Contribution of leukotriene B4 to airway inflammation and the effect of antagonists.
Inhalation of aerosols of ovalbumin in sensitized guinea pigs produced a marked, bronchoalveolar eosinophilia 24 hr after challenge. The lung eosinophilia was not prevented by the cyclooxygenase inhibitors, indomethacin or PAF antagonists (WEB-2086 and L-652731) but was inhibited by methylprednisolone, the 5-LO inhibitor, U-66858 and a series of structural analogs of LTB4, U-75302, U-77692, U-75485 and U-78489. The effectiveness of LTB4 antagonists but not PAF antagonists in vivo was consistent with in vitro studies in which LTB4 was shown to be far more chemotactic than PAF for guinea pig eosinophils. LTB4 elicited maximal directional migration of guinea pig eosinophils at concentrations from 10(-7) M to 10(-9) M while PAF showed no effect over the same concentration range. The structural analogs of LTB4 were shown to inhibit LTB4 induced chemotaxis of guinea pig eosinophils and produced a dose-related inhibition of binding of LTB4 to guinea pig eosinophil membranes. To add further proof to the hypothesis that LTB4 contributed to the antigen-induced lung eosinophilia we attempted to measure LTB4 release into BAL fluid immediately after and at various time points up to 24 hr after antigen inhalation. However, using a sensitive radioimmunoassay (detection limit 10 pg/ml) very low levels of LTB4 (24.9-67.9 pg/ml) or its metabolite, 20-OH LTB4 (24.9-98.2 pg/ml) were detected in BAL fluid and these levels did not increase significantly following antigen provocation. Inhalation of LTB4 aerosols in unsensitized Brown-Norway rats or inhalation of aerosols of ovalbumin in sensitized Brown-Norway rats also produced a marked "late-phase" eosinophil-rich influx of inflammatory cells into the lungs. The lung eosinophilia in the rat was prevented by two structurally unrelated leukotriene B4 (LTB4) antagonists, U-75302 and Ly255283. These data implicate LTB4 as a mediator of allergen-induced bronchopulmonary eosinophilia. Leukotriene B4 antagonists may provide leads for the development of compounds which inhibit the chronic airway inflammation associated with asthma in man.
Richards
I M
IM
Hypersensitivity Diseases Research, Upjohn Company, Kalamazoo, Michigan 49004.
Sun
F F
FF
Taylor
B M
BM
Shields
S K
SK
Griffin
R L
RL
Morris
J
J
Wishka
D G
DG
Smith
H W
HW
Johnson
R A
RA
Dunn
C J
CJ
D000336:Aerosols; D000818:Animals; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D004804:Eosinophils / Q000187:drug effects / Q000502:physiology; D006168:Guinea Pigs; D007249:Inflammation; D007975:Leukotriene B4 / Q000037:antagonists & inhibitors* / Q000502:physiology*; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology*; D008297:Male; D010047:Ovalbumin / Q000008:administration & dosage / Q000276:immunology; D051381:Rats; D011914:Rats, Inbred BN; D013329:Structure-Activity Relationship
D000336:Aerosols; D016859:Lipoxygenase Inhibitors; D007975:Leukotriene B4; D010047:Ovalbumin