Although recent progress provides mechanistic insights into the pathogenesis of pulmonary fibrosis (PF), rare anti-PF therapeutics show definitive promise for treating this disease. Repeated lung epithelial injury results in injury-repairing response and inflammation, which drive the development of PF. Here, we report that chronic lung injury inactivated the ubiquitin-editing enzyme A20, causing progressive accumulation of the transcription factor C/EBPb in alveolar macrophages (AMs) from PF patients and mice, which upregulated a number of immunosuppressive and profibrotic factors promoting PF development. In response to chronic lung injury, elevated glycogen synthase kinase-3b (GSK-3b) interacted with and phosphorylated A20 to suppress C/EBPb degradation. Ectopic expression of A20 or pharmacological restoration of A20 activity by disturbing the A20-GSK-3b interaction accelerated C/EBPb degradation and showed potent therapeutic efficacy against experimental PF. Our study indicates that a regulatory mechanism of the GSK-3b-A20-C/EBPb axis in AMs may be a potential target for treating PF and fibroproliferative lung diseases.

Efficient local gene transfection on a tissue scaffold is of crucial importance in facilitating tissue repair and regeneration. In this work, the gelatin‐functionalized polycaprolactone (PCL) film surfaces are prepared via surface‐initiated atom transfer radical polymerization of glycidyl methacrylate. The resultant covalent attachment of gelatin could enhance the cell‐adhesion and local gene transfection properties. The gelatin‐functionalized PCL film surfaces exhibit excellent cell‐adhesion ability to both adherent and suspension cells. The attached adherent cells demonstrate the characteristic elongated morphologies with good spreading capability, while the attached suspension cells can maintain the original status of the round morphologies without spreading. More importantly, the gelatin coupled on the PCL surface could be used to absorb the cationic vector/plasmid deoxyribonucleic acid (pDNA) complexes via electrostatic interaction. The local gene transfection property on the immobilized cells is dependent on both the density of the immobilized cells and the loading types of pDNA complexes. The transfection efficiency of different assemble methods of pDNA complex was compared. With the pre‐ and post‐loading sandwich‐like gene transfection, the gelatin‐functionalized PCL film surface can substantially enhance the transfection properties to different cell lines. The present study is very useful to spatially control local gene delivery within PCL‐based tissue scaffolds.

The obstacle of gene therapy is the shortage of efficient delivery system. The development of the gene delivery system with high transfection efficiency and low toxicity appears to be crucial. Recently, we reported that the dextran-graft-poly((2-dimethyl amino)ethyl methacrylate) (DPD) can be potentially used as efficient gene vector. Herein, DPD was systematically studied for its potential in tumor gene therapy. DPD was synthesized and characterized by agarose gel electrophoresis, particle size and zeta potential. The particle size and zeta potential of the DPD/enhanced green fluorescent protein (pEGFP-C1) plasmid complexes at various N/P ratios were 130-150 nm and about 40 mV, respectively. The results showed that DPD exhibit a higher transfection effect compared with Lipofectamine 2K (Lipo 2K), a commercialized vector. The possibility of DPD in gene therapy was evaluated using p53, a gene that has been wildly applied in the research of cancer gene therapy. DPD/pEGFP-C1-p53 complex was found to be able to inhibit tumor cell proliferation through cell cycle arrest and apoptosis. Moreover, the tumor growth was found to be restrained when DPD/pEGFP-C1-p53 complex was used in a xenograft MCF7 tumor model in vivo. These observations indicated that DPD/pEGFP-C1-p53 complex may be considered to be an efficient delivery system for tumor gene therapy.