RPR 106541, a novel, airways-selective glucocorticoid: effects against antigen-induced CD4+ T lymphocyte accumulation and cytokine gene expression in the Brown Norway rat lung.
1. The effects of a novel 17-thiosteroid, RPR 106541, were investigated in a rat model of allergic airway inflammation. 2. In sensitized Brown Norway rats, challenge with inhaled antigen (ovalbumin) caused an influx of eosinophils and neutrophils into the lung tissue and airway lumen. In the lung tissue there was also an accumulation of CD4+ T lymphocytes and increased expression of mRNA for interleukin-4 (IL-4) and IL-5, but not interferon-gamma (IFN-gamma). These findings are consistent with an eosinophilia orchestrated by activated Th2-type cells. 3. RPR 106541 (10-300 microg kg[-1]), administered by intratracheal instillation into the airways 24 h and 1 h before antigen challenge, dose-dependently inhibited cell influx into the airway lumen. RPR 106541 (100 microg kg[-1]) caused a significant (P<0.01) (98%) inhibition of eosinophil influx and a significant (P<0.01) (100%) inhibition of neutrophil influx. RPR 106541 was approximately 7 times and 4 times more potent than budesonide and fluticasone propionate, respectively. 4. When tested at a single dose (300 microg kg[-1]), RPR 106541 and fluticasone each caused a significant (P<0.01) (100%) inhibition of CD4+ T cell accumulation in lung tissue. Budesonide (300 microg kg[-1]) had no significant effect. RPR 106541 and fluticasone (300 microg kg[-1]), but not budesonide (300 microg kg[-1]), significantly (P<0.05) inhibited the expression within lung tissue of mRNA for IL-4. RPR 106541 (300 microg kg[-1]) also significantly (P<0.05) inhibited expression of mRNA for IL-5. 5. The high topical potency of RPR 106541 in this model, which mimics important aspects of airway inflammation in human allergic asthmatics, suggests that this glucocorticoid may be useful in the treatment of bronchial asthma.
Underwood
S L
SL
Rhône-Poulenc Rorer Ltd., Dagenham Research Centre, Essex.
Raeburn
D
D
Lawrence
C
C
Foster
M
M
Webber
S
S
Karlsson
J A
JA
D000730:Androstadienes / Q000494:pharmacology; D000736:Androstenes / Q000494:pharmacology*; D000818:Animals; D018927:Anti-Asthmatic Agents / Q000494:pharmacology*; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D019819:Budesonide / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D004804:Eosinophils / Q000276:immunology; D005434:Flow Cytometry; D000068298:Fluticasone; D015870:Gene Expression / Q000187:drug effects*; D015847:Interleukin-4 / Q000276:immunology; D015848:Interleukin-5 / Q000276:immunology; D008168:Lung / Q000276:immunology*; D008297:Male; D009504:Neutrophils / Q000276:immunology; D010047:Ovalbumin / Q000276:immunology; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D011914:Rats, Inbred BN
D000730:Androstadienes; D000736:Androstenes; D018927:Anti-Asthmatic Agents; D000893:Anti-Inflammatory Agents; D016207:Cytokines; D015848:Interleukin-5; D012333:RNA, Messenger; D015847:Interleukin-4; D019819:Budesonide; C109111:RPR 106541; D010047:Ovalbumin; D000068298:Fluticasone