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.

Soluble Epoxide Hydrolase Inhibitor Attenuates Inflammation and Airway Hyperresponsiveness in Mice

“…Specifically, the sEHI reduced the total inflammatory cell number by 50%. Compared with two clinically available compounds (montelukast and dexamethasone) tested in the similar animal model, sEHI had a greater effect on reduction of the inflammatory cells infiltration than montelukast and dexamethasone did (40 and 28%) (31). In addition, sEHI reduced IL-5 levels to 12.5% of those mice treated with OVA and vehicle.…”

Lipid mediators and allergic diseases

“…In a chronic model of allergen exposure, IP-deficient mice also had more airway eosinophils and lymphocytes and higher Th2 lung cytokine levels compared with WT mice 57 . Mice treated with ONO-1301, a PGI 2 analog that also has thromboxane synthase inhibitory activity, had reduced AHR and diminished findings of airway remodeling compared with vehicle-treated mice in a chronic OVA model 58 . Together, these studies suggest that PGI 2 signaling through IP downregulates allergic inflammation and may also reduce lung fibrosis and remodeling.…”

In silico modelling of prostacyclin and other lipid mediators to nuclear receptors reveal novel thyroid hormone receptor antagonist properties

“…PGI 2 has a very short half-life of 42 s, which makes direct pharmacological analysis difficult, although there are a large number of PGI 2 mimetics available such as iloprost, beraprost and treprostinil, which have half-lives of 30 min, 40 min and 4 h respectively. Prostanoid signalling is of key importance in the lung, as evidenced by the use of PGI 2 mimetics in pulmonary artery hypertension and non-steroidal anti-inflammatory drug (NSAID) induced asthma [3], and involvement in the development of asthma and COPD [4]. Lung diseases such as pulmonary artery hypertension (PAH) are treated with PGI 2 mimetics, which greatly improve the symptoms but fail to reverse or cure the vascular remodelling.…”