Pirfenidone attenuates lung fibrotic fibroblast responses to transforming growth factor-β1.

Abstract

BACKGROUND:

Pirfenidone, an antifibrotic agent used for the treatment of idiopathic pulmonary fibrosis (IPF), functions by inhibiting myofibroblast differentiation, which is involved in transforming growth factor (TGF)-β1-induced IPF pathogenesis. However, unlike normal lung fibroblasts, the relationship between pirfenidone responses of TGF-β1-induced human fibrotic lung fibroblasts and lung fibrosis has not been elucidated.

METHODS:

The effects of pirfenidone were evaluated in lung fibroblasts isolated from fibrotic human lung tissues after TGF-β1 exposure. The ability of two new pharmacological targets of pirfenidone, collagen triple helix repeat containing protein 1(CTHRC1) and four-and-a-half LIM domain protein 2 (FHL2), to mediate contraction of collagen gels and migration toward fibronectin were assessed in vitro.

RESULTS:

Compared to control lung fibroblasts, pirfenidone significantly restored TGF-β1-stimulated fibroblast-mediated collagen gel contraction, migration, and CTHRC1 release in lung fibrotic fibroblasts. Furthermore, pirfenidone attenuated TGF-β1- and CTHRC1-induced fibroblast activity, upregulation of bone morphogenic protein-4(BMP-4)/Gremlin1, and downregulation of α-smooth muscle actin, fibronectin, and FHL2, similar to that observed post-CTHRC1 inhibition. In contrast, FHL2 inhibition suppressed migration and fibronectin expression, but did not downregulate CTHRC1.

CONCLUSIONS:

Overall, pirfenidone suppressed fibrotic fibroblast-mediated fibrotic processes via inverse regulation of CTHRC1-induced lung fibroblast activity. Thus, CTHRC1 can be used for predicting pirfenidone response and developing new therapeutic targets for lung fibrosis.

• Authors: Jin Jin, Shinsaku Togo, Kotaro Kadoya, Miniwan Tulafu, Yukiko Namba, Moe Iwai, Junko Watanabe, Kumi Nagahama, Takahiro Okabe, Moulid Hidayat, Yuzo Kodama, Hideya Kitamura, Takashi Ogura, Norikazu Kitamura, Kazuho Ikeo, Shinichi Sasaki, Shigeru Tominaga, Kazuhisa Takahashi
• Journal: Respiratory research (Respir Res) Vol. 20 Issue 1 Pg. 119 (Jun 11 2019) ISSN: 1465-993X [Electronic] England
• PMID: 31185973 (Publication Type: Journal Article)

Chemical References

• Anti-Inflammatory Agents, Non-Steroidal
• Pyridones
• Transforming Growth Factor beta1
• pirfenidone

Topics

• Adult
• Aged
• Animals
• Anti-Inflammatory Agents, Non-Steroidal (pharmacology)
• Cells, Cultured
• Dose-Response Relationship, Drug
• Female
• Fibroblasts (drug effects, pathology)
• Humans
• Lung (drug effects, pathology)
• Male
• Middle Aged
• Pyridones (pharmacology)
• Rats
• Transforming Growth Factor beta1 (toxicity)