Pertussis toxin induces bronchopulmonary hyperresponsiveness in guinea-pigs while antagonizing the effects of formyl-L-methionyl-L-leucyl-L-phenylalanine.
Pertussis toxin injected i.v. at 0.8-20 micrograms/kg markedly enhanced bronchoconstriction induced by the i.v. administration of histamine or serotonin (5-HT) (0.5-16 micrograms/kg) to propranolol-treated guinea-pigs, under conditions where propranolol or pertussis toxin alone were poorly effective. In contrast, bronchoconstriction and the accompanying leukopenia induced by the i.v. administration of the secretagogue formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLP) were suppressed by pertussis toxin. Bronchoconstriction induced by histamine or 5-HT was not enhanced when perfused lungs from pertussis toxin-treated guinea-pigs were studied in vitro, under conditions where bronchoconstriction and thromboxane A2 release evoked by fMLP were suppressed. Pertussis toxin negatively modifies signal transduction in cells involved in the lung responses to fMLP both in vivo and in vitro, but positively and only in vivo it modifies signal transduction in cells involved in the lung responses to the direct constricting agents histamine and 5-HT. As hyperresponsiveness to histamine and 5-HT were exclusively found in vivo, the target for pertussis toxin is probably not the adrenergic nor the cholinergic systems, since neither hexamethonium, isoprenaline, atropine nor vagotomy were effective. In addition, since dexamethasone and nedocromil sodium were inactive and enrichment of bronchoalveolar lavage with inflammatory cells was not noted, despite lung invasion by neutrophils and lymphocytes, acute inflammation does not account for pertussis toxin-induced hyperresponsiveness.
Imaizumi
A
A
Unité de Pharmacologie Cellulaire, INSERM 285, Paris, France.
Lefort
J
J
Leduc
D
D
Lellouch-Tubiana
A
A
Vargaftig
B B
BB
D000818:Animals; D016535:Bronchial Hyperreactivity / Q000139:chemically induced*; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D016085:Bronchoconstrictor Agents / Q000494:pharmacology*; D003907:Dexamethasone / Q000494:pharmacology; D004357:Drug Synergism; D005260:Female; D006168:Guinea Pigs; D006632:Histamine / Q000494:pharmacology; D066298:In Vitro Techniques; D007958:Leukocyte Count / Q000187:drug effects; D008297:Male; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000037:antagonists & inhibitors*; D017835:Nedocromil; D010477:Perfusion; D037342:Pertussis Toxin; D015363:Quinolones / Q000494:pharmacology; D012701:Serotonin / Q000494:pharmacology; D013929:Thromboxane B2 / Q000378:metabolism; D010566:Virulence Factors, Bordetella / Q000494:pharmacology*
D016085:Bronchoconstrictor Agents; D015363:Quinolones; D010566:Virulence Factors, Bordetella; D017835:Nedocromil; D012701:Serotonin; D013929:Thromboxane B2; D009240:N-Formylmethionine Leucyl-Phenylalanine; D003907:Dexamethasone; D006632:Histamine; D037342:Pertussis Toxin