thromboxane-a2 and Pulmonary-Fibrosis

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 TXB2. 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 TXA2 synthesis and activation of the cAMP/PKA pathway.

Topics: Animals; Bleomycin; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Enzyme Inhibitors; Epoprostenol; Female; Intercellular Adhesion Molecule-1; Lung; Mice; Mice, Inbred C57BL; Pneumonia; Pulmonary Fibrosis; Pyridines; Survival Analysis; Thromboxane A2; Thromboxane-A Synthase; Vascular Cell Adhesion Molecule-1

Plasma thromboxane A2, a vasoconstrictor, and plasma prostacyclin (epoprostenol), a vasodilator, were assessed by double-antibody radioimmunological assay of their respective stable circulating metabolites, thromboxane B2 (TxB2) and 6-ketoprostaglandin F1 alpha, in 9 patients with severe diffuse pulmonary fibrosis (DPF), who were known to become hypo-oxaemic during exercise, and in 9 healthy volunteers. In the 7 patients with the most severe DPF, mean arterial PO2 fell from 68 mm Hg at rest to 51 mm Hg at peak aerobic exercise, and mean TxB2 increased to twice the value at rest. The 9 controls remained oxygen saturated throughout exercise; their mean TxB2 did not change during aerobic exercise, but during anaerobic exercise increased to twice the value at rest, and increased further during recovery. There were no significant changes in 6-keto-prostaglandin F1 alpha in either group. The selective release of TxB2 during aerobic exercise in hypo-oxaemic patients suggests that thromboxane mediates hypoxic pulmonary vasoconstriction. Its release in normal man during anaerobic exercise may reflect a more general response to the metabolic changes of tissue hypoxia.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aerobiosis; Anaerobiosis; Epoprostenol; Female; Humans; Hypoxia; Male; Physical Exertion; Prostaglandins; Pulmonary Fibrosis; Respiratory Function Tests; Thromboxane A2; Thromboxanes