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

Abstract

. Prostacyclin agonist with thromboxane synthase inhibitory activity (ONO-1301) attenuates bleomycin-induced pulmonary fibrosis in mice. Am J Physiol Lung Cell Mol Physiol 290: L59 -L65, 2006. First published September 9, 2005 doi:10.1152/ajplung.00042.2005The 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 TXB 2. A single administration of ONO-1301 significantly increased plasma cAMP level for Ͼ2 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. adenosine 3Ј,5Ј-cyclic monophosphate; fibroblast; neutrophil; survival IDIOPATHIC PULMONARY FIBROSIS (IPF) is a life-threatening disease characterized by progressive dyspnea and worsening of pulmonary function (6,22). The pathological features of IPF are fibroblast proliferation with increased amounts of extracellular matrix and varying degrees of persistent inflammation of the alveolar septa (22). Thus a novel therapeutic strategy against these abnormalities may be effective for the treatment of IPF.Prostanoids, which are metabolites of arachidonic acid, are important regulators of pulmonary homeostasis. Prostacyclin inhibits migration, proliferation, and collagen synthesis in fibroblasts (14, 29). Conversely, thromboxane A 2 (TXA 2 ) promotes fibroblast proliferation, increases pulmonary vascular permeability, and induces lung inflammation (18,21,24). Interestingly, a recent study has demonstrated that the decreased ratio of prostacyclin synthesis to thromboxane synthesis is...

Effects of a leukotriene B4 receptor antagonist on bleomycin-induced pulmonary fibrosis

“…The pathological features of IPF are fibroblast proliferation, increased amounts of extracellular matrix and varying degrees of persistent inflammation of the alveolar septa [2]. Recent reports have suggested that leukotrienes (LTs), which are arachidonic acid metabolites, are important regulators of pulmonary fibrosis [3,4].…”

A Prostacycline Analog Prevents Chronic Myocardial Remodeling in Murine Cardiac Allografts

“…The regimen used in the experiments was determined from those used in previous papers. [8][9][10][11][12] Animals and cardiac transplantation: Male inbred mice (4 to 6 weeks, 20-25 g) were used. The male BALB/c (H-2 d ) and C57BL/6 (H-2 b ) mice (4-6 weeks, 20-25 g) were obtained from Japan Clea, Co (Tokyo), and this combination was used as the major histocompatibility complex total allomismatch group for analysis of acute rejection.…”

“…6) Because ONO-1301MS does not have prostanoid structures, it is not easily metabolized and its effects remain for a longer time compared with other prostacyclin analogs, such as beraprost or iloprost. [7][8][9][10] It has been reported that local administration of a slow releasing form of ONO-1301MS into ischemic murine hearts was effective at preventing left ventricular remodeling and improving the survival rate.…”

Oral Administration of a Novel Long-Acting Prostacyclin Agonist With Thromboxane Synthase Inhibitory Activity for Pulmonary Arterial Hypertension

“…We have already reported that ONO-1301 showed a beneficial effect by inhibiting the MEK/ERK pathway, 11 and we also reported that repeated administration of ONO-1301 attenuated the development of bleomycin-induced pulmonary fibrosis and improved survival of the affected mice, at least in part by inhibiting TXA2 synthesis and activating the cAMP/PKA pathway. 22 Binding of ONO-1301 to the IP receptor stimulates adenylate cyclase activity, which increases the level of cAMP, which then induces endogenous HGF production and increases PKA activity. 23 PKA has been shown to induce endogenous HGF production 23 and inhibit the MEK/ERK pathway.…”