Circulation: Cardiovascular Genetics HCG TLR4 Regulates Platelet Function and Contributes to Coagulation Abnormality and Organ Injury in Hemorrhagic Shock and Resuscitation Platelet TLR4 regulates injury after hemorrhage CIRCCVG/2013/000398 CIRCCVG/2013/000398 10.1161/CIRCGENETICS.113.000398 7 10/21/14 5 Sine Kristina 617-542-5100 617-542-6539 Grosser, Tilo University of Pennsylvania Dr. Matthew D Neal nealm2@upmc.edu Dr. University of Pittsburgh NW 607 MUH 3459 Fifth Avenue Pittsburgh Pennsylvania 15261 UNITED STATES 4126476015 4126475959 173683 Ning Ding Guangzhou First People's Hospital, Guangzhou Medical University dingninggz@hotmail.com 173684 Guoqiang Chen Shanghai tenth people's hospital,Tongji University,school of medicine, angus_nosL@hotmail.com 173685 Rosemary Hoffman University of Pittsburgh hoffmanr3@upmc.edu 207010 Patricia Loughran University of Pittsburgh loughranp@upmc.edu 173686 Chhinder P. Sodhi University of Pittsburgh School of Medicine sodhi.chhinder@chp.edu 173380 David J. Hackam University of Pittsburgh School of Medicine hackamd@upmc.edu 173381 Timothy R. Billiar University of Pittsburgh School of Medicine billiartr@upmc.edu 9297 Matthew D Neal University of Pittsburgh nealm2@upmc.edu 173683 10/23/2013 10/23/2013 05/19/2014 06/04/2014 07/24/2014 10/21/2014 Original Article Hemorrhagic shock TLR4 <P><B><I>Background</I></B>—Growing evidence indicates that the presence of 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, however, remains unexplored. </P><P><B><I>Methods and Results</I></B>—Using thromboelastography and platelet aggregometry, we demonstrate that platelet function is impaired in a mouse model of hemorrhagic shock with resuscitation (HS-R). Further analysis using cellular specific TLR4 deletion in mice revealed that platelet TLR4 is essential for platelet activation and function in HS-R 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 knock-out mice were protected from lung and liver injury and exhibited a marked reduction in systemic inflammation as measured by circulating IL-6 following HS-R. </P><P><B><I>Conclusions</I></B>—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 hemorrhagic shock and resuscitation.</P> 0 0 0 8 8 yes CircGenetics_CIRCCVG-2013-000398.xml CircGenetics_CIRCCVG-2013-000398_file1.doc

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CircGenetics_CIRCCVG-2013-000398_supp1.pdf 000398_clinical perspective.docx CircGenetics_CIRCCVG-2013-000398_supp3.pdf CircGenetics_CIRCCVG-2013-000398_merge.pdf CircGenetics_CIRCCVG-2013-000398_Neal_173683_disclosure.pdf CircGenetics_CIRCCVG-2013-000398_Neal_173683_copyright.pdf CircGenetics_CIRCCVG-2013-000398_Loughran_173686_disclosure.pdf CircGenetics_CIRCCVG-2013-000398_Loughran_173686_copyright.pdf CircGenetics_CIRCCVG-2013-000398_Hackam_173381_disclosure.pdf CircGenetics_CIRCCVG-2013-000398_Hackam_173381_copyright.pdf CircGenetics_CIRCCVG-2013-000398_Hoffman_207010_disclosure.pdf CircGenetics_CIRCCVG-2013-000398_Hoffman_207010_copyright.pdf CircGenetics_CIRCCVG-2013-000398_Ding_173684_disclosure.pdf CircGenetics_CIRCCVG-2013-000398_Ding_173684_copyright.pdf CircGenetics_CIRCCVG-2013-000398_Sodhi_173380_disclosure.pdf CircGenetics_CIRCCVG-2013-000398_Sodhi_173380_copyright.pdf CircGenetics_CIRCCVG-2013-000398_Chen_173685_disclosure.pdf CircGenetics_CIRCCVG-2013-000398_Chen_173685_copyright.pdf CircGenetics_CIRCCVG-2013-000398_Billiar_9297_disclosure.pdf CircGenetics_CIRCCVG-2013-000398_Billiar_9297_copyright.pdf Bill authors $70 per pg; no excess pgs. Article has supplemental material (1 PDF) and a clinical perspective. No tables Drs. Ding and Chen contributed equally as co-first authors; Drs. Billiar and Neal contributed equally as co-senior authors. Rec'd 10/23/13 Please set the flag 'exportcadmusahafundingtypecodes' with the funding type code of the sources you wish to list. Subject Codes: [130] Animal models of human disease [181] Signal transduction [174] Coagulation [92] Platelets ksine