title: Ethyl pyruvate inhibits hypoxic pulmonary vasoconstriction and attenuates pulmonary artery cytokine expression.
abstract: Hypoxic pulmonary vasoconstriction is a common consequence of acute lung injury and may be mediated by increased local production of proinflammatory cytokines. Ethyl pyruvate is a novel anti-inflammatory agent that has been shown to down-regulate proinflammatory genes following hemorrhagic shock; however, its effects on hypoxic pulmonary vasoconstriction are unknown. We hypothesized that ethyl pyruvate would inhibit hypoxic pulmonary vasoconstriction and down-regulate pulmonary artery cytokine expression during hypoxia. To study this, isometric force displacement was measured in isolated rat pulmonary artery rings (n = 8/group) during hypoxia (95% N(2)/5% CO(2)) with or without prior ethyl pyruvate (10 mm) treatment. Following 60 min of hypoxia, pulmonary artery rings were analyzed for tumor necrosis factor-alpha and interleukin-1 mRNA via reverse transcriptase polymerase chain reaction. Ethyl pyruvate inhibited hypoxic pulmonary artery contraction (4.49 +/- 2.32% versus 88.80 +/- 5.68% hypoxia alone) and attenuated the hypoxic up-regulation of pulmonary artery tumor necrosis factor and interleukin-1 mRNA (P < 0.05). These data indicate that (1) hypoxia increases pulmonary artery vasoconstriction and proinflammatory cytokine gene expression; (2) ethyl pyruvate decreases hypoxic pulmonary vasoconstriction and down-regulates hypoxia-induced pulmonary artery proinflammatory cytokine gene expression; and (3) ethyl pyruvate may represent a novel therapeutic adjunct in the treatment of acute lung injury.
authors.affiliation: Department of Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Ben M
authors.initials: BM
authors.lastname: Tsai
authors.forename: Tim
authors.initials: T
authors.lastname: Lahm
authors.forename: Eric D
authors.initials: ED
authors.lastname: Morrell
authors.forename: Paul R
authors.initials: PR
authors.lastname: Crisostomo
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Poynter
authors.forename: Meijing
authors.initials: M
authors.lastname: Wang
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Meldrum
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D016207:Cytokines / Q000378:metabolism*; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects; D000860:Hypoxia / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D007375:Interleukin-1 / Q000378:metabolism; D008168:Lung / Q000098:blood supply / Q000378:metabolism*; D008297:Male; D011651:Pulmonary Artery / Q000187:drug effects / Q000503:physiopathology; D011773:Pyruvates / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014661:Vasoconstriction / Q000187:drug effects*
chemical_list: D000893:Anti-Inflammatory Agents; D016207:Cytokines; D007375:Interleukin-1; D011773:Pyruvates; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; C046522:ethyl pyruvate