Lenalidomide Attenuates Post-Inflammation Pulmonary Fibrosis Through Blocking NF-κB Signaling Pathway

Pulmonary fibrosis is a pathological consequence of interstitial pulmonary diseases, and is characterized by the persistence of fibroblasts and excessive deposition of extracellular matrix. The etiology of pulmonary fibrosis is multifactorial, and the role of inflammation as an important component in IPF etiology is controversial and sometimes seen as an epiphenomenon of fibrosis. Stimulus increase production of pro-inflammatory cytokines and activation of NF-κB, which will further promote inflammation response and myofibroblast transition. Lenalidomide is an immunomodulatory drug. Previous study has revealed its anti-tumor effects through regulating immune response. Here we investigate the effect of lenalidomide on post-inflammation fibrosis. In vivo study showed that lenalidomide inhibited pro-inflammatory cytokines TNF-α and IL-6 while enhanced anti-fibrotic cytokines IFN-γ and IL-10 in bleomycin-induced inflammation model, and attenuated pulmonary fibrosis and collagen deposition in the following fibrosis stage. In vitro study revealed that lenalidomide inhibited NF-κB signaling in LPS-induced macrophage model, thus further attenuated macrophage-induced myofibroblast activation in the co-culture model. Meanwhile, lenalidomide could also inhibit transforming growth factor-β1 (TGF-β1) induced myofibroblast activation through suppressing TGF-β1 downstream MAPKs signaling. These data were further verified in mice model. In conclusion, our results demonstrate that lenalidomide possesses potential anti-fibrotic effects through suppressing NF-κB signaling.