Restoration of CFTR function in patients with cystic fibrosis carrying the F508del-CFTR mutation
| Autor: | Stefano, Daniela De, Villella, Valeria R, Esposito, Speranza, Tosco, Antonella, Sepe, Angela, Gregorio, Fabiola De, Salvadori, Laura, Grassia, Rosa, Leone, Carlo A, Rosa, Giuseppe De, Maiuri, Maria C, Pettoello-Mantovani, Massimo, Guido, Stefano, Bossi, Anna, Zolin, Anna, Venerando, Andrea, Pinna, Lorenzo A, Mehta, Anil, Bona, Gianni, Kroemer, Guido, Maiuri, Luigi, Raia, Valeria |
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| Přispěvatelé: | Stefano, Dd, Villella, Vr, Esposito, S, Tosco, A, Sepe, A, De Gregorio, F, Salvadori, L, Grassia, R, Leone, Ca, DE ROSA, Giuseppe, Maiuri, MARIA CHIARA, Pettoello Mantovani, M, Guido, Stefano, Bossi, A, Zolin, A, Venerando, A, Pinna, La, Mehta, A, Bona, G, Kroemer, G, Maiuri, L, Raia, Valeria |
| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
Male
Cystic Fibrosis Administration Oral Cystic Fibrosis Transmembrane Conductance Regulator Pilot Projects Translational Research Papers Catechin CSNK2 casein kinase 2 Mice Sequestosome-1 Protein cysteamine SQSTM1 sequestosome 1 CFTR Child TNF tumor necrosis factor CXCL2 chemokine (C-X-C motif) ligand 2 Homozygote CXCL8 chemokine (C-X-C motif) ligand 8 Phenotype PM plasma membrane CF cystic fibrosi Beclin-1 Female FEV forced expiratory volume TGM2 transglutaminase 2 sweat chloride Adult autophagy epigallocatechin gallate Adolescent Cystamine Mice Transgenic Young Adult Chlorides CHX cycloheximide Animals Humans Mice Inbred CFTR CFTR cystic fibrosis transmembrane conductance regulator BECN1/Beclin 1 autophagy-related cystic fibrosi Adaptor Proteins Signal Transducing CF cystic fibrosis Tumor Necrosis Factor-alpha Cell Membrane Interleukin-8 Membrane Proteins Mutation RPD rectal potential difference Apoptosis Regulatory Proteins EGCG epigallocatechin gallate |
| Zdroj: | Autophagy |
| Popis: | 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 24 h 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. |
| Databáze: | OpenAIRE |
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