Campbell, Robert A;
Vieira-de-Abreu, Adriana;
Rowley, Jesse W;
Franks, Zechariah G;
Rondina, Matthew T;
Kraiss, Larry W;
Majersik, Jennifer J;
Zimmerman, Guy A;
Weyrich, Andrew
Abstract 354: Clots Are Potent Triggers of Inflammatory Cell Gene Expression: Indications for Timely Fibrinolysis
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Media type:
E-Article
Title:
Abstract 354: Clots Are Potent Triggers of Inflammatory Cell Gene Expression: Indications for Timely Fibrinolysis
Contributor:
Campbell, Robert A;
Vieira-de-Abreu, Adriana;
Rowley, Jesse W;
Franks, Zechariah G;
Rondina, Matthew T;
Kraiss, Larry W;
Majersik, Jennifer J;
Zimmerman, Guy A;
Weyrich, Andrew
Description:
<jats:p>
<jats:bold>Objective:</jats:bold>
Blood vessel wall damage often results in the formation of a fibrin clot that traps inflammatory cells, including monocytes. The effect of clot formation and subsequent lysis on the expression of monocyte-derived genes involved in the development and progression of ischemic stroke and other vascular diseases, however, is unknown. Determine if clot formation and lysis regulates the expression of human monocyte-derived genes that modulate vascular diseases.
</jats:p>
<jats:p>
<jats:bold>Approach and Results:</jats:bold>
We performed Next Generation RNA sequencing on monocytes extracted from whole blood clots. Thousands of mRNAs were differentially expressed by monocytes from clotted versus unclotted whole blood, including upregulation of interleukin 8 (IL-8) and monocyte chemoattractant protein-1 (MCP-1). Clotted plasma also increased expression of IL-8 and MCP-1, which far exceeded responses observed in LPS-stimulated monocytes. Upregulation of IL-8 and MCP-1 occurred in a thrombin-independent, but fibrin-dependent manner. Fibrinolysis initiated shortly after plasma clot formation (i.e., 1-2 hours) reduced the synthesis of IL-8 and MCP-1, while delayed fibrinolysis was far less effective. Consistent with these
<jats:italic>in vitro</jats:italic>
models, monocytes embedded in unresolved thrombi from patients undergoing thrombectomy stained positively for IL-8 and MCP-1.
</jats:p>
<jats:p>
<jats:bold>Conclusions:</jats:bold>
These findings demonstrate that clots are potent inducers of monocyte gene expression, and that timely fibrinolysis attenuates inflammatory responses. Dampening of inflammatory gene expression by timely clot lysis may contribute to the clinically-proven efficacy of fibrinolytic drug treatment within hours of stroke onset.
</jats:p>