Pirfenidone and BIBF1120 Suppress Collagen Synthesis In Skin Fibroblast From Patients With Systemic Sclerosis

Yuko Ota¹, Yasushi Kawaguchi¹, Kae Takagi¹, Hisae Ichida¹, Yasuhiro Katsumata¹, Takahisa Gono¹, Yuko Okamoto¹, Tomoaki Higuchi², Hidenaga Kawasumi¹ and Hisashi Yamanaka¹, ¹Institute of Rheumatology, Tokyo Women's Medical University, Tokyo, Japan, ²Institute Of Rheumatology, Tokyo Women's Medical University, Tokyo, Japan

Meeting: 2013 ACR/ARHP Annual Meeting

Keywords: Collagen, Fibroblasts, Systemic sclerosis, transforming growth factor and tyrosine kinase inhibition

Session Information

Title: Systemic Sclerosis, Fibrosing Syndromes and Raynaud's I

Session Type: Abstract Submissions (ACR)

Background/Purpose: Pirfenidone (5-methyle-1-phenyl-2- [1H]-pyridone) and BIBF1120 (Nintedanib) are currently evaluated in clinical trials as a potential idiopathic pulmonary fibrosis (IPF). Pirfenidone was approved as the first antifibrotic therapy for IPF based on demonstrated sustained clinical efficacy. BIBF1120 is a triple tyrosine kinase inhibitor and potent antagonist of growth factors such as platelet-drived growth factor (PDGF), vascular endothelial growth factor (VEGF), and basic fibroblast growth factor (bFGF). The aim of the present study was to investigate the antifibrotic effects of pirfenidone and BIBF1120 on skin fibroblasts from patients with systemic sclerosis (SSc). We also examined signal transductions of these drugs.

Methods: Skin fibroblasts from six patients with diffuse cutaneous SSc were cultured with increasing concentrations of pirfenidone or BIBF1120 for various times. The resulting supernatants were collected and stored at -80°C. Procollagen type I C-peptide level was then measured using commercial ELISA kits. As we also evaluated the effects of pirfenidone or BIBF1120 for TGF-β1 induced skin fibrosis, skin fibroblasts stimulated with TGF-β1 were treated with pirfenidone or BIBF1120 and procollagen type I C-peptide level was measured using commercial ELISA kits. In addition, mRNA levels of collagen1α (I), collagen1a (II), TGF-β1, CTGF, IL-6 were estimated using real-time PCR.

Results: In the supernatants of fibroblasts cultured with 500 μg/ml of pirfenidone for 48 and 72 hours, the levels of procollagen type I C-peptide were significantly suppressed (p = 0.034 and p = 0.009, respectively) as compared with those in supernatants obtained from cultures lacking pirfenidone. Procollagen type I C peptide production was suppressed by 1 μM of BIBF1120 in cultured SSc fibroblasts (p = 0.011) compared to no stimulation. Both pirfenidone and BIBF1120 significantly down-regulated the collagen sysnthesis in TGF-b1-induced skin fibroblasts (p < 0.05, Figure 1). RT-PCR analysis revealed that COL1A1, COL1A2, CTGF and TGFB1 mRNAs were suppressed by pirfenidone or BIBF1120 in cultured skin fibroblasts from patients with SSc. Inerestingly, pirfenidone inhibited IL-6 mRNA, but BIBF1120 promoted it adversely.

Conclusion: Our results showed that both pirfenidone and BIBF1120 attenuate collagen production via TGF-β1 and CTGF pathway in skin fibroblasts from patients with SSc. Pirfenidone and BIBF1120 may represent a novel therapy for skin fibrosis in patients with SSc.

Disclosure:

Y. Ota,
None;

Y. Kawaguchi,
None;

K. Takagi,
None;

H. Ichida,
None;

Y. Katsumata,
None;

T. Gono,
None;

Y. Okamoto,
None;

T. Higuchi,
None;

H. Kawasumi,
None;

H. Yamanaka,
None.

« Back to 2013 ACR/ARHP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/pirfenidone-and-bibf1120-suppress-collagen-synthesis-in-skin-fibroblast-from-patients-with-systemic-sclerosis/