科研之友
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摘要
Background: Tumor necrosis factor alpha (TNF-alpha) is a proinflammatory cytokine that has been implicated in the airway pathology of asthma and result in resistance to hormone therapy. Tumor necrosis factor a inhibitors have become a major research focus in the treatment of asthma. Methods: Recombinant adenovirus (Ad-sTNFR1-IgGFc) expressing a fusion protein (sTNFR1-IgGFc), which was consisted of the soluble extracellular region of TNF receptor 1 and Fc fragment of IgG (sTNFR1-IgGFc), was used to transduce primary human airway smooth muscle cells (HASMCs). Enzyme-linked immunosorbent assay, flow cytometry, and immunocytochemistry confirmed the expression of sTNFR1-IgGFc. MTT was used to test the effect of sTNFR1-IgGFc to antagonism TNF-alpha-induced proliferates of HASMCs. To investigate the in vivo effectiveness of sTNFR1-IgGFc, mouse model of asthma was established. Ad-sTNFR1-IgGFc was delivered to the lung via nasal spray. Expression of sTNFR1-IgGFc in the tissue was confirmed by in situ hybridization and immunohistochemistry. The 2 major cell types that are involved in the inflamed asthmatic airway, neutrophils and eosinophils, in bronchoalveolar lavage fluid were observed. Results: The sTNFR1-IgGFc isolated from transduced HASMC culture supernatant was able to antagonize HASMC proliferation stimulated by TNF-alpha. Asthma-induced pathologies and alterations in the cell composition in bronchoalveolar lavage fluid were reduced in mice subjected to Ad-sTNFR1-IgGFc therapy. Conclusions: The soluble extracellular region of TNF receptor 1 and Fc fragment of IgG was able to functionally antagonize TNF-alpha in vitro and showed promise as a therapeutic agent for the localized treatment of severe refractory asthma.
- 出版日期2015-6
- 单位南方医科大学
