Combination Therapy with Pirfenidone plus Prednisolone Ameliorates Paraquat-Induced Pulmonary Fibrosis

Abstract

Pirfenidone is known to slow the decline in vital capacity and increase survival in idiopathic pulmonary fibrosis (IPF). Besides, administration of glucocorticoids, e.g., prednisolone has been the conventional strategy to the treatment of patients with this disease, although their efficacy is under debate. Since multiple coactivated pathways are involved in the pathogenesis of IPF, combination therapy is a foundation strategy to cover many more synergetic mechanisms and increase response. The aim of the present study was to compare the therapeutic efficacy of prednisolone plus pirfenidone with pirfenidone alone in PQ-induced lung fibrosis. After development of PQ-induced lung fibrosis, pirfenidone, prednisolone, and their combination were administered for 14 consecutive days. Lung pathological lesions, along with increased hydroxyproline were determined in the paraquat group. Paraquat also caused oxidative stress and increasing the proinflammatory and profibrotic gene expression. Pirfenidone attenuated the PQ-induced pulmonary fibrosis from the analysis of antioxidant enzymes but prednisolone had no such effect. Co-treatment with pirfenidone and prednisolone suppressed lung hydroxyproline content, TGF-β1, and TNF-α; however, prednisolone alone could not suppress pulmonary fibrosis which was significantly suppressed only by pirfenidone. Pirfenidone also suppressed the increase in MMP-2 and TIMP-1 induced by PQ. All of these effects were exaggerated when pirfenidone coadministered with prednisolone. These findings suggest that pirfenidone exerts its antifibrotic effect through regulation of hydroxyproline content, oxidative stress and proinflammatory and profibrotic gene expression during the development of PQ-induced pulmonary fibrosis in rats and combination therapy with prednisolone can represent more potent therapeutic effects.