Epidermal growth factor receptor paracrine upregulation in idiopathic pulmonary fibrosis fibroblasts is blocked by nintedanib.
Am J Physiol Lung Cell Mol Physiol
; 316(6): L1025-L1034, 2019 06 01.
Article
em En
| MEDLINE
| ID: mdl-30810067
ABSTRACT
Although present in normal cells, epidermal growth factor receptor (EGFR) is overexpressed in a variety of tumors and has been associated with decreased survival. Because activated fibroblasts are considered key effectors in fibrosis and because metastatic and fibrotic processes were shown to share similar signaling pathways, we investigated the contribution of EGFR signaling to idiopathic pulmonary fibrosis (IPF) progression in lung fibroblasts derived from patients with IPF (IPF-HLF). EGFR expression and EGFR-related signaling were evaluated by Western blot and immunohistochemistry. Supernatants (SN) from cultured IPF-HLF and N-HLF were added to N-HLF, and their effect on cell phenotype was tested. Growth factor levels in the SN were measured by ELISA-based arrays. EGFR activity was blocked by erlotinib (Tarceva, 0.1-0.5 µM). Expression of EGFR, phosphorylated (p)EGFR-1068 and pAkt-473 was significantly higher in IPF-HLF compared with lung fibroblasts from control donors (N-HLF) (P < 0.05). Apparent expression of p/total EGFR and pAkt-473 was found in the myofibroblastic foci of IPF patients. Erlotinib significantly inhibited IPF-HLF but not N-HLF proliferation. IPF-HLF-SN elevated N-HLF cell number, viability, EGFR expression, and pAkt-473 and ERK1/2 phosphorylation (P < 0.05). Because high basic fibroblast growth factor levels were found in the IPF-HLF-SN, nintedanib (10-100 nM) was used to inhibit fibroblast growth factor receptor (FGFR) activation. Unlike erlotinib, nintedanib completely blocked IPF-HLF-SNs' effects on the N-HLF cells in a concentration-dependent manner. In summary, IPF-HLF paracrine signaling elevates EGFR expression, which in turn, affects N-HLF survival. The FGF-EGFR interplay facilitates cellular responses that could potentially promote fibrotic disease. This interplay was successfully blocked by nintedanib.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Comunicação Parácrina
/
Inibidores de Proteínas Quinases
/
Fibrose Pulmonar Idiopática
/
Indóis
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Revista:
Am J Physiol Lung Cell Mol Physiol
Assunto da revista:
BIOLOGIA MOLECULAR
/
FISIOLOGIA
Ano de publicação:
2019
Tipo de documento:
Article
País de afiliação:
Israel