Macrophage‐targeted delivery of siRNA to silence Mecp2 gene expression attenuates pulmonary fibrosis

Bioengineering & Translational Medicine

Yi Wang¹  Yongjian Xu¹  Guo‐Rao Wu¹  Qi Wang¹  Ting Pan¹  Yong Mou¹  Lei Zhang¹  Weining Xiong²  Qing Zhou³ 

[1] Department of Respiratory and Critical Care Medicine, NHC Key Laboratory of Pulmonary Diseases, Key Site of National Clinical Research Center for Respiratory Disease, Wuhan Clinical Medical Research Center for Chronic Airway Diseases, Tongji Hospital, Tongji Medical College Huazhong University of Science and Technology Wuhan China;Department of Respiratory and Critical Care Medicine, Shanghai Key Laboratory of Tissue Engineering, Shanghai Ninth People's Hospital Shanghai Jiaotong University School of Medicine Shanghai China;The Center for Biomedical Research, Tongji Hospital, Tongji Medical College Huazhong University of Science and Technology Wuhan China;

关键词: alternatively activated macrophages;    idiopathic pulmonary fibrosis;    liposomes;    macrophages;    Mecp2;   

DOI  :  10.1002/btm2.10280

来源: DOAJ

【 摘 要 】

Abstract Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease characterized by the infiltration of macrophages in the fibrotic region. Currently, no therapeutic strategies effectively control disease progression, and the 5‐year mortality of patients after diagnosis is unacceptably high. Thus, developing an effective and safe treatment for IPF is urgently needed. The present study illustrated that methyl‐CpG‐binding protein 2 (MECP2), a protein responsible for the interpretation of DNA methylome‐encoded information, was abnormally expressed in lung and bronchoalveolar lavage fluid samples of IPF patients and mice with onset of pulmonary fibrosis. And further studies verified that the overexpression of MECP2 occurred mainly in macrophages. Inhibition of Mecp2 expression in macrophages robustly abrogated alternatively activated macrophage (M2) polarization by regulating interferon regulatory factor 4 expression. Accordingly, cationic liposomes loading Mecp2 small interfering RNA (siRNA) were raised for the treatment of pulmonary fibrosis. It was noted that the liposomes accumulated in the fibrotic region after intratracheal injection, especially in macrophages. In addition, intratracheal administration of Mecp2 siRNA‐loaded liposomes significantly reversed the established pulmonary fibrosis with few side‐effects and high safety coefficients. Collectively, these results are essential not only for further understanding the DNA methylation in pathogenesis of IPF but also for providing a potent therapeutic strategy for IPF treatment in the clinic practice.

【 授权许可】

Unknown