期刊
AUTOPHAGY
卷 10, 期 11, 页码 2053-2074出版社
TAYLOR & FRANCIS INC
DOI: 10.4161/15548627.2014.973737
关键词
cystic fibrosis; CFTR; autophagy; cysteamine; epigallocatechin gallate; sweat chloride
类别
资金
- European Institute for Research in Cystic Fibrosis (IERFC)
- Italian Cystic Fibrosis Association (LIFC)
- Regional Cystic Fibrosis Association of Sicilia
- Regional Cystic Fibrosis Association of Lazio
- Regional Cystic Fibrosis Association of Lucania
- Regional Cystic Fibrosis Association of Friuli-Venezia-Giulia
- Canceropole Ile-de-France
- Ligue Nationale contre le Cancer (equipe labellisee)
- Agence Nationale pour la Recherche
- Association pour la Recherche sur le Cancer
- European Research Council
- Fondation Bettencourt-Schueller
- Fondation pour la Recherche Medicale
- Institut National du Cancer
- LabEx Onco-Immunology
- Wellcome Trust [088929, 069150]
Restoration of BECN1/Beclin 1-dependent autophagy and depletion of SQSTM1/p62 by genetic manipulation or autophagy-stimulatory proteostasis regulators, such as cystamine, have positive effects on mouse models of human cystic fibrosis (CF). These measures rescue the functional expression of the most frequent pathogenic CFTR mutant, F508del, at the respiratory epithelial surface and reduce lung inflammation in Cftr(F508del) homozygous mice. Cysteamine, the reduced form of cystamine, is an FDA-approved drug. Here, we report that oral treatment with cysteamine greatly reduces the mortality rate and improves the phenotype of newborn mice bearing the F508del-CFTR mutation. Cysteamine was also able to increase the plasma membrane expression of the F508del-CFTR protein in nasal epithelial cells from F508del homozygous CF patients, and these effects persisted for 24h after cysteamine withdrawal. Importantly, this cysteamine effect after washout was further sustained by the sequential administration of epigallocatechin gallate (EGCG), a green tea flavonoid, both in vivo, in mice, and in vitro, in primary epithelial cells from CF patients. In a pilot clinical trial involving 10 F508del-CFTR homozygous CF patients, the combination of cysteamine and EGCG restored BECN1, reduced SQSTM1 levels and improved CFTR function from nasal epithelial cells in vivo, correlating with a decrease of chloride concentrations in sweat, as well as with a reduction of the abundance of TNF/TNF-alpha (tumor necrosis factor) and CXCL8 (chemokine [C-X-C motif] ligand 8) transcripts in nasal brushing and TNF and CXCL8 protein levels in the sputum. Altogether, these results suggest that optimal schedules of cysteamine plus EGCG might be used for the treatment of CF caused by the F508del-CFTR mutation.
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