A prostacyclin agonist with thromboxane inhibitory activity for airway allergic inflammation in mice.
BACKGROUND
ONO-1301 is a novel drug that acts as a prostacyclin agonist with thromboxane A(2) (TxA(2)) synthase inhibitory activity. We investigated the effect of ONO-1301 on development of airway allergic inflammation.


METHODS
Mice sensitized and challenged to ovalbumin (OVA) received ONO-1301, OKY-046 (TxA(2) synthase inhibitor), beraprost, a prostacyclin receptor (IP) agonist, ONO-1301 plus CAY10449 (selective IP antagonist) or vehicle during the challenge period. Twenty-four hours after the OVA challenge, airway hyperresponsiveness (AHR) to methacholine was assessed and bronchoalveolar lavage was performed. Lung specimens were excised for goblet cell staining and analysis of lung dendritic cells (DCs). Bone marrow-derived dendritic cells (BMDCs) were generated, in the presence or absence of drugs, for analysis of DC function.


RESULTS
Mice that received ONO-1301 showed significantly lower AHR, airway eosinophilia, T-helper type 2 cytokine levels, mucus production and lung DCs numbers than vehicle-treated mice. These effects of ONO-1301 were mostly reversed by CAY10449. BMDCs treated with ONO-1301 alone showed lower DC functions, such as expression of costimulatory factors or stimulation to spleen T cells.


CONCLUSIONS
These data suggest that ONO-1301 may suppress AHR and airway allergic inflammation through modulation of DCs, mainly mediated through the IP receptor. This agent may be effective as an anti-inflammatory drug in the treatment of asthma.
Hayashi
M
M
Department of Homeostatic Regulation and Development, Division of Respiratory Medicine, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
Koya
T
T
Kawakami
H
H
Sakagami
T
T
Hasegawa
T
T
Kagamu
H
H
Takada
T
T
Sakai
Y
Y
Suzuki
E
E
Gelfand
E W
EW
Gejyo
F
F
D000818:Animals; D016535:Bronchial Hyperreactivity / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D003713:Dendritic Cells / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D011464:Epoprostenol / Q000008:administration & dosage / Q000819:agonists* / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D007249:Inflammation / Q000188:drug therapy*; D008689:Methacrylates / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D008807:Mice, Inbred BALB C; D010047:Ovalbumin / Q000008:administration & dosage / Q000009:adverse effects; D011725:Pyridines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*; D013931:Thromboxanes / Q000037:antagonists & inhibitors*
D008689:Methacrylates; D011725:Pyridines; D013931:Thromboxanes; C105488:ONO 1301; C048081:beraprost; D010047:Ovalbumin; D011464:Epoprostenol; D013930:Thromboxane-A Synthase; C034364:ozagrel