PMID- 33981019 OWN - NLM STAT- MEDLINE DCOM- 20220325 LR - 20221003 IS - 1476-5403 (Electronic) IS - 1350-9047 (Print) IS - 1350-9047 (Linking) VI - 28 IP - 10 DP - 2021 Oct TI - The long non-coding RNA PFI protects against pulmonary fibrosis by interacting with splicing regulator SRSF1. PG - 2916-2930 LID - 10.1038/s41418-021-00792-1 [doi] AB - Pulmonary fibrosis (PF) is a type of interstitial pneumonia with complex etiology and high mortality, characterized by progressive scarring of the alveolar interstitium and myofibroblastic lesions. Recently, there has been growing appreciation of the importance of long non-coding RNAs (lncRNAs) in organ fibrosis. The aim of this study was to investigate the role of lncRNAs in lung fibrosis. We used a qRT-PCR assay to identify dysregulated lncRNAs in the lungs of mice with experimental, bleomycin (BLM)-induced pulmonary fibrosis, and a series of molecular assays to assess the role of the novel lncRNA NONMMUT060091, designated as pulmonary fibrosis inhibitor (PFI), which was significantly downregulated in lung fibrosis. Functionally, knockdown of endogenous PFI by smart silencer promoted proliferation, differentiation, and extracellular matrix (ECM) deposition in primary mouse lung fibroblasts (MLFs). In contrast, overexpression of PFI partially abrogated TGF-beta1-induced fibrogenesis both in MLFs and in the human fetal lung fibroblast MRC-5 cells. Similarly, PFI overexpression attenuated BLM-induced pulmonary fibrosis compared with wild type (WT) mice. Mechanistically, using chromatin isolation by RNA purification-mass spectrometry (ChIRP-MS) and an RNA pull-down assay, PFI was found to directly bind Serine/arginine-rich splicing factor 1 (SRSF1), and to repress its expression and pro-fibrotic activity. Furthermore, silencing of SRSF1 inhibited TGF-beta1-induced proliferation, differentiation, and ECM deposition in MRC-5 cells by limiting the formation of the EDA+Fn1 splicing isoform; whereas forced expression of SRSF1 by intratracheal injection of adeno-associated virus 5 (AAV5) ablated the anti-fibrotic effect of PFI in BLM-treated mice. Overall, these data reveal that PFI mitigated pulmonary fibrosis through negative regulation of the expression and activity of SRSF1 to decrease the formation of the EDA+Fn1 splicing isoform, and suggest that PFI and SRSF1 may serve as potential targets for the treatment of lung fibrosis. CI - (c) 2021. The Author(s), under exclusive licence to ADMC Associazione Differenziamento e Morte Cellulare. FAU - Sun, Jian AU - Sun J AUID- ORCID: 0000-0001-8483-7198 AD - Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, Heilongjiang, P. R. China. AD - Northern Translational Medicine Research and Cooperation Center, Heilongjiang Academy of Medical Sciences, Harbin Medical University, Harbin, Heilongjiang, P. R. China. FAU - Jin, Tongzhu AU - Jin T AD - Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, Heilongjiang, P. R. China. AD - Northern Translational Medicine Research and Cooperation Center, Heilongjiang Academy of Medical Sciences, Harbin Medical University, Harbin, Heilongjiang, P. R. China. FAU - Su, Wei AU - Su W AD - Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, Heilongjiang, P. R. China. AD - Northern Translational Medicine Research and Cooperation Center, Heilongjiang Academy of Medical Sciences, Harbin Medical University, Harbin, Heilongjiang, P. R. China. FAU - Guo, Yingying AU - Guo Y AD - Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, Heilongjiang, P. R. China. AD - Northern Translational Medicine Research and Cooperation Center, Heilongjiang Academy of Medical Sciences, Harbin Medical University, Harbin, Heilongjiang, P. R. China. FAU - Niu, Zhihui AU - Niu Z AD - Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, Heilongjiang, P. R. China. AD - Northern Translational Medicine Research and Cooperation Center, Heilongjiang Academy of Medical Sciences, Harbin Medical University, Harbin, Heilongjiang, P. R. China. FAU - Guo, Jiayu AU - Guo J AD - Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, Heilongjiang, P. R. China. AD - Northern Translational Medicine Research and Cooperation Center, Heilongjiang Academy of Medical Sciences, Harbin Medical University, Harbin, Heilongjiang, P. R. China. FAU - Li, Liangliang AU - Li L AD - Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, Heilongjiang, P. R. China. AD - Northern Translational Medicine Research and Cooperation Center, Heilongjiang Academy of Medical Sciences, Harbin Medical University, Harbin, Heilongjiang, P. R. China. FAU - Wang, Jiayi AU - Wang J AD - Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, Heilongjiang, P. R. China. AD - Northern Translational Medicine Research and Cooperation Center, Heilongjiang Academy of Medical Sciences, Harbin Medical University, Harbin, Heilongjiang, P. R. China. FAU - Ma, Lu AU - Ma L AD - Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, Heilongjiang, P. R. China. AD - Northern Translational Medicine Research and Cooperation Center, Heilongjiang Academy of Medical Sciences, Harbin Medical University, Harbin, Heilongjiang, P. R. China. FAU - Yu, Tong AU - Yu T AD - Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, Heilongjiang, P. R. China. AD - Northern Translational Medicine Research and Cooperation Center, Heilongjiang Academy of Medical Sciences, Harbin Medical University, Harbin, Heilongjiang, P. R. China. FAU - Li, Xuelian AU - Li X AD - Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, Heilongjiang, P. R. China. FAU - Zhou, Yuhong AU - Zhou Y AD - Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, Heilongjiang, P. R. China. FAU - Shan, Hongli AU - Shan H AD - Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, Heilongjiang, P. R. China. shanhongli@ems.hrbmu.edu.cn. AD - Northern Translational Medicine Research and Cooperation Center, Heilongjiang Academy of Medical Sciences, Harbin Medical University, Harbin, Heilongjiang, P. R. China. shanhongli@ems.hrbmu.edu.cn. AD - Research Unit of Noninfectious Chronic Diseases in Frigid Zone (2019RU070), Chinese Academy of Medical Sciences, Harbin, Heilongjiang, P. R. China. shanhongli@ems.hrbmu.edu.cn. FAU - Liang, Haihai AU - Liang H AD - Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, Heilongjiang, P. R. China. lianghaihai@ems.hrbmu.edu.cn. AD - Northern Translational Medicine Research and Cooperation Center, Heilongjiang Academy of Medical Sciences, Harbin Medical University, Harbin, Heilongjiang, P. R. China. lianghaihai@ems.hrbmu.edu.cn. AD - Research Unit of Noninfectious Chronic Diseases in Frigid Zone (2019RU070), Chinese Academy of Medical Sciences, Harbin, Heilongjiang, P. R. China. lianghaihai@ems.hrbmu.edu.cn. LA - eng GR - 91949109/National Natural Science Foundation of China (National Science Foundation of China)/ GR - 31671187/National Natural Science Foundation of China (National Science Foundation of China)/ PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20210512 PL - England TA - Cell Death Differ JT - Cell death and differentiation JID - 9437445 RN - 0 (RNA, Long Noncoding) RN - 0 (SRSF1 protein, human) RN - 0 (Srsf1 protein, mouse) RN - 170974-22-8 (Serine-Arginine Splicing Factors) SB - IM MH - Animals MH - Cell Differentiation/physiology MH - Cell Proliferation/physiology MH - Humans MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Mice, Transgenic MH - Pulmonary Fibrosis/genetics/metabolism/pathology MH - RNA, Long Noncoding/*genetics/metabolism MH - Serine-Arginine Splicing Factors/genetics/*metabolism MH - Signal Transduction PMC - PMC8481258 COIS- The authors declare no competing interests. EDAT- 2021/05/14 06:00 MHDA- 2022/03/26 06:00 PMCR- 2022/10/01 CRDT- 2021/05/13 06:17 PHST- 2020/11/06 00:00 [received] PHST- 2021/04/21 00:00 [accepted] PHST- 2021/04/17 00:00 [revised] PHST- 2021/05/14 06:00 [pubmed] PHST- 2022/03/26 06:00 [medline] PHST- 2021/05/13 06:17 [entrez] PHST- 2022/10/01 00:00 [pmc-release] AID - 10.1038/s41418-021-00792-1 [pii] AID - 792 [pii] AID - 10.1038/s41418-021-00792-1 [doi] PST - ppublish SO - Cell Death Differ. 2021 Oct;28(10):2916-2930. doi: 10.1038/s41418-021-00792-1. Epub 2021 May 12.