beraprost and ozagrel

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.. 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.. 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.. 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.

Topics: Animals; Bronchial Hyperreactivity; Dendritic Cells; Disease Models, Animal; Epoprostenol; Female; Inflammation; Methacrylates; Mice; Mice, Inbred BALB C; Ovalbumin; Pyridines; Thromboxane-A Synthase; Thromboxanes

Our in vivo assay system developed to search for allergy-preventive substances, assesses the blood flow decrease in tail vein microcirculation of mice subjected to sensitization with hen-egg white lysozyme (HEL). The blood flow decrease appears to be regulated by various factors such as nitric oxide (NO), thromboxane (TX) A(2), prostacyclin (PGI(2)) and endothelin (ET)-1 together with cyclooxygenase (COX)-1, COX-2, inducible nitric oxide synthase (iNOS), and constitutive nitric oxide synthase (cNOS). In this study, we examined in detail the roles of iNOS in this assay system using an iNOS knockout (KO) mouse. We found that the blood flow decrease in the HEL-sensitized iNOS KO mice was slightly weaker than that in their wild type (WT) mice. This blood flow decrease was not affected by a selective COX-1 inhibitor, a selective COX-2 inhibitor and a PGI(2) agonist unlike the case of the WT mice. However, it was inhibited by a nonselective NOS inhibitor, a specific TXA(2) synthase inhibitor and a specific ET-1 receptor blocker as in the case of the WT mice. The present results indicate that the blood flow decrease occurs via two pathways; one is an iNOS-independent response involving TXA(2) and ET-1, and the other is an iNOS-dependent response involving COX-1, COX-2 and PGI(2). cNOS appears to play some roles in the blood flow decrease and iNOS acts as an exacerbation factor. Our method using HEL-sensitized should be useful for searching for agents that can prevent allergy via new mechanisms.

Topics: Animals; Epoprostenol; Female; Hypersensitivity; Methacrylates; Mice; Mice, Inbred C57BL; Muramidase; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase Type II; Nitrobenzenes; Peptides, Cyclic; Regional Blood Flow; Sulfonamides; Thromboxane A2; Veins