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Alveolar macrophages and eicosanoids but not neutrophils, mediate bronchoconstriction induced by FMLP in the
M A Boukili1, M F Bureau, A Lellouch-Tubiana
1Unité de Pharmacologie cellulaire, Unité Associée Institut Pasteur/INSERM no. 285, Paris, France.
Abstract:
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.
Insights
N-formyl-methionyl-leucyl-phenylalanine (FMLP) aerosol causes dose-dependent bronchoconstriction in guinea pigs, involving local mechanisms and inflammatory cell activation. Both cyclooxygenase and lipoxygenase metabolites contribute to this FMLP-induced airway response.
Area of Science:
- Pulmonary Pharmacology
- Respiratory Medicine
- Inflammation Research
Background:
- N-formyl-methionyl-leucyl-phenylalanine (FMLP) is a potent chemoattractant for neutrophils and other inflammatory cells.
- The role of FMLP in inducing airway hyperresponsiveness and bronchoconstriction requires further elucidation, particularly concerning its administration route and underlying mechanisms.
Purpose of the Study:
- To investigate the effects of aerosolized N-formyl-methionyl-leucyl-phenylalanine (FMLP) on guinea pig airways.
- To characterize the cellular and biochemical mechanisms underlying FMLP-induced bronchoconstriction (BC).
- To compare the effects of aerosol versus intravenous FMLP administration on lung physiology and inflammatory markers.
Main Methods:
- Aerosolized and intravenous administration of FMLP to guinea pigs.
- Measurement of dose-dependent bronchoconstriction (BC).
- Electron microscopy for cellular analysis in lung tissue.
- Assessment of albumin extravasation and inflammatory cell sequestration (neutrophils, platelets) using radiolabeled tracers.
- Pharmacological inhibition studies using aspirin, indomethacin, BW755C, and mepyramine.
- Leukocyte depletion using vinblastine.
Main Results:
- Aerosolized FMLP induced dose-dependent BC and desensitization, with no significant changes in blood leukocyte or platelet counts.
- Electron microscopy revealed alveolar macrophage activation, eosinophil presence, and platelet microaggregates in the lungs following aerosolized FMLP.
- Intravenous FMLP, but not aerosolized FMLP, led to albumin extravasation and neutrophil sequestration in the lungs.
- Aspirin and indomethacin (especially inhaled) partially or significantly inhibited FMLP-induced BC, while BW755C (dual inhibitor) suppressed it effectively.
- Histamine H1-antagonist mepyramine was ineffective, and leukocyte depletion did not reduce FMLP-induced BC.
Conclusions:
- Aerosolized FMLP induces bronchoconstriction primarily through local lung mechanisms, involving activated alveolar macrophages and inflammatory mediators.
- Both cyclooxygenase and lipoxygenase metabolites play a significant role in mediating aerosolized FMLP-induced bronchoconstriction.
- The mechanisms of bronchoconstriction differ between aerosolized and intravenous FMLP, with the latter involving systemic inflammatory cell recruitment.