Lai W.-Y.Wang J.-W.Huang B.-T.Lin E.P.-Y.PAN-CHYR YANG2020-12-022020-12-0220191838-7640https://www.scopus.com/inward/record.uri?eid=2-s2.0-85065481293&doi=10.7150%2fthno.30972&partnerID=40&md5=a884985c996387130145cb8d48640681https://scholars.lib.ntu.edu.tw/handle/123456789/523439Rationale: The TNF-α pathway plays as a double-edged sword that simultaneously regulates cell apoptosis and proliferation. The dysregulated TNF-α signaling can trigger cytokine storms that lead to profound cell death during the phase of acute tissue injury. On the other hand, an optimal level of TNF-α signaling is required for tissue repair following the acute injury phase. The TNF-α pathway is commonly upregulated in acute lung injury (ALI) and acute liver failure (ALF). Previous studies investigated the feasibility of adopting protein-based TNF-α blockers as disease modifiers in ALI and ALF, but none of these came out with a positive result. One of the potential reasons that resides behind the failure of the trials might be the long half-life of these inhibitors that led to undesired side effects. Developing alternative TNF-α blockers with manageable half-lives remain an unmet need in this regard. Methods: In the current study, we developed a novel TNF-α-targeting aptamer (aptTNF-α) and its PEG-derivate (aptTNF-α-PEG) with antagonistic functions. We investigated the in vivo antagonistic effects using mouse ALI and ALF models. Results: Our data showed that aptTNF-α possessed good in vitro binding affinity towards human/mouse TNF-α and successfully targeted TNF-α in vivo. In the mouse ALI model, aptTNF-α/aptTNF-α-PEG treatment attenuated the severity of LPS-induced ALI, as indicated by the improvement of oxygen saturation and lung injury scores, the reduction of protein-rich fluid leakage and neutrophil infiltration in the alveolar spaces, and the suppression of pro-inflammatory cytokines/chemokines expressions in the lung tissues. In the mouse ALF model, we further showed that aptTNF-α/aptTNF-α-PEG treatment not only attenuated the degree of hepatocyte damage upon acute injury but also potentiated early regeneration of the liver tissues. Conclusion: The results implicated potential roles of aptTNF-α/aptTNF-α-PEG in ALI and ALF. The data also suggested their translational potential as a new category of TNF-α blocking agent. ? Ivyspring International Publisher.Acute liver failure; Acute lung injury; Aptamer; TNF-α[SDGs]SDG3aptamer; chemokine; cytokine; oxygen; tumor necrosis factor inhibitor; antiinflammatory agent; aptamer; tumor necrosis factor; acute liver failure; acute lung injury; animal cell; animal experiment; animal model; animal tissue; Article; binding affinity; controlled study; disease severity; human; in vitro study; in vivo study; liver cell damage; liver regeneration; lung parenchyma; mouse; neutrophil chemotaxis; nonhuman; oxygen saturation; protein expression; protein targeting; respiratory tract disease assessment; scoring system; acute liver failure; acute lung injury; animal; disease model; isolation and purification; molecularly targeted therapy; pathology; procedures; treatment outcome; Acute Lung Injury; Animals; Anti-Inflammatory Agents; Aptamers, Nucleotide; Disease Models, Animal; Humans; Liver Failure, Acute; Mice; Molecular Targeted Therapy; Treatment Outcome; Tumor Necrosis Factor-alphajournal article10.7150/thno.30972310371352-s2.0-85065481293