Pirfenidone attenuates lung fibrotic fibroblast responses to transforming growth factor-ß1.
Respir Res
; 20(1): 119, 2019 Jun 11.
Article
en En
| MEDLINE
| ID: mdl-31185973
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)-ß1-induced IPF pathogenesis. However, unlike normal lung fibroblasts, the relationship between pirfenidone responses of TGF-ß1-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-ß1 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-ß1-stimulated fibroblast-mediated collagen gel contraction, migration, and CTHRC1 release in lung fibrotic fibroblasts. Furthermore, pirfenidone attenuated TGF-ß1- 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.Palabras clave
Texto completo:
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Base de datos:
MEDLINE
Asunto principal:
Piridonas
/
Antiinflamatorios no Esteroideos
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Factor de Crecimiento Transformador beta1
/
Fibroblastos
/
Pulmón
Tipo de estudio:
Prognostic_studies
Idioma:
En
Revista:
Respir Res
Año:
2019
Tipo del documento:
Article