Antifibrotic action of pirfenidone and prednisolone: different effects on pulmonary cytokines and growth factors in bleomycin-induced murine pulmonary fibrosis.
Pirfenidone, a broad-spectrum antifibrotic agent, is known to have efficacy in certain fibrotic disease models, and is under clinical trials in patients with idiopathic pulmonary fibrosis. We investigated the antifibrotic effect of pirfenidone, and its regulatory effect on various pulmonary cytokines, in bleomycin-induced lung fibrosis in mice at the protein level, using prednisolone as a reference agent. Pirfenidone attenuated the bleomycin-induced pulmonary fibrosis at a minimum effective dose of 30 mg/kg/day t.i.d. from the analysis of lung hydroxyproline content. Both pirfenidone (30, 100 mg/kg/day t.i.d) and prednisolone (3, 15 mg/kg/day q.d.) suppressed lung inflammatory edema; however, prednisolone failed to suppress pulmonary fibrosis, which was significantly suppressed only by pirfenidone. Both pirfenidone and prednisolone suppressed the increase in lung interleukin (IL)-1beta, IL-6, IL-12p40 and monocyte chemoattractant protein (MCP)-1 levels induced by bleomycin. On the other hand, pirfenidone prevented the bleomycin-induced decrease in lung interferon (IFN)-gamma levels, while prednisolone had no such effect. Furthermore, pirfenidone suppressed elevation of lung basic-fibroblast growth factor (bFGF) and transforming growth factor (TGF)-beta1 levels, but prednisolone had no such effect. The increases in lung stroma cell derived factor (SDF)-1alpha and IL-18 were also suppressed. These findings suggest that pirfenidone exerts its antifibrotic effect through regulation of lung IFN-gamma, bFGF and TGF-beta1 levels during the development of bleomycin-induced pulmonary fibrosis in mice. The effect on SDF-1alpha and IL-18 levels may also be related to the antifibrotic effects of pirfenidone.
Oku
Hisashi
H
Division of Frontier Drug Discovery, Discovery Research Laboratories, Shionogi & Co., Ltd., 2-5-1, Mishima, Settsu, Osaka 566-0022, Japan. hisashi.oku@shionogi.co.jp
Shimizu
Toshikatsu
T
Kawabata
Tomoji
T
Nagira
Morio
M
Hikita
Ichiro
I
Ueyama
Azumi
A
Matsushima
Shuuichi
S
Torii
Mikinori
M
Arimura
Akinori
A
D000818:Animals; D001761:Bleomycin / Q000633:toxicity*; D018925:Chemokines / Q000096:biosynthesis; D016207:Cytokines / Q000096:biosynthesis*; D004305:Dose-Response Relationship, Drug; D016222:Fibroblast Growth Factor 2 / Q000096:biosynthesis; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis*; D007371:Interferon-gamma / Q000096:biosynthesis; D053762:Interleukin-12 Subunit p40 / Q000096:biosynthesis; D008168:Lung / Q000378:metabolism*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D011239:Prednisolone / Q000494:pharmacology* / Q000627:therapeutic use; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000188:drug therapy*; D011728:Pyridones / Q000494:pharmacology* / Q000627:therapeutic use; D053773:Transforming Growth Factor beta1 / Q000096:biosynthesis; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D018925:Chemokines; D016207:Cytokines; D036341:Intercellular Signaling Peptides and Proteins; D053762:Interleukin-12 Subunit p40; D011728:Pyridones; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha; D016222:Fibroblast Growth Factor 2; D001761:Bleomycin; D007371:Interferon-gamma; D011239:Prednisolone; C093844:pirfenidone