Journal
RESPIRATORY RESEARCH
Volume 20, Issue -, Pages -Publisher
BMC
DOI: 10.1186/s12931-019-1093-z
Keywords
Pirfenidone; Collagen triple helix repeat containing protein 1(CTHRC1); Four-and-a-half LIM domain protein 2(FHL-2); BMP-4; Transforming growth factor-1; Lung fibroblast; Lung fibrosis
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Funding
- Platform Project for Supporting Drug Discovery and Life Science Research from AMED [JP16am0101057]
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BackgroundPirfenidone, 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)-1-induced IPF pathogenesis. However, unlike normal lung fibroblasts, the relationship between pirfenidone responses of TGF-1-induced human fibrotic lung fibroblasts and lung fibrosis has not been elucidated.MethodsThe effects of pirfenidone were evaluated in lung fibroblasts isolated from fibrotic human lung tissues after TGF-1 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.ResultsCompared to control lung fibroblasts, pirfenidone significantly restored TGF-1-stimulated fibroblast-mediated collagen gel contraction, migration, and CTHRC1 release in lung fibrotic fibroblasts. Furthermore, pirfenidone attenuated TGF-1- and CTHRC1-induced fibroblast activity, upregulation of bone morphogenic protein-4(BMP-4)/Gremlin1, and downregulation of -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.ConclusionsOverall, 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.
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