title: SK&F 86002, a dual cytokine and eicosanoid inhibitor, attenuates endotoxin-induced cardiopulmonary dysfunction in the pig.
abstract: Cytokines and eicosanoids are well documented important mediators of endotoxemia. Bicyclic imidazoles are a novel class of nonsteroidal anti-inflammatory compounds that display unique pharmacological profiles by reducing cytokine production and arachidonic acid metabolism. In this study, we evaluated the ability of the bicyclic imidazole, SK&F 86002, to attenuate endotoxin-induced cardiopulmonary dysfunction. Pigs were randomly assigned to one of four groups: LPS (n = 5), given .5 microgram/kg/h 055:B5 Escherichia coli lipopolysaccharide (LPS) intravenously (i.v.) for 6 h; saline (n = 5); SK&F 86002 (n = 3), given 50 mg/kg SK&F 86002 orally 30 min prior to anesthesia; and SK&F 86002 + LPS (n = 5). Administration of LPS resulted in cardiopulmonary dysfunction characterized by decreased stroke volume and arterial oxygen tension, and increased room air alveolar-arterial oxygen gradient, pulmonary arterial pressure, pulmonary vascular resistance, and peak intratracheal pressure. Additionally, LPS administration was associated with leukopenia and increased pulmonary myeloperoxidase activity. Pretreatment with SK&F 86002 attenuated LPS induced hypotension, hypoxemia and bronchoconstriction and blocked the pulmonary hypertension. SK&F 86002 blocked the LPS-induced increase in myeloperoxidase activity, indicating a reduction in pulmonary neutrophil infiltration, but had no effect on systemic leukopenia. Pretreatment with SK&F 86002 significantly attenuated LPS-induced increases in plasma thromboxane B2 and tumor necrosis factor-alpha. We hypothesize that ameliorating effects of SK&F 86002 in this endotoxin model of cardiopulmonary dysfunction are related to inhibition of cytokine and eicosanoid biosynthesis.
authors.affiliation: Department of Medical Science, School of Veterinary Medicine, University of Wisconsin, Madison 53706, USA.
authors.forename: E A
authors.initials: EA
authors.lastname: Triplett
authors.forename: K T
authors.initials: KT
authors.lastname: Kruse-Elliott
authors.forename: A P
authors.initials: AP
authors.lastname: Hart
authors.forename: B R
authors.initials: BR
authors.lastname: Schram
authors.forename: P S
authors.initials: PS
authors.lastname: MacWilliams
authors.forename: A J
authors.initials: AJ
authors.lastname: Cooley
authors.forename: M K
authors.initials: MK
authors.lastname: Clayton
authors.forename: B J
authors.initials: BJ
authors.lastname: Darien
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D016207:Cytokines / Q000096:biosynthesis* / Q000187:drug effects; D015777:Eicosanoids / Q000096:biosynthesis*; D019446:Endotoxemia / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006321:Heart / Q000187:drug effects / Q000503:physiopathology*; D007093:Imidazoles / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000633:toxicity; D008168:Lung / Q000098:blood supply / Q000187:drug effects / Q000503:physiopathology; D009195:Peroxidase / Q000187:drug effects / Q000378:metabolism; D013318:Stroke Volume / Q000187:drug effects; D013552:Swine; D013844:Thiazoles / Q000494:pharmacology*; D013931:Thromboxanes / Q000096:biosynthesis; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000187:drug effects; D014655:Vascular Resistance / Q000187:drug effects
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D016207:Cytokines; D015777:Eicosanoids; D007093:Imidazoles; D008070:Lipopolysaccharides; D013844:Thiazoles; D013931:Thromboxanes; D014409:Tumor Necrosis Factor-alpha; C052026:6-(4-fluorophenyl)-2,3-dihydro-5-(4-pyridinyl)imidazo(2,1-b)thiazole; D009195:Peroxidase