Toll-like receptor 4 regulates platelet function and contributes to coagulation abnormality and organ injury in hemorrhagic shock and resuscitation

Ning Ding, Guoqiang Chen, Rosemary Hoffman, Patricia A. Loughran, Chhinder Sodhi, David Hackam, Timothy R. Billiar, Matthew D. Neal

Research output: Contribution to journalArticle

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.Methods and 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.

Original languageEnglish (US)
Pages (from-to)615-624
Number of pages10
JournalCirculation: Cardiovascular Genetics
Volume7
Issue number5
DOIs
StatePublished - Oct 1 2014
Externally publishedYes

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Keywords

  • Blood platelets
  • Hemorrhagic
  • Inflammation
  • Shock
  • Toll-like receptor 4

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Genetics(clinical)
  • Genetics

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