Resolvin E1, an EPA-derived mediator in whole blood, selectively counterregulates leukocytes and platelets.
Resolvin E1 (RvE1) is an omega-3 eicosapentaenoic acid (EPA)-derived lipid mediator generated during resolution of inflammation and in human vasculature via leukocyte-endothelial cell interactions. RvE1 possesses anti-inflammatory and proresolving actions. Here, we report that RvE1 in human whole blood rapidly regulates leukocyte expression of adhesion molecules. RvE1 in the 10- to 100-nM range stimulated L-selectin shedding, while reducing CD18 expression in both neutrophils and monocytes. When added to whole blood, RvE1 did not stimulate reactive oxygen species by either neutrophils or monocytes, nor did it directly stimulate cytokine/chemokine production in heparinized blood. Intravital microscopy (IVM) demonstrated that RvE1 rapidly reduced leukocyte rolling (approximately 40%) in venules of mice. In human platelet-rich plasma (PRP), RvE1 selectively blocked both ADP-stimulated and thromboxane receptor agonist U46619-stimulated platelet aggregation in a concentration-dependent manner. In contrast, Delta 6,14-trans-RvE1 isomer was inactive. RvE1 did not block collagen-stimulated aggregation, and regulation of ADP-induced platelet aggregation was not further enhanced with aspirin treatment. These results indicate RvE1 is a potent modulator of leukocytes as well as selective platelet responses in blood and PRP, respectively. Moreover, the results demonstrate novel agonist-specific antiplatelet actions of RvE1 that are potent and may underlie some of the beneficial actions of EPA in humans.
Dona
Maria
M
Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Fredman
Gabrielle
G
Schwab
Jan M
JM
Chiang
Nan
N
Arita
Makoto
M
Goodarzi
Ahmad
A
Cheng
Guiying
G
von Andrian
Ulrich H
UH
Serhan
Charles N
CN
D000818:Animals; D001769:Blood; D001792:Blood Platelets / Q000378:metabolism*; D018821:CD18 Antigens / Q000235:genetics; D015815:Cell Adhesion Molecules / Q000235:genetics; D015118:Eicosapentaenoic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D019041:L-Selectin / Q000235:genetics; D036904:Leukocyte Rolling / Q000187:drug effects; D007962:Leukocytes / Q000378:metabolism*; D051379:Mice; D009000:Monocytes / Q000378:metabolism; D009504:Neutrophils / Q000378:metabolism; D010974:Platelet Aggregation / Q000187:drug effects; D014699:Venules
D018821:CD18 Antigens; D015815:Cell Adhesion Molecules; D019041:L-Selectin; D015118:Eicosapentaenoic Acid; C499823:5S,12R,18R-trihydroxy-6Z,8E,10E,14Z,16E-eicosapentaenoic acid