Effect of thromboxane A2 inhibitors on allergic pulmonary inflammation in mice.
Thromboxane (Tx)A2 synthase inhibitors and thromboxane prostanoid (TP) receptor antagonists have been developed as anti-asthma drugs. TxA2 may contribute to airflow limitation and bronchial hyperresponsiveness, and these compounds have been demonstrated to improve them. However, it is not known whether TxA2 is involved in bronchial inflammation. To address this question, we explored the influences of OKY-046 (a TxA2 synthase inhibitor) and S-1452 (a TP receptor antagonist) on eosinophilic inflammation of the airways using a murine model. BALB/c mice sensitized with ovalbumin and challenged by repeated exposure to ovalbumin yielded marked eosinophilia in bronchoalveolar lavage fluid (BALF). Treatment with either compound significantly reduced the number of total cells and eosinophils in BALF in a dose-dependent manner. The production of interleukin (IL)-5, IL-2 and interferon (IFN)-gamma by antigen-stimulated splenic mononuclear cells (SMNC) was significantly decreased in mice treated with either compound compared to that in untreated mice. Furthermore, both compounds inhibited proliferation and cytokine production of SMNC in vitro. These results suggest that both OKY-046 and S-1452 are capable of inhibiting production of cytokines, which in turn inhibits eosinophil infiltration into the murine airway. Thus, both thromboxane A2 synthesis inhibitors and thromboxane prostanoid antagonists may be effective as anti-inflammatory drugs in the treatment of asthma.
Shi
H
H
Second Dept of Internal Medicine, Ehime University School of Medicine, Japan.
Yokoyama
A
A
Kohno
N
N
Hirasawa
Y
Y
Kondo
K
K
Sakai
K
K
Hiwada
K
K
D000818:Animals; D001249:Asthma / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D001643:Bridged Bicyclo Compounds / Q000627:therapeutic use*; D016535:Bronchial Hyperreactivity / Q000188:drug therapy / Q000276:immunology / Q000503:physiopathology; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D016207:Cytokines / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005229:Fatty Acids, Monounsaturated / Q000627:therapeutic use*; D008689:Methacrylates / Q000627:therapeutic use*; D051379:Mice; D008807:Mice, Inbred BALB C; D011448:Prostaglandin Antagonists / Q000627:therapeutic use*; D011657:Pulmonary Eosinophilia / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*
D001643:Bridged Bicyclo Compounds; D016207:Cytokines; D004791:Enzyme Inhibitors; D005229:Fatty Acids, Monounsaturated; D008689:Methacrylates; D011448:Prostaglandin Antagonists; C056566:S 145; D013930:Thromboxane-A Synthase; C034364:ozagrel