Enhanced arachidonic acid metabolism in alveolar macrophages from wheezy infants. Modulation by dexamethasone.
To test the hypothesis that alveolar macrophages (AM) from wheezy infants release increased amounts of eicosanoids, as do AM from adults with asthma, we compared eicosanoid release by unstimulated- and ionophore-A23187-stimulated AM from 13 wheezy and six nonwheezy infants and analyzed its regulation by dexamethasone in vitro. Alveolar macrophages from wheezy infants released greater amounts of thromboxane A2 (TxA2) and leukotriene B4 (LTB4) under resting conditions and of TxA2 upon stimulation than did those from control subjects. Dexamethasone induced a dose-dependent inhibition of the spontaneous and A23187-stimulated release of TxA2, but not of the A23187-stimulated release of lipoxygenase products. The inhibition of TxA2 formation was maintained when free arachidonic acid was added during A23187 stimulation, demonstrating that dexamethasone acted mainly at a postphospholipase A2 site. AM exposed to acetylsalicylate and then incubated overnight exhibited de novo cyclooxygenase synthesis, suggesting the presence of the inducible cyclooxygenase as a target for inhibition by dexamethasone. In conclusion, our findings suggest that AM from wheezy infants are activated in vivo to release eicosanoids, as are AM from asthmatic adults, and they support the therapeutic indications of glucocorticoids in severe recurrent wheezing of infancy.
Azevedo
I
I
Unité de Pharmacologie Cellulaire, Unité Associée Institut Pasteur-INSERM, Paris, France.
de Blic
J
J
Scheinmann
P
P
Vargaftig
B B
BB
Bachelet
M
M
D000328:Adult; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D016718:Arachidonic Acid / Q000378:metabolism*; D001241:Aspirin / Q000031:analogs & derivatives / Q000494:pharmacology; D000001:Calcimycin / Q000494:pharmacology; D016022:Case-Control Studies; D003907:Dexamethasone / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D007223:Infant; D007476:Ionophores / Q000494:pharmacology; D007975:Leukotriene B4 / Q000378:metabolism; D008239:Lysine / Q000031:analogs & derivatives / Q000494:pharmacology; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D012135:Respiratory Sounds; D013928:Thromboxane A2 / Q000378:metabolism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D005938:Glucocorticoids; D007476:Ionophores; D007975:Leukotriene B4; D016718:Arachidonic Acid; D000001:Calcimycin; D013928:Thromboxane A2; D003907:Dexamethasone; D008239:Lysine; D001241:Aspirin; C010395:acetylsalicylic acid lysinate