Adenoviral Delivery of Recombinant Soluble Human Tumor Necrosis Factor Receptor 1 Partially Normalized Mouse Model of Asthma. Issue 5 (June 2015)

• Record Type: Journal Article
• Authors: Huang, Guo-Hua; Zeng, Xiao-Li; Cheng, Yuan-Xiong; Zhu, Shun-Fang; Luo, Wei; Wen, Qian; Cai, Shao-Xi; Su, Jin
• Is Part Of: Journal of investigative medicine. Volume 63:Issue 5(2015:Jun.)
• Page Start: 765
• Page End: 772
• Publication Date: 2015-06
• Subjects: adenoviral vector -- asthma -- gene therapy -- human airway smooth muscle cells (HASMCs) -- soluble tumor necrosis factor α receptor (sTNFR); Clinical medicine -- Periodicals; Medicine -- Research -- Periodicals; Medicine; Research -- United States; Clinical medicine; Medicine -- Research; Periodicals; 616.075
• DOI: 10.1097/JIM.0000000000000200
• Languages: English
• ISSNs: 1081-5589

Abstract

Background: Tumor necrosis factor α (TNF-α) is a proinflammatory cytokine that has been implicated in the airway pathology of asthma and result in resistance to hormone therapy. Tumor necrosis factor α 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-α–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-α. 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-α in vitro and showed promise as a therapeutic agent for the localized treatment of severe refractory asthma.