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CGS 8515 and indomethacin attenuate cytokine-induced cardiopulmonary dysfunction in pigs.

Abstract
We evaluated the effect of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 alpha (IL-1 alpha) on pig cardiopulmonary function by intravenously infusing each cytokine individually or in combination (0.5 microgram/kg from 0 to 0.5 h + 5 ng.kg-1 x min-1 from 0.5 to 6 h for each cytokine). The role of eicosanoids in mediating the TNF-alpha + IL-1 alpha-induced cardiopulmonary dysfunction was also investigated by pretreating cytokine-infused pigs with CGS 8515 (5-lipoxygenase inhibitor) or indomethacin (cyclooxygenase inhibitor). Coinfusion of TNF-alpha with IL-1 alpha caused additive increases (P < 0.05) in total peripheral resistance and plasma concentrations of 6-keto-prostaglandin F1 alpha (PGF1 alpha). The increases in mean pulmonary arterial pressure (Ppa), pulmonary vascular resistance (PVR), alveolar-arterial O2 gradient (AaDO2), alveolar dead space-to-tidal volume ratio (VD/VT), and plasma concentrations of thromboxane B2 were either additive or synergistic. CGS 8515 blocked the TNF-alpha + IL-1 alpha-induced increases (P < 0.05) in mean aortic pressure, total peripheral resistance (4-6 h), VD/VT (5-6 h), and, at 6 h, attenuated the increases in Ppa, PVR, and AaDO2. Indomethacin blocked or attenuated the cytokine-induced increases (P < 0.05) in Ppa, PVR, AaDO2, VD/VT, and plasma concentrations of thromboxane B2 and 6-keto-PGF1 alpha. The 1-to 2-h systemic hypotension, caused by TNF-alpha + IL-1 alpha, was not abrogated by either indomethacin or CGS 8515. The cytokines did not alter plasma concentrations of leukotriene B4 or 5-hydroxyeicosatetraenoic acid. We conclude that coinfusion of TNF-alpha with IL-1 alpha induces physiological responses that are additive or synergistic and that cyclooxygenase and 5-lipoxygenase products (other than leukotriene B4 and 5-hydroxyeicosatetraenoic acid) importantly mediate cardiopulmonary dysfunction in pigs infused with TNF-alpha + IL-1 alpha.
AuthorsK T Kruse-Elliott, N C Olson
JournalThe American journal of physiology (Am J Physiol) Vol. 264 Issue 4 Pt 2 Pg. H1076-86 (Apr 1993) ISSN: 0002-9513 [Print] United States
PMID8386479 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Albumins
  • Arachidonic Acids
  • Cyclooxygenase Inhibitors
  • Cytokines
  • Eicosanoids
  • Hydroxyeicosatetraenoic Acids
  • Interleukin-1
  • Lipoxygenase Inhibitors
  • Naphthoquinones
  • Tumor Necrosis Factor-alpha
  • ortho-Aminobenzoates
  • methyl 2-((3,4-dihydro-3,4-dioxo-1-naphthalenyl)amino)benzoate
  • Leukotriene B4
  • 5-hydroxy-6,8,11,14-eicosatetraenoic acid
  • Thromboxane B2
  • 6-Ketoprostaglandin F1 alpha
  • Dinoprost
  • Indomethacin
Topics
  • 6-Ketoprostaglandin F1 alpha (blood)
  • Albumins (analysis)
  • Animals
  • Arachidonic Acids (metabolism)
  • Bronchoalveolar Lavage Fluid (chemistry)
  • Chromatography, High Pressure Liquid
  • Cyclooxygenase Inhibitors (pharmacology)
  • Cytokines (adverse effects)
  • Dinoprost (blood)
  • Drug Synergism
  • Eicosanoids (metabolism)
  • Heart (drug effects, physiopathology)
  • Heart Diseases (chemically induced, physiopathology)
  • Hydroxyeicosatetraenoic Acids (blood)
  • Indomethacin (pharmacology)
  • Injections, Intravenous
  • Interleukin-1 (administration & dosage, pharmacology)
  • Leukotriene B4 (blood)
  • Lipoxygenase Inhibitors (pharmacology)
  • Lung (blood supply, chemistry, physiopathology)
  • Lung Diseases (chemically induced, physiopathology)
  • Naphthoquinones (pharmacology)
  • Swine (physiology)
  • Thromboxane B2 (blood)
  • Tumor Necrosis Factor-alpha (administration & dosage, pharmacology)
  • Vascular Resistance (drug effects, physiology)
  • ortho-Aminobenzoates (pharmacology)

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