A novel prostacyclin agonist protects against airway hyperresponsiveness and remodeling in mice.

Abstract

Airway remodeling in bronchial asthma results from chronic, persistent airway inflammation. The effects of the reversal of airway remodeling by drug interventions remain to be elucidated. We investigated the effects of ONO-1301, a novel prostacyclin agonist with thromboxane inhibitory activity, on the prevention and reversibility of airway remodeling in an experimental chronic asthma model. Mice sensitized and challenged to ovalbumin (OVA) three times a week for 5 consecutive weeks were administered ONO-1301 or vehicle twice a day from the fourth week of OVA challenges. Twenty-four hours after the final OVA challenge, airway hyperresponsiveness (AHR) was assessed, and bronchoalveolar lavage was performed. Lung specimens were excised for staining to detect goblet-cell metaplasia, airway smooth muscle, and submucosal fibrosis. Mice administered ONO-1301 showed limited increases in AHR compared with mice administered the vehicle. The histological findings of airway remodeling were improved in ONO-1301-treated mice compared with vehicle-treated mice. Presumably, these therapeutic effects of ONO-1301 are attributable to the up-regulation of production of hepatocyte growth factor (HGF) in lung tissue, because the neutralization of HGF by antibodies prevented the effects of ONO-1301 on AHR and airway remodeling. Mice administered ONO-1301 showed similar levels of AHR and airway remodeling as mice administered montelukast, a cysteinyl-leukotriene-1 receptor antagonist, and lower levels were observed in mice administered dexamethasone. These data suggest that ONO-1301 exerts the effect of reversing airway remodeling, at least in part through an elevation of HGF in the lungs, and may be effective as an anti-remodeling drug in the treatment of asthma.

• Authors: Cristiane Yamabayashi, Toshiyuki Koya, Hiroshi Kagamu, Hidenori Kawakami, Yosuke Kimura, Toshiki Furukawa, Takuro Sakagami, Takashi Hasegawa, Yoshiki Sakai, Kunio Matsumoto, Mizuho Nakayama, Erwin W Gelfand, Eiichi Suzuki, Ichiei Narita
• Journal: American journal of respiratory cell and molecular biology (Am J Respir Cell Mol Biol) Vol. 47 Issue 2 Pg. 170-7 (Aug 2012) ISSN: 1535-4989 [Electronic] United States
• PMID: 22403804 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Acetates
• Cyclopropanes
• Pyridines
• Quinolines
• Receptors, Leukotriene
• Sulfides
• Thromboxanes
• ONO 1301
• Hepatocyte Growth Factor
• Dexamethasone
• Ovalbumin
• Epoprostenol
• leukotriene D4 receptor
• montelukast

Topics

• Acetates (pharmacology)
• Airway Remodeling (drug effects, genetics)
• Animals
• Asthma (drug therapy, genetics, immunology, metabolism)
• Bronchial Hyperreactivity (drug therapy, genetics, metabolism)
• Bronchoalveolar Lavage Fluid
• Cyclopropanes
• Dexamethasone (pharmacology)
• Epoprostenol (agonists, metabolism)
• Female
• Goblet Cells (drug effects, metabolism)
• Hepatocyte Growth Factor (genetics, metabolism)
• Inflammation (drug therapy, genetics, metabolism)
• Lung (drug effects, metabolism)
• Metaplasia (drug therapy, genetics, metabolism)
• Mice
• Mice, Inbred BALB C
• Muscle, Smooth (drug effects, metabolism)
• Ovalbumin (immunology)
• Pulmonary Fibrosis (drug therapy, genetics, metabolism)
• Pyridines (pharmacology)
• Quinolines (pharmacology)
• Receptors, Leukotriene (genetics, metabolism)
• Sulfides
• Thromboxanes (antagonists & inhibitors, metabolism)
• Up-Regulation (drug effects, genetics)