PMID- 28775073
OWN - NLM
STAT- MEDLINE
DCOM- 20171010
LR  - 20200429
IS  - 1524-4636 (Electronic)
IS  - 1079-5642 (Print)
IS  - 1079-5642 (Linking)
VI  - 37
IP  - 10
DP  - 2017 Oct
TI  - Clots Are Potent Triggers of Inflammatory Cell Gene Expression: Indications for 
      Timely Fibrinolysis.
PG  - 1819-1827
LID - 10.1161/ATVBAHA.117.309794 [doi]
AB  - OBJECTIVE: 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 whether clot formation and lysis 
      regulates the expression of human monocyte-derived genes that modulate vascular 
      diseases. APPROACH AND RESULTS: We performed next-generation RNA sequencing on 
      monocytes extracted from whole blood clots and using a purified plasma clot 
      system. Numerous mRNAs were differentially expressed by monocytes embedded in 
      clots compared with unclotted controls, and IL-8 (interleukin 8) and MCP-1 
      (monocyte chemoattractant protein-1) were among the upregulated transcripts in 
      both models. Clotted plasma also increased expression of IL-8 and MCP-1, which 
      far exceeded responses observed in lipopolysaccharide-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 (ie, 1-2 hours) reduced the synthesis of IL-8 and MCP-1, whereas 
      delayed fibrinolysis was far less effective. Consistent with these in vitro 
      models, monocytes embedded in unresolved thrombi from patients undergoing 
      thrombectomy stained positively for IL-8 and MCP-1. CONCLUSIONS: These findings 
      demonstrate that clots are potent inducers of monocyte gene expression and that 
      timely fibrinolysis attenuates inflammatory responses, specifically IL-8 and 
      MCP-1. 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.
CI  - (c) 2017 American Heart Association, Inc.
FAU - Campbell, Robert A
AU  - Campbell RA
AD  - From the Program in Molecular Medicine (R.A.C., J.W.R., Z.G.F., B.K.M., M.T.R., 
      L.W.K., A.S.W.) and Departments of Internal Medicine (R.A.C., A.V.-d.-A., J.W.R., 
      M.T.R., G.A.Z., A.S.W.), Surgery (L.W.K.), and Neurology (J.J.M.), University of 
      Utah, Salt Lake City. rcampbell@u2m2.utah.edu.
FAU - Vieira-de-Abreu, Adriana
AU  - Vieira-de-Abreu A
AD  - From the Program in Molecular Medicine (R.A.C., J.W.R., Z.G.F., B.K.M., M.T.R., 
      L.W.K., A.S.W.) and Departments of Internal Medicine (R.A.C., A.V.-d.-A., J.W.R., 
      M.T.R., G.A.Z., A.S.W.), Surgery (L.W.K.), and Neurology (J.J.M.), University of 
      Utah, Salt Lake City.
FAU - Rowley, Jesse W
AU  - Rowley JW
AD  - From the Program in Molecular Medicine (R.A.C., J.W.R., Z.G.F., B.K.M., M.T.R., 
      L.W.K., A.S.W.) and Departments of Internal Medicine (R.A.C., A.V.-d.-A., J.W.R., 
      M.T.R., G.A.Z., A.S.W.), Surgery (L.W.K.), and Neurology (J.J.M.), University of 
      Utah, Salt Lake City.
FAU - Franks, Zechariah G
AU  - Franks ZG
AD  - From the Program in Molecular Medicine (R.A.C., J.W.R., Z.G.F., B.K.M., M.T.R., 
      L.W.K., A.S.W.) and Departments of Internal Medicine (R.A.C., A.V.-d.-A., J.W.R., 
      M.T.R., G.A.Z., A.S.W.), Surgery (L.W.K.), and Neurology (J.J.M.), University of 
      Utah, Salt Lake City.
FAU - Manne, Bhanu Kanth
AU  - Manne BK
AD  - From the Program in Molecular Medicine (R.A.C., J.W.R., Z.G.F., B.K.M., M.T.R., 
      L.W.K., A.S.W.) and Departments of Internal Medicine (R.A.C., A.V.-d.-A., J.W.R., 
      M.T.R., G.A.Z., A.S.W.), Surgery (L.W.K.), and Neurology (J.J.M.), University of 
      Utah, Salt Lake City.
FAU - Rondina, Matthew T
AU  - Rondina MT
AD  - From the Program in Molecular Medicine (R.A.C., J.W.R., Z.G.F., B.K.M., M.T.R., 
      L.W.K., A.S.W.) and Departments of Internal Medicine (R.A.C., A.V.-d.-A., J.W.R., 
      M.T.R., G.A.Z., A.S.W.), Surgery (L.W.K.), and Neurology (J.J.M.), University of 
      Utah, Salt Lake City.
FAU - Kraiss, Larry W
AU  - Kraiss LW
AD  - From the Program in Molecular Medicine (R.A.C., J.W.R., Z.G.F., B.K.M., M.T.R., 
      L.W.K., A.S.W.) and Departments of Internal Medicine (R.A.C., A.V.-d.-A., J.W.R., 
      M.T.R., G.A.Z., A.S.W.), Surgery (L.W.K.), and Neurology (J.J.M.), University of 
      Utah, Salt Lake City.
FAU - Majersik, Jennifer J
AU  - Majersik JJ
AD  - From the Program in Molecular Medicine (R.A.C., J.W.R., Z.G.F., B.K.M., M.T.R., 
      L.W.K., A.S.W.) and Departments of Internal Medicine (R.A.C., A.V.-d.-A., J.W.R., 
      M.T.R., G.A.Z., A.S.W.), Surgery (L.W.K.), and Neurology (J.J.M.), University of 
      Utah, Salt Lake City.
FAU - Zimmerman, Guy A
AU  - Zimmerman GA
AD  - From the Program in Molecular Medicine (R.A.C., J.W.R., Z.G.F., B.K.M., M.T.R., 
      L.W.K., A.S.W.) and Departments of Internal Medicine (R.A.C., A.V.-d.-A., J.W.R., 
      M.T.R., G.A.Z., A.S.W.), Surgery (L.W.K.), and Neurology (J.J.M.), University of 
      Utah, Salt Lake City.
FAU - Weyrich, Andrew S
AU  - Weyrich AS
AD  - From the Program in Molecular Medicine (R.A.C., J.W.R., Z.G.F., B.K.M., M.T.R., 
      L.W.K., A.S.W.) and Departments of Internal Medicine (R.A.C., A.V.-d.-A., J.W.R., 
      M.T.R., G.A.Z., A.S.W.), Surgery (L.W.K.), and Neurology (J.J.M.), University of 
      Utah, Salt Lake City.
LA  - eng
GR  - U24 NS107228/NS/NINDS NIH HHS/United States
GR  - R01 HL066277/HL/NHLBI NIH HHS/United States
GR  - U10 NS086606/NS/NINDS NIH HHS/United States
GR  - R03 AG040631/AG/NIA NIH HHS/United States
GR  - U54 HL112311/HL/NHLBI NIH HHS/United States
GR  - K23 HL092161/HL/NHLBI NIH HHS/United States
GR  - R37 HL044525/HL/NHLBI NIH HHS/United States
GR  - K01 GM103806/GM/NIGMS NIH HHS/United States
GR  - R01 AG048022/AG/NIA NIH HHS/United States
GR  - R01 HL126547/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20170803
PL  - United States
TA  - Arterioscler Thromb Vasc Biol
JT  - Arteriosclerosis, thrombosis, and vascular biology
JID - 9505803
RN  - 0 (Chemokine CCL2)
RN  - 0 (Interleukin-8)
SB  - IM
MH  - Blood Coagulation/*physiology
MH  - Chemokine CCL2/biosynthesis/*genetics
MH  - *Gene Expression
MH  - Humans
MH  - Interleukin-8/biosynthesis/*genetics
MH  - Monocytes/*metabolism
MH  - Stroke/drug therapy/*genetics/*physiopathology
MH  - Thrombolytic Therapy
MH  - Thrombosis/drug therapy/prevention & control
MH  - Transcription, Genetic
PMC - PMC5620127
MID - NIHMS895310
OTO - NOTNLM
OT  - fibrin
OT  - fibrinogen
OT  - inflammation
OT  - monocytes
OT  - thrombin
EDAT- 2017/08/05 06:00
MHDA- 2017/10/11 06:00
PMCR- 2018/10/01
CRDT- 2017/08/05 06:00
PHST- 2016/11/09 00:00 [received]
PHST- 2017/07/21 00:00 [accepted]
PHST- 2017/08/05 06:00 [pubmed]
PHST- 2017/10/11 06:00 [medline]
PHST- 2017/08/05 06:00 [entrez]
PHST- 2018/10/01 00:00 [pmc-release]
AID - ATVBAHA.117.309794 [pii]
AID - 10.1161/ATVBAHA.117.309794 [doi]
PST - ppublish
SO  - Arterioscler Thromb Vasc Biol. 2017 Oct;37(10):1819-1827. doi: 
      10.1161/ATVBAHA.117.309794. Epub 2017 Aug 3.