单位：[1]Department of Dermatology, Huashan Hospital and State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, P. R. China.[2]Human Phenome Institute and Collaborative Innovation Center for Genetics and Development, Fudan University, Shanghai, P. R. China.[3]Division of Rheumatology, Huashan hospital, Fudan University, Shanghai, P. R. China.[4]MOE Key Laboratory of Contemporary Anthropology, Department of Anthropology and Human Genetics, School of Life Sciences, Fudan University, Shanghai, P. R. China.[5]Institute for Six-sector Economy, Fudan University, Shanghai, P. R. China.[6]Division of Rheumatology, Shanghai TCM-Integrated Hospital, Shanghai, P. R. China.[7]The Clinical Laboratory of Tongren Hosipital, Shanghai Jiaotong University, Shanghai, P. R. China.[8]Department of Pathology and Pathophysiology, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, P. R. China.[9]Department of Internal Medicine 3 and Institute for Clinical Immunology, University of Erlangen, Nuremberg, Germany.[10]Department of Rheumatology, Xiangya Hospital, Central South University, Changsha, Hunan Province, P. R. China.[11]Wuxi Lung Transplant Center, Wuxi People's Hospital affiliated to Nanjing Medical University, Wuxi, P. R. China.[12]State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, P. R. China.[13]Rheumatology and Immunology Department, Peking University Shenzhen Hospital, Shenzhen, P. R. China.北京大学深圳医院深圳市康宁医院深圳医学信息中心[14]Department of Pulmonary and Critical Care Medicine, China-Japan Friendship Hospital National Clinical Research Center for Respiratory Diseases, Institute of Respiratory Medicine, Chinese Academy of Medical Science, Beijing, P. R. China.[15]School of Medicine, Tsinghua University, Beijing, P. R. China.[16]Department of Rheumatology and Immunology, Yiling Hospital Affiliated to Hebei Medical University, Shijiazhuang, Hebei Province, P. R. China.[17]Department of Nephrology, Zhongshan Hospital, Fudan University, Fudan Zhangjiang Institute, Shanghai, P. R. China.[18]Institute of Rheumatology, Immunology and Allergy, Fudan University, Shanghai, P. R. China.[19]Institute of Metabolism and Integrative Biology, Fudan University, Shanghai, P. R. China.[20]Research Unit of Dissecting the Population Genetics and Developing New Technologies for Treatment and Prevention of Skin Phenotypes and Dermatological Diseases (2019RU058), Chinese Academy of Medical Sciences, Shanghai, P. R. China.
Treatments for pulmonary fibrosis (PF) are ineffective because its molecular pathogenesis and therapeutic targets are unclear. Here, we show that the expression of low-density lipoprotein receptor (LDLR) was significantly decreased in alveolar type II (ATII) and fibroblast cells, whereas it was increased in endothelial cells from systemic sclerosis-related PF (SSc-PF) patients and idiopathic PF (IPF) patients compared with healthy controls. However, the plasma levels of low-density lipoprotein (LDL) increased in SSc-PF and IPF patients. The disrupted LDL-LDLR metabolism was also observed in four mouse PF models. Upon bleomycin (BLM) treatment, Ldlr-deficient (Ldlr-/-) mice exhibited remarkably higher LDL levels, abundant apoptosis, increased fibroblast-like endothelial and ATII cells and significantly earlier and more severe fibrotic response compared to wild-type mice. In vitro experiments revealed that apoptosis and TGF-beta 1 production were induced by LDL, while fibroblast-like cell accumulation and ET-1 expression were induced by LDLR knockdown. Treatment of fibroblasts with LDL or culture medium derived from LDL-pretreated endothelial or epithelial cells led to obvious fibrotic responses in vitro. Similar results were observed after LDLR knockdown operation. These results suggest that disturbed LDL-LDLR metabolism contributes in various ways to the malfunction of endothelial and epithelial cells, and fibroblasts during pulmonary fibrogenesis. In addition, pharmacological restoration of LDLR levels by using a combination of atorvastatin and alirocumab inhibited BLM-induced LDL elevation, apoptosis, fibroblast-like cell accumulation and mitigated PF in mice. Therefore, LDL-LDLR may serve as an important mediator in PF, and LDLR enhancing strategies may have beneficial effects on PF.
基金：
National Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81903203, 8203000633, 31521003, 81770066]; Shanghai Municipal Science and Technology Major Project [2017SHZDZX01]; Chinese Academy of Medical Sciences [2019-I2M-5-066]; Science andTechnology Innovation Plan-Basic Research Projects [20JC1417300]; 111 ProjectMinistry of Education, China - 111 Project [B13016]
第一作者单位：[1]Department of Dermatology, Huashan Hospital and State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, P. R. China.
通讯作者：
通讯机构：[1]Department of Dermatology, Huashan Hospital and State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, P. R. China.[2]Human Phenome Institute and Collaborative Innovation Center for Genetics and Development, Fudan University, Shanghai, P. R. China.[18]Institute of Rheumatology, Immunology and Allergy, Fudan University, Shanghai, P. R. China.[20]Research Unit of Dissecting the Population Genetics and Developing New Technologies for Treatment and Prevention of Skin Phenotypes and Dermatological Diseases (2019RU058), Chinese Academy of Medical Sciences, Shanghai, P. R. China.[*1]Department ofDermatology, HuashanHospital, and StateKey Laboratory of GeneticEngineering, School of Life Sciences, Fudan University, Shanghai, P. R. China.
推荐引用方式(GB/T 7714)：
Shi Xiangguang,Chen Yahui,Liu Qingmei,et al.LDLR dysfunction induces LDL accumulation and promotes pulmonary fibrosis[J].CLINICAL and TRANSLATIONAL MEDICINE.2022,12(1):doi:10.1002/ctm2.711.
APA：
Shi Xiangguang,Chen Yahui,Liu Qingmei,Mei Xueqian,Liu Jing...&Wang Jiucun.(2022).LDLR dysfunction induces LDL accumulation and promotes pulmonary fibrosis.CLINICAL and TRANSLATIONAL MEDICINE,12,(1)
MLA：
Shi Xiangguang,et al."LDLR dysfunction induces LDL accumulation and promotes pulmonary fibrosis".CLINICAL and TRANSLATIONAL MEDICINE 12..1(2022)
医学