Novel inhibitors of pulmonary eosinophil accumulation.
The effects of representatives of three classes of compounds were investigated on antigen-induced bronchopulmonary eosinophilia in sensitized Brown-Norway rats. Rats were sensitized by 3 weekly inhalation provocations with aerosols of ovalbumin. Twenty-four hours after a fourth weekly antigen provocation, cell populations were enumerated following bronchoalveolar lavage (BAL) in animals treated with test compounds or the appropriate vehicle. A marked eosinophil-rich influx of inflammatory cells into the bronchial lumen followed the antigen provocation in sensitized animals. Dose-related inhibitions of antigen-induced lung eosinophilia were demonstrated with: 1) glucocorticoids, given po (methylprednisolone acetate, U-8210) or by inhalation (methylprednisolone suleptanate, U-67590A); 2)the non-glucocorticoid 21-amino steroid, U-75412E, and 3) the leukotriene B4 antagonist, U-75302. The steroids methylprednisolone and U-75412E were tested for glucocorticoid activity using phorbol ester-differentiated U937 (human macrophage) cells. Methylprednisolone but not U-75412E produced a dose-dependent inhibition of lipopolysaccharide-stimulated thromboxane synthesis by the U937 cells. Leukotriene B4 antagonists and the novel 21-aminosteroid, U-75412E, which lacks glucorticoid activity, 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, MI 49004.
Shields
S K
SK
Bienkowski
M J
MJ
Dunn
C J
CJ
Jacobsen
E J
EJ
D000284:Administration, Oral; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D005233:Fatty Alcohols / Q000494:pharmacology*; D005938:Glucocorticoids / Q000494:pharmacology; D006018:Glycols / Q000494:pharmacology*; D007975:Leukotriene B4 / Q000037:antagonists & inhibitors; D008297:Male; D008775:Methylprednisolone / Q000494:pharmacology; D011657:Pulmonary Eosinophilia / Q000517:prevention & control*; D051381:Rats; D013256:Steroids / Q000494:pharmacology*
D005233:Fatty Alcohols; D005938:Glucocorticoids; D006018:Glycols; D013256:Steroids; C062137:U 75302; C069980:U 75412E; D007975:Leukotriene B4; D008775:Methylprednisolone