Shanghai Tenth People's Hospital, Tongji University, School of Medicine, Shanghai, People's Republic of China (G.C.); and Division of Pediatric Surgery, Department of Surgery, Children's Hospital of Pittsburgh of UPMC, PA (C.P.S., D.J.H.). nealm2@upmc.edu billiartr@upmc.edu.
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Billiar
authors.affiliation: From the Department of Surgery, University of Pittsburgh, PA (N.D., G.C., R.H., P.A.L., T.R.B., M.D.N.); Department of Anesthesiology, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, People's Republic of China (N.D.); Department of Anesthesiology, Shanghai Tenth People's Hospital, Tongji University, School of Medicine, Shanghai, People's Republic of China (G.C.); and Division of Pediatric Surgery, Department of Surgery, Children's Hospital of Pittsburgh of UPMC, PA (C.P.S., D.J.H.). nealm2@upmc.edu billiartr@upmc.edu.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Neal
mesh_terms: D000818:Animals; D001778:Blood Coagulation Disorders / Q000235:genetics / Q000378:metabolism*; D001792:Blood Platelets / Q000378:metabolism* / Q000502:physiology; D019446:Endotoxemia; D017353:Gene Deletion; D005786:Gene Expression Regulation; D006487:Hemostasis; D007249:Inflammation; D015850:Interleukin-6 / Q000097:blood; D008264:Macrophages / Q000166:cytology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009195:Peroxidase / Q000378:metabolism; D010974:Platelet Aggregation; D010979:Platelet Function Tests; D012151:Resuscitation; D012771:Shock, Hemorrhagic / Q000378:metabolism*; D013916:Thrombelastography / Q000379:methods; D051197:Toll-Like Receptor 4 / Q000378:metabolism*
chemical_list: D015850:Interleukin-6; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D009195:Peroxidase
keywords: blood platelets; inflammation; shock, hemorrhagic; toll-like receptor 4