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Liposomal UHRF1 siRNA shows lung fibrosis treatment potential through regulation of fibroblast activation
Demin Cheng, … , Yi Liu, Chunhui Ni
Demin Cheng, … , Yi Liu, Chunhui Ni
Published September 27, 2022
Citation Information: JCI Insight. 2022;7(22):e162831. https://doi.org/10.1172/jci.insight.162831.
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Research Article Pulmonology

Liposomal UHRF1 siRNA shows lung fibrosis treatment potential through regulation of fibroblast activation

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Abstract

Pulmonary fibrosis is a chronic and progressive interstitial lung disease associated with the decay of pulmonary function, which leads to a fatal outcome. As an essential epigenetic regulator of DNA methylation, the involvement of ubiquitin-like containing PHD and RING finger domains 1 (UHRF1) in fibroblast activation remains largely undefined in pulmonary fibrosis. In the present study, we found that TGF-β1–mediated upregulation of UHRF1 repressed beclin 1 via methylated induction of its promoter, which finally resulted in fibroblast activation and lung fibrosis both in vitro and in vivo. Moreover, knockdown of UHRF1 significantly arrested fibroblast proliferation and reactivated beclin 1 in lung fibroblasts. Thus, intravenous administration of UHRF1 siRNA–loaded liposomes significantly protected mice against experimental pulmonary fibrosis. Accordingly, our data suggest that UHRF1 might be a novel potential therapeutic target in the pathogenesis of pulmonary fibrosis.

Authors

Demin Cheng, Yue Wang, Ziwei Li, Haojie Xiong, Wenqing Sun, Sichuan Xi, Siyun Zhou, Yi Liu, Chunhui Ni

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Figure 9

Administration of UHRF1 siRNA liposomes attenuates BLM-induced pulmonary fibrosis in mice.

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Administration of UHRF1 siRNA liposomes attenuates BLM-induced pulmonary...
(A) Strategy for UHRF1 siRNA–loaded liposome administration in the BLM-induced pulmonary fibrosis mouse model. (B) H&E, Sirius red, and Masson’s trichrome staining assays were performed to measure the severity of fibrotic lesions. (C) The severity of fibrosis was evaluated by Ashcroft scores. Data are shown as the mean ± SEM (n = 6 in each group). (D) Lungs of mice following different treatments were analyzed for hydroxyproline content. Data are shown as the mean ± SEM (n = 6 in each group). (E) Western blot of UHRF1, fibrotic markers, and beclin 1 in mouse lung tissues in the different groups. (F and G) The expression of collagen I and α-SMA was detected by immunofluorescence staining in mouse lung tissues. Collagen I stained blue; α-SMA stained red; DAPI stained blue. Scale bar: 100 μm (B, F, and G). (C and D) P values were from a 1-way ANOVA post hoc test with Tukey’s correction.

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