Modulation by dexamethasone of phospholipase A2 activities in endotoxemic guinea pigs.
One hour after lipopolysaccharide (LPS) administration (intravenous) in guinea pigs, alveolar macrophages are primed for an ex vivo increased secretion of arachidonic acid metabolites from the cyclooxygenase and the lipoxygenase pathways, with challenge by a second stimulus. At the same time, maximal levels of tumor necrosis factor-alpha (TNF-alpha) are observed in the circulation and in the bronchoalveolar lavage fluid. An extracellular form of phospholipase A2, corresponding probably to the low-molecular-mass type II enzyme, known to accumulate in inflammatory exudates, appears later in the serum of guinea pigs, to reach maximal levels 6 h after the LPS. Unlike the intracellular enzyme, extracellular phospholipase A2 is not increased by LPS in alveolar macrophages or in bronchoalveolar lavage fluids. After 24 h, at the time when neither TNF-alpha nor extracellular phospholipase A2 is present and priming of macrophages is over, maximal neutrophil infiltration is observed in the alveolar space of LPS-treated guinea pigs. Dexamethasone administered repeatedly during 3 days (subcutaneous) before the LPS challenge prevented both early events such as the macrophage priming and the TNF-alpha appearance and later events such as extracellular phospholipase A2 release and neutrophil recruitment.
De Castro
C M
CM
Unité de Pharmacologie Cellulaire, Unité Associée Institut Pasteur-Institut National de la Santé et de la Recherche Médicale 285, Paris, France.
Bureau
M F
MF
Nahori
M A
MA
Dumarey
C H
CH
Vargaftig
B B
BB
Bachelet
M
M
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D016718:Arachidonic Acid / Q000378:metabolism; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D003907:Dexamethasone / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects; D006168:Guinea Pigs; D007700:Kinetics; D017997:Leukotriene C4 / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000633:toxicity; D008168:Lung / Q000201:enzymology / Q000503:physiopathology; D008262:Macrophage Activation / Q000187:drug effects; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009504:Neutrophils / Q000187:drug effects; D010741:Phospholipases A / Q000378:metabolism*; D054467:Phospholipases A2; D012772:Shock, Septic / Q000201:enzymology*; D013928:Thromboxane A2 / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D000893:Anti-Inflammatory Agents; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D016718:Arachidonic Acid; D017997:Leukotriene C4; D013928:Thromboxane A2; D009240:N-Formylmethionine Leucyl-Phenylalanine; D003907:Dexamethasone; D010741:Phospholipases A; D054467:Phospholipases A2