Alveolar macrophages and eicosanoids but not neutrophils, mediate bronchoconstriction induced by FMLP in the guinea-pig.
1. N-formyl-methionyl-leucyl-phenylalanine (FMLP), when administered by aerosol to guinea-pigs, induced a dose-dependent bronchoconstriction (BC) with no overt effect on platelet and leukocyte blood counts. Repeated administration of FMLP by aerosol was followed by desensitization. 2. Electron microscopy studies showed that administration of FMLP by aerosol is accompanied by alveolar macrophage activation, accumulation and aggregation in the alveolar lumens. Non-degranulated eosinophils were observed in the lungs and a few platelet micro-aggregates in the pulmonary microvasculature. 3. No significant accumulation of 131I-labelled albumin, 111In-labelled neutrophils or 111Inlabelled platelets was detected in the lungs after the administration of FMLP by aerosol, whereas the intravenous administration was accompanied by an increase of extravascular albumin and significant neutrophil sequestration in the lungs. 4. Aspirin administered intravenously or by aerosol reduced significantly the BC induced by an aerosol of FMLP. By contrast, intravenous indomethacin reduced only BC induced by the sub-maximal dose of FMLP as an aerosol whereas, when administered by inhalation, it inhibited BC induced by FMLP administered either intravenously or by aerosol at all the concentrations tested. 5. FMLP induced a dose-dependent contraction of the guinea-pig trachea, which was not inhibited by indomethacin. 6. The dual cyclo-oxygenase/lipoxygenase inhibitor compound BW755C suppressed the BC induced by an aerosol of FMLP at all the concentrations used, whereas the histamine H1-antagonist mepyramine was inactive. 7. Leukocyte depletion with vinblastine failed to reduce BC induced by intravenous or an aerosol of FMLP. 8. Our studies indicate that: (a) FMLP administered by aerosol induces dose-dependent BC followed by desensitization, indicating that local mechanisms account for BC; (b) BC induced by i.v. FMLP, but not by its inhalation, is accompanied by albumin extravasation and neutrophil sequestration in the lungs; (c) BC by either i.v. or an aerosol of FMLP is not due to neutrophil activation; (d) inhalation of FMLP induces BC accompanied by accumulation of activated alveolar macrophages, non-degranulated eosinophils and a few platelet microaggregates in the lung; (e) both cyclo-oxygenase and lipoxygenase metabolites are involved in the BC induced by an aerosol of FMLP.
Boukili
M A
MA
Unité de Pharmacologie cellulaire, Unité Associée Institut Pasteur/INSERM no. 285, Paris, France.
Bureau
M F
MF
Lellouch-Tubiana
A
A
Lefort
J
J
Simon
M T
MT
Vargaftig
B B
BB
D015772:4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-amine / Q000494:pharmacology; D000336:Aerosols; D000818:Animals; D001241:Aspirin / Q000494:pharmacology; D001980:Bronchi / Q000187:drug effects / Q000502:physiology; D016861:Cyclooxygenase Inhibitors; D015777:Eicosanoids / Q000502:physiology*; D005260:Female; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D008084:Lipoxygenase / Q000378:metabolism; D008264:Macrophages / Q000502:physiology*; D008297:Male; D009130:Muscle, Smooth / Q000187:drug effects*; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000008:administration & dosage / Q000494:pharmacology*; D009504:Neutrophils / Q000502:physiology*; D011650:Pulmonary Alveoli / Q000166:cytology*; D014132:Trachea / Q000187:drug effects; D014747:Vinblastine / Q000494:pharmacology
D000336:Aerosols; D016861:Cyclooxygenase Inhibitors; D015777:Eicosanoids; D009240:N-Formylmethionine Leucyl-Phenylalanine; D014747:Vinblastine; D015772:4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-amine; D008084:Lipoxygenase; D001241:Aspirin; D007213:Indomethacin