title: HMGB1 exacerbates bronchiolitis obliterans syndrome via RAGE/NF-κB/HPSE signaling to enhance latent TGF-β release from ECM.
abstract: Bronchiolitis obliterans syndrome (BOS), characterized by progressive airflow obstruction, is the main barrier to long-term graft survival after lung transplantation. Despite extensive studies, the mechanisms underlying BOS remain poorly understood, and targeted interventions have not yet been fully developed. In the present study, we employed a mouse model of tracheal transplantation and demonstrated that blockade of HMGB1 alone or combined with heparanase (HPSE) attenuates the development of BOS. It was noted that HMGB1 was first passively released from necrotic/damaged cells as a result of early unavoidable allograft injuries, leading to macrophage infiltration along with HMGB1 active secretion. Mechanistic studies revealed that extracellular HMGB1 acted through its receptor, RAGE, to activate NF-κB, which then bound to the HPSE promoter to transcribe its expression. The enhanced HPSE next released HS-bonded latent TGF-β from myofibroblast ECM by cleaving HS chains to promote the initiation and progression of BOS. Together, our data suggest that HMGB1 and HPSE could be viable targets for prevention and intervention of fibrotic diseases such BOS after lung transplantation.
authors.affiliation: The Center for Biomedical Research, Key Laboratory of Organ Transplantation, Ministry of Education, Key Laboratory of Organ Transplantation, Ministry of Health, Tongji Hospital, Tongji Medical College, Huazhong University of Sciences and Technology Wuhan 430030, China.
authors.forename: Long
authors.initials: L
authors.lastname: He
authors.affiliation: The Center for Biomedical Research, Key Laboratory of Organ Transplantation, Ministry of Education, Key Laboratory of Organ Transplantation, Ministry of Health, Tongji Hospital, Tongji Medical College, Huazhong University of Sciences and Technology Wuhan 430030, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Sun
authors.affiliation: The Center for Biomedical Research, Key Laboratory of Organ Transplantation, Ministry of Education, Key Laboratory of Organ Transplantation, Ministry of Health, Tongji Hospital, Tongji Medical College, Huazhong University of Sciences and Technology Wuhan 430030, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Wang
authors.affiliation: The Center for Biomedical Research, Key Laboratory of Organ Transplantation, Ministry of Education, Key Laboratory of Organ Transplantation, Ministry of Health, Tongji Hospital, Tongji Medical College, Huazhong University of Sciences and Technology Wuhan 430030, China.
authors.forename: Jianghui
authors.initials: J
authors.lastname: Zhu
authors.affiliation: The Center for Biomedical Research, Key Laboratory of Organ Transplantation, Ministry of Education, Key Laboratory of Organ Transplantation, Ministry of Health, Tongji Hospital, Tongji Medical College, Huazhong University of Sciences and Technology Wuhan 430030, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Fang
authors.affiliation: The Center for Biomedical Research, Key Laboratory of Organ Transplantation, Ministry of Education, Key Laboratory of Organ Transplantation, Ministry of Health, Tongji Hospital, Tongji Medical College, Huazhong University of Sciences and Technology Wuhan 430030, China.
authors.forename: Shu
authors.initials: S
authors.lastname: Zhang
authors.affiliation: The Center for Biomedical Research, Key Laboratory of Organ Transplantation, Ministry of Education, Key Laboratory of Organ Transplantation, Ministry of Health, Tongji Hospital, Tongji Medical College, Huazhong University of Sciences and Technology Wuhan 430030, China.
authors.forename: Qilin
authors.initials: Q
authors.lastname: Yu
authors.affiliation: Clinical and Molecular Immunology Research Center, Department of Immunology, Medical College of Yangtze University Jingzhou, Hubei, China.
authors.forename: Quan
authors.initials: Q
authors.lastname: Gong
authors.affiliation: Clinical and Molecular Immunology Research Center, Department of Immunology, Medical College of Yangtze University Jingzhou, Hubei, China.
authors.forename: Boxue
authors.initials: B
authors.lastname: Ren
authors.affiliation: Department of Emergency Medicine, Institute of Emergency Medicine and Rare Diseases, The Second Xiangya Hospital, Central South University Changsha, China.
authors.forename: Xudong
authors.initials: X
authors.lastname: Xiang
authors.affiliation: The Center for Biomedical Research, Key Laboratory of Organ Transplantation, Ministry of Education, Key Laboratory of Organ Transplantation, Ministry of Health, Tongji Hospital, Tongji Medical College, Huazhong University of Sciences and TechnologyWuhan 430030, China; Department of Sponsored Program Administration, Tongji Hospital, Tongji Medical College, Huazhong University of Sciences and TechnologyWuhan 430030, China.
authors.forename: Zhishui
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Department of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan 430030, China.
authors.forename: Qin
authors.initials: Q
authors.lastname: Ning
authors.affiliation: Department of Sponsored Program Administration, Tongji Hospital, Tongji Medical College, Huazhong University of Sciences and Technology Wuhan 430030, China.
authors.forename: Jifa
authors.initials: J
authors.lastname: Hu
authors.affiliation: The Center for Biomedical Research, Key Laboratory of Organ Transplantation, Ministry of Education, Key Laboratory of Organ Transplantation, Ministry of Health, Tongji Hospital, Tongji Medical College, Huazhong University of Sciences and Technology Wuhan 430030, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Yang
authors.affiliation: The Center for Biomedical Research, Key Laboratory of Organ Transplantation, Ministry of Education, Key Laboratory of Organ Transplantation, Ministry of Health, Tongji Hospital, Tongji Medical College, Huazhong University of Sciences and TechnologyWuhan 430030, China; Department of Sponsored Program Administration, Tongji Hospital, Tongji Medical College, Huazhong University of Sciences and TechnologyWuhan 430030, China.
authors.forename: Cong-Yi
authors.initials: CY
authors.lastname: Wang
keywords: BOS; HMGB1; HPSE; Lung transplantation; RAGE/NF-κB pathway; TGF-β