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Am J Respir Cell Mol Biol ; 59(1): 104-113, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29394092

RESUMO

Bronchial epithelial cells (BECs) from healthy children inhibit human lung fibroblast (HLF) expression of collagen and fibroblast-to-myofibroblast transition (FMT), whereas asthmatic BECs do so less effectively, suggesting that diminished epithelial-derived regulatory factors contribute to airway remodeling. Preliminary data demonstrated that secretion of the activin A inhibitor follistatin-like 3 (FSTL3) by healthy BECs was greater than that by asthmatic BECs. We sought to determine the relative secretion of FSTL3 and activin A by asthmatic and healthy BECs, and whether FSTL3 inhibits FMT. To quantify the abundance of the total proteome FSTL3 and activin A in supernatants of differentiated BEC cultures from healthy children and children with asthma, we performed mass spectrometry and ELISA. HLFs were cocultured with primary BECs and then HLF expression of collagen I and α-smooth muscle actin (α-SMA) was quantified by qPCR, and FMT was quantified by flow cytometry. Loss-of-function studies were conducted using lentivirus-delivered shRNA. Using mass spectrometry and ELISA results from larger cohorts, we found that FSTL3 concentrations were greater in media conditioned by healthy BECs compared with asthmatic BECs (4,012 vs. 2,553 pg/ml; P = 0.002), and in media conditioned by asthmatic BECs from children with normal lung function relative to those with airflow obstruction (FEV1/FVC ratio < 0.8; n = 9; 3,026 vs. 1,922 pg/ml; P = 0.04). shRNA depletion of FSTL3 in BECs (n = 8) increased HLF collagen I expression by 92% (P = 0.001) and α-SMA expression by 88% (P = 0.02), and increased FMT by flow cytometry in cocultured HLFs, whereas shRNA depletion of activin A (n = 6) resulted in decreased α-SMA (22%; P = 0.01) expression and decreased FMT. Together, these results indicate that deficient FSTL3 expression by asthmatic BECs impairs epithelial regulation of HLFs and FMT.


Assuntos
Asma/patologia , Epitélio/metabolismo , Epitélio/patologia , Proteínas Relacionadas à Folistatina/deficiência , Pulmão/patologia , Miofibroblastos/metabolismo , Miofibroblastos/patologia , Actinas/metabolismo , Ativinas/metabolismo , Adolescente , Sequência de Aminoácidos , Criança , Colágeno Tipo I/metabolismo , Células Epiteliais/metabolismo , Feminino , Proteínas Relacionadas à Folistatina/química , Proteínas Relacionadas à Folistatina/metabolismo , Técnicas de Silenciamento de Genes , Humanos , Masculino , RNA Interferente Pequeno/metabolismo
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