Identification of a novel role for TL1A/DR3 deficiency in acute respiratory distress syndrome that exacerbates alveolar epithelial disruption
Abstract Alveolar epithelial barrier is a potential therapeutic target for acute respiratory distress syndrome (ARDS). However, an effective intervention against alveolar epithelial barrier has not been developed. Here, based on single-cell RNA and mRNA sequencing results, death receptor 3 (DR3) and...
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BMC
2023-07-01
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Series: | Respiratory Research |
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Online Access: | https://doi.org/10.1186/s12931-023-02488-1 |
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author | Dong Zhang Jianning Zhang Jintao Zhang Xiang Ji Qian Qi Jiawei Xu Yun Pan Xiaofei Liu Fang Sun Rong Zeng Liang Dong |
author_facet | Dong Zhang Jianning Zhang Jintao Zhang Xiang Ji Qian Qi Jiawei Xu Yun Pan Xiaofei Liu Fang Sun Rong Zeng Liang Dong |
author_sort | Dong Zhang |
collection | DOAJ |
description | Abstract Alveolar epithelial barrier is a potential therapeutic target for acute respiratory distress syndrome (ARDS). However, an effective intervention against alveolar epithelial barrier has not been developed. Here, based on single-cell RNA and mRNA sequencing results, death receptor 3 (DR3) and its only known ligand tumor necrosis factor ligand-associated molecule 1A (TL1A) were significantly reduced in epithelium from an ARDS mice and cell models. The apparent reduction in the TL1A/DR3 axis in lungs from septic-ARDS patients was correlated with the severity of the disease. The examination of knockout (KO) and alveolar epithelium conditional KO (CKO) mice showed that TL1A deficiency exacerbated alveolar inflammation and permeability in lipopolysaccharide (LPS)-induced ARDS. Mechanistically, TL1A deficiency decreased glycocalyx syndecan-1 and tight junction-associated zonula occludens 3 by increasing cathepsin E level for strengthening cell-to-cell permeability. Additionally, DR3 deletion aggravated barrier dysfunction and pulmonary edema in LPS-induced ARDS through the above mechanisms based on the analyses of DR3 CKO mice and DR3 overexpression cells. Therefore, the TL1A/DR3 axis has a potential value as a key therapeutic signaling for the protection of alveolar epithelial barrier. |
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format | Article |
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institution | Directory Open Access Journal |
issn | 1465-993X |
language | English |
last_indexed | 2024-03-12T23:21:10Z |
publishDate | 2023-07-01 |
publisher | BMC |
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series | Respiratory Research |
spelling | doaj.art-4efd8965fed14a52b335becc42df515d2023-07-16T11:25:27ZengBMCRespiratory Research1465-993X2023-07-0124112010.1186/s12931-023-02488-1Identification of a novel role for TL1A/DR3 deficiency in acute respiratory distress syndrome that exacerbates alveolar epithelial disruptionDong Zhang0Jianning Zhang1Jintao Zhang2Xiang Ji3Qian Qi4Jiawei Xu5Yun Pan6Xiaofei Liu7Fang Sun8Rong Zeng9Liang Dong10Department of Respiratory, Shandong Provincial Qianfoshan Hospital, Shandong UniversityDepartment of Respiratory and Intensive Care Unit, The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital, Shandong Institute of Respiratory DiseasesDepartment of Respiratory, Shandong Provincial Qianfoshan Hospital, Shandong UniversityDepartment of Respiratory and Intensive Care Unit, The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital, Shandong Institute of Respiratory DiseasesDepartment of Respiratory and Intensive Care Unit, The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital, Shandong Institute of Respiratory DiseasesDepartment of Respiratory and Intensive Care Unit, The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital, Shandong Institute of Respiratory DiseasesDepartment of Respiratory, Shandong Provincial Qianfoshan Hospital, Shandong UniversityDepartment of Respiratory and Intensive Care Unit, The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital, Shandong Institute of Respiratory DiseasesDepartment of Respiratory and Intensive Care Unit, The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital, Shandong Institute of Respiratory DiseasesDepartment of Respiratory, Shandong Provincial Qianfoshan Hospital, Shandong UniversityDepartment of Respiratory, Shandong Provincial Qianfoshan Hospital, Shandong UniversityAbstract Alveolar epithelial barrier is a potential therapeutic target for acute respiratory distress syndrome (ARDS). However, an effective intervention against alveolar epithelial barrier has not been developed. Here, based on single-cell RNA and mRNA sequencing results, death receptor 3 (DR3) and its only known ligand tumor necrosis factor ligand-associated molecule 1A (TL1A) were significantly reduced in epithelium from an ARDS mice and cell models. The apparent reduction in the TL1A/DR3 axis in lungs from septic-ARDS patients was correlated with the severity of the disease. The examination of knockout (KO) and alveolar epithelium conditional KO (CKO) mice showed that TL1A deficiency exacerbated alveolar inflammation and permeability in lipopolysaccharide (LPS)-induced ARDS. Mechanistically, TL1A deficiency decreased glycocalyx syndecan-1 and tight junction-associated zonula occludens 3 by increasing cathepsin E level for strengthening cell-to-cell permeability. Additionally, DR3 deletion aggravated barrier dysfunction and pulmonary edema in LPS-induced ARDS through the above mechanisms based on the analyses of DR3 CKO mice and DR3 overexpression cells. Therefore, the TL1A/DR3 axis has a potential value as a key therapeutic signaling for the protection of alveolar epithelial barrier.https://doi.org/10.1186/s12931-023-02488-1Alveolar epithelial barrierTL1A/DR3 axisCathepsin ESyndecan-1Tight junction-associated zonula occludens 3 |
spellingShingle | Dong Zhang Jianning Zhang Jintao Zhang Xiang Ji Qian Qi Jiawei Xu Yun Pan Xiaofei Liu Fang Sun Rong Zeng Liang Dong Identification of a novel role for TL1A/DR3 deficiency in acute respiratory distress syndrome that exacerbates alveolar epithelial disruption Respiratory Research Alveolar epithelial barrier TL1A/DR3 axis Cathepsin E Syndecan-1 Tight junction-associated zonula occludens 3 |
title | Identification of a novel role for TL1A/DR3 deficiency in acute respiratory distress syndrome that exacerbates alveolar epithelial disruption |
title_full | Identification of a novel role for TL1A/DR3 deficiency in acute respiratory distress syndrome that exacerbates alveolar epithelial disruption |
title_fullStr | Identification of a novel role for TL1A/DR3 deficiency in acute respiratory distress syndrome that exacerbates alveolar epithelial disruption |
title_full_unstemmed | Identification of a novel role for TL1A/DR3 deficiency in acute respiratory distress syndrome that exacerbates alveolar epithelial disruption |
title_short | Identification of a novel role for TL1A/DR3 deficiency in acute respiratory distress syndrome that exacerbates alveolar epithelial disruption |
title_sort | identification of a novel role for tl1a dr3 deficiency in acute respiratory distress syndrome that exacerbates alveolar epithelial disruption |
topic | Alveolar epithelial barrier TL1A/DR3 axis Cathepsin E Syndecan-1 Tight junction-associated zonula occludens 3 |
url | https://doi.org/10.1186/s12931-023-02488-1 |
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