Gene and cell based therapy for chronic obstructive pulmonary disease

• Main Authors: Hsuan Lin, 林軒
• Other Authors: Cheng-Wen Wu
• Format: Others
• Language: en_US
• Published: 2015
• Online Access: http://ndltd.ncl.edu.tw/handle/qn8ygm

碩士 === 國立陽明大學 === 生化暨分子生物研究所 === 103 === Chronic obstructive pulmonary disease (COPD) has became the third leading cause of death worldwide since 2014, and currently still lacks efficient treatment. Pathogenesis of COPD is characterized by the chronic inflammatory injuries that lead to irreversible events in lung epithelia such as apoptosis of epithelial cells and proteolysis of extracellular matrix components. The clinical manifestations of the COPD syndrome include chronic bronchitis, a condition of large-airway inflammation and remodeling, and emphysema, the loss of surface area for gas exchange. In the current study, using mouse model of elastase-induced emphysema, we tried to analyze the endogenous repair mechanism of alveolus, and evaluated the potentials of gene or cell-based therapy for the disease. We found that in the absence of therapeutic treatment, alveolar epithelial cells (AECs) actually started to proliferate within 24 hr in response to injury, but finally were insufficient to mediated an efficient repair of alveoli. Unexpectedly, the type-1 AECs (AECs-1) proliferated prior to AEC-2 after injury. In vivo gene delivery of Bmi-1 alone or Oct4-Sox2-Klf4-cMyc cassette (OSKM) in AECs using PEI after elastase induced injury significantly improved lung function, alveolar surface area, and cell proliferations. The newly proliferated AECs showed normal AEC-1 and -2 phenotype, without symptom of oncogenesis. Transplantation of Oct4+ stem/progenitor cells in mice with elastase injury increased 1.7-fold of proliferated cells, and most of which were AEC1 phenotype. In summary, our study showed that gene or cell based therapy could be promising strategies for the treatment of COPD, which currently has no effective pharmaceuticals. Further insights in endogenous alveolar repair mechanism will assistant in uncovering the genes crucial for alveolar regeneration, and designing more efficient therapeutic strategies.