ovalbumin and beraprost

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

The inhibition of prostaglandin (PG) synthesis is at the center of current anti-inflammatory therapies. Because cyclooxygenase-2 (COX-2) inhibitors and nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit the formation of multiple PGs, there is currently a strong focus on characterizing the role of the different PGs in the inflammation process and development of arthritis. Evidence to date suggests that both PGE(2) and PGI(2) act as mediators of pain and inflammation. Most of the data indicating a role for PGI(2) in this context have been generated in animal models of acute pain. Herein, we describe the role of PGI(2) in models of osteoarthritis (OA) and rheumatoid arthritis using a highly selective PGI(2) receptor (IP, Ptgir) antagonist and IP receptor-deficient mice. In the rat OA model using monoiodoacetate injection into the knee joint, the IP antagonist reduced pain with an efficacy approaching that of the NSAID diclofenac. In a chronic model of inflammatory arthritis, collagen-antibody induced arthritis model in mice, IP receptor-deficient mice displayed a 91% reduction in arthritis score. Interestingly, pretreatment with the IP [N-[4-(imidazolidin-2-ylideneamino)-benzyl]-4-methoxy-benzamide] antagonist in this model also caused a significant reduction of the symptoms, whereas administration of the compound after the initiation of arthritis had no detectable effect. Our data indicate that, in addition to its role in acute inflammation, PGI(2) is involved in the development of chronic inflammation. The results also suggest that the inhibition of PGI(2) synthesis by NSAIDs and COX-2 inhibitors, in addition to that of PGE(2), contributes to their efficacy in treating the signs of arthritis.

Topics: Animals; Arthritis, Experimental; Carrageenan; Chromatography, High Pressure Liquid; Chronic Disease; Collagen; Cyclooxygenase 2 Inhibitors; Edema; Epoprostenol; Hot Temperature; Hyperalgesia; Inflammation; Iodoacetates; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Osteoarthritis; Ovalbumin; Pain; Prostaglandins I; Rats; Rats, Sprague-Dawley; Receptors, Epoprostenol