title: Effect of cyclo-oxygenase inhibitors and modulators of cyclic AMP formation on lipopolysaccharide-induced neutrophil infiltration in mouse lung.
abstract: 1. The adult respiratory distress syndrome (ARDS) is an acute lung inflammation developed after direct or indirect contact with pathogenic agents. In the present study, a mouse model was developed to mimic this condition using aerosolized bacterial lipopolysaccharide (LPS) and to investigate the mechanisms involved in the lung inflammatory response. 2. Inhalation of LPS led to a time and dose-dependent increase in tumour necrosis factor-alpha (TNF-alpha) production and neutrophil recruitment into the bronchoalveolar lavage fluid (BALF) of Balb/c mice. Under the same conditions, neutrophil infiltration was also found in the BALF of the LPS-sensitive mouse strain C3H/HeN, but was absent in the LPS-resistant strain C3H/HeJ. Intranasal administration of murine recombinant TNF-alpha also triggered neutrophil recruitment. 3. One hour after inhalation of LPS, half of the maximal level of TNF-alpha was measured in the BALF, but only a few neutrophils were detected at this time. The peak TNF-alpha concentration was reached at 3 h, when the neutrophil amount started to increase. At 24 h, maximal neutrophil number was found in the BALF and TNF-alpha was no longer present. 4. Pretreatment of mice under different experimental conditions demonstrated that: (a) cycloheximide almost completely blocks both neutrophil recruitment and TNF-alpha production; (b) anti TNF-alpha antibodies block neutrophil recruitment; (c) indomethacin or aspirin enhance by two fold neutrophil recruitment; (d) indomethacin significantly increases TNF-alpha production 1 h after inhalation of LPS; (e) dibutyryl cyclic AMP and prostaglandin E2 (PGE2) block both neutrophil recruitment and TNF-alpha production. 5. It is concluded that aerosolized LPS in mice triggers an acute lung inflammation which can be used as a potential model of inhalational ARDS and that, strategies leading to the elevation of cyclic AMP levels in vivo can be effective in modulating LPS-induced TNF-alpha synthesis and neutrophil recruitment.
authors.affiliation: Unité de Pharmacologie Cellulaire, Unité Associée Institut Pasteur/INSERM 285, U.K.
authors.forename: V L
authors.initials: VL
authors.lastname: Goncalves de Moraes
authors.forename: B
authors.initials: B
authors.lastname: Boris Vargaftig
authors.forename: J
authors.initials: J
authors.lastname: Lefort
authors.forename: A
authors.initials: A
authors.lastname: Meager
authors.forename: M
authors.initials: M
authors.lastname: Chignard
mesh_terms: D000280:Administration, Inhalation; D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology; D001241:Aspirin / Q000494:pharmacology; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry*; D000242:Cyclic AMP / Q000096:biosynthesis; D003513:Cycloheximide / Q000494:pharmacology; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004195:Disease Models, Animal; D004926:Escherichia coli; D007213:Indomethacin / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000494:pharmacology*; D008168:Lung / Q000187:drug effects; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D009504:Neutrophils / Q000187:drug effects* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000737:chemistry / Q000378:metabolism*
chemical_list: D000935:Antifungal Agents; D016861:Cyclooxygenase Inhibitors; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D003513:Cycloheximide; D000242:Cyclic AMP; D001241:Aspirin; D007213:Indomethacin