5-Lipoxygenase and endotoxin-induced microvascular albumin exchanges and leucocyte recruitment in guinea-pig lungs.
The interference of the 5-lipoxygenase inhibitor, BW B70C ((E)-N-(3-[3-(4-fluorophenoxy)phenyl]-1(R,S)-methyl prop-2-enyl)-N-hydroxyurea), with Escherichia coli lipopolysaccharide (endotoxin)-induced lung leucocyte sequestration and microvascular albumin exchanges was evaluated in the anaesthetised guinea-pig using radioactive tracers, in parallel to the effects on cell counts in the broncho-alveolar lavage fluid, blood tumour necrosis factor (TNF-alpha) content, secretion of phospholipase A2 and synthesis of leukotriene C4 by alveolar macrophages. Intravenous injections of 0.1 or 1 mg/kg endotoxin induced lung leucocyte sequestration but only the higher dose induced an increase in albumin microvascular exchanges and the infiltration of leucocytes towards the airway lumen. Leukotriene B4, a potential mediator of the 5-lipoxygenase-dependent endotoxin effects, induced a rapid and transient lung leucocyte sequestration and leucopenia associated with a more progressive increase in microvascular exchanges. The 5-lipoxygenase inhibitor, BW B70C, injected i.p. (30 mg/kg) prevented leukotriene C4 synthesis by alveolar macrophages and reduced leucocyte migration to the airways lumen as well as albumin microvascular leakage but did not affect the endotoxin-induced increase in the blood level of TNF-alpha and of secreted phospholipase A2. However, BW B70C failed to modify vascular leucocyte margination induced by 1 mg/kg endotoxin, suggesting that, apart from a role of 5-lipoxygenase, alternative pathways operate in response to endotoxin in guinea-pig.
Bureau
M F
MF
Unité de Pharmacologie Cellulaire, Unité Associée Institut Pasteur/INSERM U 285, Paris, France. mbureau@infobiogen.fr
De Castro
C M
CM
Cortese
C
C
Bachelet
M
M
Vargaftig
B B
BB
D000818:Animals; D001798:Blood Proteins / Q000378:metabolism; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D001998:Bronchopulmonary Sequestration / Q000139:chemically induced / Q000188:drug therapy*; D002452:Cell Count; D002469:Cell Separation; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004926:Escherichia coli / Q000187:drug effects / Q000378:metabolism; D006168:Guinea Pigs; D006898:Hydroxylamines / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D006918:Hydroxyurea / Q000031:analogs & derivatives*; D007275:Injections, Intravenous; D007553:Isotope Labeling; D007962:Leukocytes / Q000166:cytology / Q000187:drug effects*; D007970:Leukopenia / Q000139:chemically induced; D007975:Leukotriene B4 / Q000633:toxicity; D017997:Leukotriene C4 / Q000096:biosynthesis; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000633:toxicity*; D016859:Lipoxygenase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D008168:Lung / Q000166:cytology / Q000187:drug effects*; D008262:Macrophage Activation / Q000187:drug effects; D016676:Macrophages, Alveolar / Q000166:cytology / Q000378:metabolism; D008782:Methylurea Compounds / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D010741:Phospholipases A / Q000378:metabolism; D054467:Phospholipases A2; D011863:Radioimmunoassay; D012709:Serum Albumin / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D001798:Blood Proteins; D006898:Hydroxylamines; D008070:Lipopolysaccharides; D016859:Lipoxygenase Inhibitors; D008782:Methylurea Compounds; D012709:Serum Albumin; D014409:Tumor Necrosis Factor-alpha; C080871:BW B70C; D007975:Leukotriene B4; D017997:Leukotriene C4; D010741:Phospholipases A; D054467:Phospholipases A2; D006918:Hydroxyurea