Prostacyclin agonist with thromboxane synthase inhibitory activity (ONO-1301) attenuates bleomycin-induced pulmonary fibrosis in mice

Shinsuke Murakami, Noritoshi Nagaya, Takefumi Itoh, Masaharu Kataoka, Takashi Iwase, Takeshi Horio, Yoshinori Miyahara, Yoshiki Sakai, Kenji Kangawa, Hiroshi Kimura

Research output: Contribution to journalArticle

53 Citations (Scopus)

Abstract

The balance between prostacyclin and thromboxane A 2 (TXA 2 ) 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 TXB 2 . A single administration of ONO-1301 significantly increased plasma cAMP level for >2 h. 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 TXA 2 synthesis and activation of the cAMP/PKA pathway.

Original languageEnglish
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume290
Issue number1
DOIs
Publication statusPublished - 2006 Jan 1
Externally publishedYes

Fingerprint

Pulmonary Fibrosis
Thromboxanes
Bleomycin
Epoprostenol
Lung
Cyclic AMP-Dependent Protein Kinases
Fibroblasts
Cell Proliferation
ONO 1301
Injections
Hydroxyproline
Bronchoalveolar Lavage Fluid
Bronchoalveolar Lavage
Protein Kinase Inhibitors
varespladib methyl
Prostaglandins
Neutrophils
Homeostasis
Cell Count

Keywords

  • Adenosine 3′,5′-cyclic monophosphate
  • Fibroblast
  • Neutrophil
  • Survival

ASJC Scopus subject areas

  • Physiology
  • Pulmonary and Respiratory Medicine
  • Physiology (medical)
  • Cell Biology

Cite this

Prostacyclin agonist with thromboxane synthase inhibitory activity (ONO-1301) attenuates bleomycin-induced pulmonary fibrosis in mice. / Murakami, Shinsuke; Nagaya, Noritoshi; Itoh, Takefumi; Kataoka, Masaharu; Iwase, Takashi; Horio, Takeshi; Miyahara, Yoshinori; Sakai, Yoshiki; Kangawa, Kenji; Kimura, Hiroshi.

In: American Journal of Physiology - Lung Cellular and Molecular Physiology, Vol. 290, No. 1, 01.01.2006.

Research output: Contribution to journalArticle

Murakami, Shinsuke ; Nagaya, Noritoshi ; Itoh, Takefumi ; Kataoka, Masaharu ; Iwase, Takashi ; Horio, Takeshi ; Miyahara, Yoshinori ; Sakai, Yoshiki ; Kangawa, Kenji ; Kimura, Hiroshi. / Prostacyclin agonist with thromboxane synthase inhibitory activity (ONO-1301) attenuates bleomycin-induced pulmonary fibrosis in mice. In: American Journal of Physiology - Lung Cellular and Molecular Physiology. 2006 ; Vol. 290, No. 1.
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