Effect of AA-2414, a thromboxane A2 receptor antagonist, on airway inflammation in subjects with asthma.
BACKGROUND
Asthma is a chronic inflammatory disease of the airways. The chemokines are potent chemoattractants for eosinophils and other types of cells associated with allergic inflammation. AA-2414, a new thromboxane A2 receptor antagonist, reduces bronchial hyperresponsiveness in asthmatic subjects, but its mechanism of action is unclear.


OBJECTIVE
We tested the hypothesis that the beneficial effects of AA-2414 in asthma result from reduction in the number of inflammatory cells infiltrating the airway associated with inhibition of chemokine release.


METHODS
We studied bronchial biopsy specimens from 31 asthmatic subjects before and after oral treatment with AA-2414 (80 mg/day) or matched placebo for 4 months in a double-blind manner. Biopsy specimens were examined by immunohistochemistry. Each subject recorded symptom score and peak expiratory flow (PEF). Lung function and bronchial responsiveness to methacholine were measured before and after treatment.


RESULTS
After treatment, significant improvements in symptom score (P <.05), PEF (P <.01), diurnal variation of PEF (P <.01), and bronchial responsiveness (P <.01) were observed in the AA-2414 group compared with the placebo group. These improvements were accompanied by a significant decrease in the number of submucosal EG2(+) eosinophils (P <.05). There was also a reduction in the number of cells expressing RANTES (P <.05) and macrophage inflammatory protein (MIP)-1alpha (P <.05) in the epithelium and of cells expressing monocyte chemotactic protein-3 (P <.01), RANTES (P <.05), MIP-1alpha (P <.01), and eotaxin (P <.01) in the submucosa in the AA-2414 treatment group. A significant correlation was found between the number of EG2(+) eosinophils and numbers of monocyte chemotactic protein-3(+) (rs = 0.52, P <.005), MIP-1alpha+ (rs = 0.34, P <.05), and eotaxin+ cells (r s = 0.47, P <.01) in the submucosa. There was a significant negative correlation between the increase in bronchial responsiveness and the change in number of submucosal EG2(+) cells (rs = -0.65, P <.001).


CONCLUSIONS
These findings suggest that AA-2414 treatment of patients with asthma may inhibit activated eosinophil infiltration in part by modulating the expression of chemokines in bronchial tissues.
Hoshino
M
M
Second Department of Internal Medicine, Toho University School of Medicine, Tokyo, Japan.
Sim
J
J
Shimizu
K
K
Nakayama
H
H
Koya
A
A
D000293:Adolescent; D000328:Adult; D018927:Anti-Asthmatic Agents; D001249:Asthma / Q000188:drug therapy / Q000503:physiopathology*; D016227:Benzoquinones / Q000494:pharmacology*; D001706:Biopsy; D001980:Bronchi / Q000166:cytology / Q000473:pathology; D016535:Bronchial Hyperreactivity / Q000188:drug therapy; D002452:Cell Count / Q000187:drug effects; D018925:Chemokines / Q000096:biosynthesis; D005260:Female; D006538:Heptanoic Acids / Q000494:pharmacology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009092:Mucous Membrane / Q000166:cytology / Q000187:drug effects
D018927:Anti-Asthmatic Agents; D016227:Benzoquinones; D018925:Chemokines; D006538:Heptanoic Acids; C060230:seratrodast