Targeting Delivery Of Tnf-alpha Antisense Oligonucleotide In The Treatment Of Pulmonary Fibrosis

Background:Anti-tumor necrosis factor a therapeutics has represented the potential to alleviate pulmonary fibrosis. However, systemic administration of anti-tumor necrosis factor a agents brought about contradictory results and frequently many aspects of adverse effects, such as infections, immunogenicity, malignancies and so on.Objective:We tried local administration of tumor necrosis factor a antisense oligonucleotide and evaluated the treatment effects on pulmonary fibrosis in bleomycin-induced pulmonary fibrosis mouse model.Methods:Flow cytometry for Tregs, RT-PCR for crucial gene expression, western blotting for crucial protein products, immunofluorescent analysis for TH2cells and myofibroblasts, as well as histology analysis for pathological examination was used.Results:By local administration of tumor necrosis factor α antisense oligonucleotide, we investigated that tumor necrosis factor α expression in epithelial cells was significantly inhibited and extracellular matrix overexpression was dramatically reduced. These treatment effects were associated with the induced regulatory T cells, the reduced Th2cells and the generally decreased TH2-type cytokines expression. Systemic immunosuppression was not triggered by local antisense oligonucleotide administration as the proportion of regulatory T cells in blood; thymus or spleen was not affected.Conclusions:These findings demonstrate that local administration of tumor necrosis factor a antisense oligonucleotide contributes to anti-fibrotic action via sustained up-regulated level of regulatory T cells, which inhibits TH2-biased responses, pro-fibrotic mediator’s production and ECM deposition with no systemic immunosupression associated with systemically induced regulatory T cells.