title: Ethyl pyruvate exerts combined anti-inflammatory and anticoagulant effects on human monocytic cells.
abstract: Sepsis is characterized by a concurrent activation of inflammation and coagulation. Recently, recombinant human activated protein C was shown to decrease mortality in patients with severe sepsis presumably due to a combined anti-inflammatory and anticoagulant effect. These promising findings led to a search for other products that influence both the inflammatory and the procoagulant response to severe infection. Ethyl pyruvate (EP) was recently identified as an experimental anti-inflammatory agent during endotoxemia and sepsis. The aim of the present study was to investigate whether EP influences coagulation besides its anti-inflammatory effects. For this we investigated the effects of EP on the expression and function of tissue factor (TF), the principal initiator of coagulation activation in sepsis, in human monocytic (THP-1) cell cultures. EP dose-dependently inhibited the production of tumor necrosis factor (TNF)-alpha, macrophage inflammatory protein (MIP)-1alpha and MIP-1beta by lipopolysaccharide (LPS)-stimulated THP-1 cells at mRNA and protein level, thereby confirming its anti-inflammatory properties in this in-vitro system. In addition, EP dose-dependently attenuated the increases in TF mRNA levels, TF-protein-surface expression and cell-surface-associated TF activity in LPS-stimulated THP-1 cells. These results demonstrate for the first time that EP is a compound with combined anti-inflammatory and anticoagulant effects.
authors.affiliation: Center for Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. M.A.vanZoelen@amc.uva.nl
authors.forename: Marieke A D
authors.initials: MA
authors.lastname: van Zoelen
authors.forename: Kamran
authors.initials: K
authors.lastname: Bakhtiari
authors.forename: Mark C
authors.initials: MC
authors.lastname: Dessing
authors.forename: Cornelis
authors.initials: C
authors.lastname: van't Veer
authors.forename: C Arnold
authors.initials: CA
authors.lastname: Spek
authors.forename: Michael
authors.initials: M
authors.lastname: Tanck
authors.forename: Joost C
authors.initials: JC
authors.lastname: Meijers
authors.forename: Tom
authors.initials: T
authors.lastname: van der Poll
mesh_terms: D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D000925:Anticoagulants / Q000494:pharmacology*; D001777:Blood Coagulation / Q000187:drug effects; D002460:Cell Line; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D019742:Chemokines, CC / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D009000:Monocytes / Q000187:drug effects* / Q000378:metabolism; D011773:Pyruvates / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D013918:Thrombin Time; D013925:Thromboplastin / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D000925:Anticoagulants; C515429:CCL3 protein, human; C066507:CCL4 protein, human; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D019742:Chemokines, CC; D008070:Lipopolysaccharides; D011773:Pyruvates; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; C440499:lipopolysaccharide, Escherichia coli O111 B4; C046522:ethyl pyruvate; D013925:Thromboplastin