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1 Department of Regenerative Medicine and Tissue Engineering, National Cardiovascular Center Research Institute, Suita, Osaka, Japan; Second Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan
2 Department of Regenerative Medicine and Tissue Engineering, National Cardiovascular Center Research Institute, Suita, Osaka, Japan; Department of Internal Medicine, National Cardiovascular Center, Suita, Osaka, Japan
3 Second Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan
4 Department of Regenerative Medicine and Tissue Engineering, National Cardiovascular Center Research Institute, Suita, Osaka, Japan
5 Department of Internal Medicine, National Cardiovascular Center, Suita, Osaka, Japan
6 Department of Cardiac Physiology, National Cardiovascular Center Research Institute, Suita, Osaka, Japan
7 Research Headquarters, Ono Pharmaceutical Co., Ltd., Mishima, Osaka, Japan
8 Department of Biochemistry, National Cardiovascular Center Research Institute, Suita, Osaka, Japan
* To whom correspondence should be addressed. E-mail: nnagaya{at}ri.ncvc.go.jp.
The balance between prostacyclin and thromboxane A2 (TXA2) plays an important role in pulmonary homeostasis. However, little information is available regarding the therapeutic potency of these prostanoids for pulmonary fibrosis. We have recently developed ONO-1301, a novel long-acting prostacyclin agonist with thromboxane synthase inhibitory activity. Thus, we investigated whether repeated administration of ONO-1301 attenuates bleomycin-induced pulmonary fibrosis in mice. After intratracheal injection of bleomycin or saline, mice were randomized to receive repeated subcutaneous administration of ONO-1301 or vehicle. Bronchoalveolar lavage (BAL) and histological analyses were performed at 3, 7, and 14 days after bleomycin injection. In vitro studies using mouse lung fibroblasts were also performed. ONO-1301 significantly attenuated the development of bleomycin-induced pulmonary fibrosis, as indicated by significant decreases in Ashcroft score and lung hydroxyproline content. ONO-1301 significantly reduced total cell count, neutrophil count, and total protein level in BAL fluid in association with a marked reduction of thromboxane B2. A single administration of ONO-1301 significantly increased plasma cAMP level for more than two hours. In vitro, ONO-1301 and a cAMP analog dose-dependently reduced cell proliferation in mouse lung fibroblasts. The reduction in cell proliferation by ONO-1301 was attenuated by a protein kinase A (PKA) inhibitor. Furthermore, bleomycin mice treated with ONO-1301 had a significantly higher survival rate than those given vehicle. These results suggest that repeated administration of ONO-1301 attenuates the development of bleomycin-induced pulmonary fibrosis and improves survival in bleomycin mice, at least in part by inhibition of TXA2 synthesis and activation of the cAMP/PKA pathway.
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