Anti-inflammatory activity of inhaled mometasone furoate in allergic mice.
Mometasone furoate (CAS 83919-23-7, Sch 32088) is a new inhaled corticosteroid that is being developed to treat allergic inflammatory airway disorders such as rhinitis and asthma. In this study, we investigated the effects of inhaled mometasone furoate in allergic mice that, after antigen challenge, develop an influx of eosinophils and T cells and display an increased mRNA expression of proinflammatory cytokines in the lungs. Mometasone furoate aerosol was generated from metered dose inhalers and delivered into an animal exposure chamber. The mice were exposed to mometasone furoate by nose-only inhalation at respired doses ranging from 0.5-33 micrograms/kg given 24, 18 and 2 h before aeroallergen challenge. The elevated eosinophil numbers in the bronchoalveolar lavage fluid and lung tissues of sensitized, ovalbumin challenged mice were dose-dependently inhibited by inhaled mometasone furoate. Increased numbers of Thy1+ T cells and CD4+ (T-helper) and CD8+ (T-cytotoxic) T cell subsets were seen in the bronchoalveolar lavage fluid of ovalbumin-challenged mice. Pretreatment of these animals with mometasone furoate (33 micrograms/kg) reduced the number of Thy1+ T cells and the T-helper subset. Furthermore, mometasone furoate (33 micrograms/kg) reduced the percentage of CD44+ T-helper cells (activated/memory cells) to the levels observed in non-sensitized, ovalbumin-challenged mice. There were increased levels of steady-state mRNA for interleukin-4, interleukin-5, and to a lesser extent, gamma-interferon in the lungs of sensitized mice after ovalbumin challenge and pretreatment with mometasone furoate reduced the steady-state mRNA levels of these cytokines. Our results demonstrate a potent lung anti-inflammatory effect of inhaled mometasone furoate and identify that inhibition of T cell influx, eosinophil accumulation and modulation of cytokine activity are important components of this response.
Chapman
R W
RW
Department of Allergy, Schering-Plough Research Institute, Kenilworth, New Jersey, USA.
Sehring
S J
SJ
Garlisi
C G
CG
Falcone
A
A
Kung
T T
TT
Stelts
D
D
Minnicozzi
M
M
Jones
H
H
Umland
S
S
Egan
R W
RW
Kreutner
W
W
D000280:Administration, Inhalation; D000485:Allergens; D000818:Animals; D018926:Anti-Allergic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D016207:Cytokines / Q000378:metabolism; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D000068656:Mometasone Furoate; D010641:Phenotype; D016133:Polymerase Chain Reaction; D011244:Pregnadienediols / Q000008:administration & dosage / Q000627:therapeutic use*; D012313:RNA / Q000302:isolation & purification
D000485:Allergens; D018926:Anti-Allergic Agents; D000893:Anti-Inflammatory Agents; D016207:Cytokines; D011244:Pregnadienediols; D000068656:Mometasone Furoate; D012313:RNA