Effects of wortmannin on airways inflammation induced by allergen in actively sensitised Brown Norway rats.
We have investigated the effect of wortmannin, a potent and selective inhibitor of phosphatidylinositol-3-kinase, on the immediate-type allergic response and the late phase pulmonary inflammation induced by allergen challenge in the ovalbumin-sensitised Brown Norway rat. Intratracheal (i.t.) instillation of ovalbumin induced dose-related bronchoconstrictor responses. Administration of wortmannin (1, 10 or 100 microg kg(-1) i.t., 1 h prior to challenge) induced a marked and dose-dependent inhibition of ovalbumin-induced bronchospasm (ED(50) ca. 5 microg kg(-1) i.t.). At similar doses, wortmannin also suppressed the bronchoconstrictor responses to 5-hydroxytryptamine and methacholine but the degree of blockade of these spasmogens (1.4-1.9-fold) was less than that of ovalbumin (>20-fold). Wortmannin, given intratracheally 1 h prior to allergen challenge, also suppressed the increases in bronchoalveolar lavage fluid leukocyte numbers and eosinophil peroxidase activity measured 24 h post challenge. However, relatively high doses were necessary (ED(50) ca. 100 microg kg(-1) i.t.). The potency of wortmannin was increased when dosed 1 h prior to and 24 h after allergen challenge and the readout was 48 h after challenge (ED(50) 3-5 microg kg(-1) i.t.). Thus, wortmannin is a potent inhibitor of the bronchoconstrictor response induced by allergen in the airways of actively sensitised Brown Norway rats. Inhibition of phosphatidylinositol-3-kinase, an obligatory step in mast cell activation in response to allergen, is the presumed mechanism of action. The fact that similar doses of wortmannin do not suppress the late response to allergen suggests a minimal role for the mast cell in generating the late response to allergen in this model. The striking increase in potency to inhibit the late response when dosed 1 h prior to and 24 h after allergen challenge with the readout taken at 48 h may represent an effect of wortmannin to suppress the migration of leukocytes.
Tigani
B
B
Research Department, Novartis Pharma AG, WSJ-386.510, CH-4002 Basel, Switzerland.
Hannon
J P
JP
Mazzoni
L
L
Fozard
J R
JR
D000485:Allergens / Q000276:immunology*; D000730:Androstadienes / Q000494:pharmacology*; D000818:Animals; D016084:Bronchoconstriction / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D007249:Inflammation / Q000517:prevention & control*; D008168:Lung / Q000187:drug effects*; D008297:Male; D008407:Mast Cells / Q000502:physiology; D010047:Ovalbumin / Q000276:immunology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051381:Rats; D011914:Rats, Inbred BN; D000077191:Wortmannin
D000485:Allergens; D000730:Androstadienes; D004791:Enzyme Inhibitors; D010047:Ovalbumin; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D000077191:Wortmannin