Effect of dexamethasone and endogenous corticosterone on airway hyperresponsiveness and eosinophilia in the mouse.
1. Mice were sensitized by 7 intraperitoneal injections of ovalbumin without adjuvant (10 micrograms in 0.5 ml of sterile saline) on alternate days and after 3 weeks exposed to either ovalbumin (2 mg ml-1 in sterile saline) or saline aerosol for 5 min on 8 consecutive days. One day before the first challenge, animals were injected intraperitoneally on a daily basis with vehicle (0.25 ml sterile saline), dexamethasone (0.5 mg kg-1) or metyrapone (30 mg kg-1). 2. In vehicle-treated ovalbumin-sensitized animals ovalbumin challenge induced a significant increase of airway responsiveness to metacholine both in vitro (27%, P < 0.05) and in vivo (40%, P < 0.05) compared to saline-challenged mice. Virtually no eosinophils could be detected after saline challenge, whereas the numbers of eosinophils were significantly increased (P < 0.01) at both 3 and 24 h after the last ovalbumin challenge (5.48 +/- 3.8 x 10(3) and 9.13 +/- 1.7 x 10(3) cells, respectively). Furthermore, a significant increase in ovalbumin-specific immunoglobulin E level (583 +/- 103 units ml-1, P < 0.05) was observed after ovalbumin challenge compared to saline challenge (201 +/- 38 units ml-1). 3. Plasma corticosterone level was significantly reduced (-92%, P < 0.001) after treatment with metyrapone. Treatment with metyrapone significantly increased eosinophil infiltration (17.4 +/- 9.93 x 10(3) and 18.7 +/- 2.57 x 10(3) cells, P < 0.05 at 3 h and 24 h, respectively) and potentiated airway hyperresponsiveness to methacholine compared to vehicle-treated ovalbumin-challenged animals. Dexamethasone inhibited both in vitro and in vivo hyperresponsiveness as well as antigen-induced infiltration of eosinophils (0, P < 0.05 and 0.7 +/- 0.33 x 10(3) cells, P < 0.05 at 3 h and 24 h, respectively). Metyrapone as well as dexamethasone did not affect the increase in ovalbumin-specific immunoglobulin E levels after ovalbumin challenge (565 +/- 70 units/ml-1; P < 0.05; 552 +/- 48 units ml-1, P < 0.05 respectively). 4. From these data it can be concluded that exogenously applied corticosteroids can inhibit eosinophil infiltration as well as airway hyperresponsiveness. Vise versa, endogenously produced corticosteroids play a down-regulating role on the induction of both eosinophil infiltration and airway hyperresponsiveness.
De Bie
J J
JJ
Department of Pharmacology and Pathophysiology, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, The Netherlands.
Hessel
E M
EM
Van Ark
I
I
Van Esch
B
B
Hofman
G
G
Nijkamp
F P
FP
Van Oosterhout
A J
AJ
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001249:Asthma / Q000473:pathology / Q000503:physiopathology; D016535:Bronchial Hyperreactivity / Q000473:pathology / Q000503:physiopathology*; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D001993:Bronchodilator Agents / Q000494:pharmacology; D003345:Corticosterone / Q000097:blood / Q000502:physiology*; D003907:Dexamethasone / Q000494:pharmacology*; D004802:Eosinophilia / Q000097:blood*; D007073:Immunoglobulin E / Q000096:biosynthesis; D066298:In Vitro Techniques; D008297:Male; D016210:Methacholine Chloride / Q000494:pharmacology; D008797:Metyrapone / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D010047:Ovalbumin / Q000276:immunology
D000893:Anti-Inflammatory Agents; D001993:Bronchodilator Agents; D016210:Methacholine Chloride; D007073:Immunoglobulin E; D003907:Dexamethasone; D010047:Ovalbumin; D003345:Corticosterone; D008797:Metyrapone