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Mol Ther ; 25(3): 654-665, 2017 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-28187947

RESUMO

Cystic fibrosis (CF) is a fatal recessive genetic disorder caused by a mutation in the gene encoding CF transmembrane conductance regulator (CFTR) protein. Alteration in CFTR leads to thick airway mucus and bacterial infection. Cell therapy has been proposed for CFTR restoration, but efficacy has been limited by low engraftment levels. In our previous studies, we have shown that using a pre-conditioning regimen in combination with optimization of cell number and time of delivery, we could obtain greater bone marrow cell (BMC) retention in the lung. Here, we found that optimized delivery of wild-type (WT) BMC contributed to apical CFTR expression in airway epithelium and restoration of select ceramide species and fatty acids in CFTR-/- mice. Importantly, WT BMC delivery delayed Pseudomonas aeruginosa lung infection and increased survival of CFTR-/- recipients. Only WT BMCs had a beneficial effect beyond 6 months, suggesting a dual mechanism of BMC benefit: a non-specific effect early after cell delivery, possibly due to the recruitment of macrophages and neutrophils, and a late beneficial effect dependent on long-term CFTR expression. Taken together, our results suggest that BMC can improve overall lung function and may have potential therapeutic benefit for the treatment of CF.


Assuntos
Terapia Baseada em Transplante de Células e Tecidos , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Fibrose Cística/genética , Fibrose Cística/metabolismo , Animais , Células da Medula Óssea/metabolismo , Líquido da Lavagem Broncoalveolar , Ceramidas/metabolismo , Fibrose Cística/mortalidade , Fibrose Cística/terapia , Citocinas , Modelos Animais de Doenças , Ácidos Graxos/metabolismo , Feminino , Pulmão/metabolismo , Macrófagos/metabolismo , Camundongos , Neutrófilos/metabolismo , Mucosa Respiratória/metabolismo
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