2. Academic Validation
  3. Inhibition of lncEPS by TLR4/NF-κB pathway induces ventilator-induced lung injury by decreasing its binding to and upregulating Hspa5

Inhibition of lncEPS by TLR4/NF-κB pathway induces ventilator-induced lung injury by decreasing its binding to and upregulating Hspa5

  • Int J Biol Macromol. 2025 Jan:286:138238. doi: 10.1016/j.ijbiomac.2024.138238.
Shengsong Chen 1,  Zhijiang Qi 2,  Yu Bai 1,  Yi Zhang 3,  Qingyuan Zhan 4,  Jingen Xia 5
Affiliations

Affiliations

  • 1 Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, China-Japan Friendship Hospital, No 2, East Yinghua Road, Chaoyang District, Beijing 100029, PR China; Peking Union Medical College, Chinese Academy of Medical Sciences, No 9, Dongdan Santiao, Dongcheng District, Beijing 100730, PR China; National Center for Respiratory Medicine, No 2, East Yinghua Road, Chaoyang District, Beijing 100029, PR China; Institute of Respiratory Medicine, Chinese Academy of Medical Sciences, No 2, East Yinghua Road, Chaoyang District, Beijing 100029, PR China; National Clinical Research Center for Respiratory Diseases, No 2, East Yinghua Road, Chaoyang District, Beijing 100029, PR China; WHO Collaborating Centre for Tobacco Cessation and Respiratory Diseases Prevention, No 2, East Yinghua Road, Chaoyang District, Beijing 100029, PR China.
  • 2 Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, China-Japan Friendship Hospital, No 2, East Yinghua Road, Chaoyang District, Beijing 100029, PR China; National Center for Respiratory Medicine, No 2, East Yinghua Road, Chaoyang District, Beijing 100029, PR China; Institute of Respiratory Medicine, Chinese Academy of Medical Sciences, No 2, East Yinghua Road, Chaoyang District, Beijing 100029, PR China; National Clinical Research Center for Respiratory Diseases, No 2, East Yinghua Road, Chaoyang District, Beijing 100029, PR China; WHO Collaborating Centre for Tobacco Cessation and Respiratory Diseases Prevention, No 2, East Yinghua Road, Chaoyang District, Beijing 100029, PR China.
  • 3 Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, China-Japan Friendship Hospital, No 2, East Yinghua Road, Chaoyang District, Beijing 100029, PR China; National Center for Respiratory Medicine, No 2, East Yinghua Road, Chaoyang District, Beijing 100029, PR China; Institute of Respiratory Medicine, Chinese Academy of Medical Sciences, No 2, East Yinghua Road, Chaoyang District, Beijing 100029, PR China; National Clinical Research Center for Respiratory Diseases, No 2, East Yinghua Road, Chaoyang District, Beijing 100029, PR China; WHO Collaborating Centre for Tobacco Cessation and Respiratory Diseases Prevention, No 2, East Yinghua Road, Chaoyang District, Beijing 100029, PR China. Electronic address: czzhangyi1985@126.com.
  • 4 Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, China-Japan Friendship Hospital, No 2, East Yinghua Road, Chaoyang District, Beijing 100029, PR China; Peking Union Medical College, Chinese Academy of Medical Sciences, No 9, Dongdan Santiao, Dongcheng District, Beijing 100730, PR China; National Center for Respiratory Medicine, No 2, East Yinghua Road, Chaoyang District, Beijing 100029, PR China; Institute of Respiratory Medicine, Chinese Academy of Medical Sciences, No 2, East Yinghua Road, Chaoyang District, Beijing 100029, PR China; National Clinical Research Center for Respiratory Diseases, No 2, East Yinghua Road, Chaoyang District, Beijing 100029, PR China; WHO Collaborating Centre for Tobacco Cessation and Respiratory Diseases Prevention, No 2, East Yinghua Road, Chaoyang District, Beijing 100029, PR China. Electronic address: drzhanqy@163.com.
  • 5 Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, China-Japan Friendship Hospital, No 2, East Yinghua Road, Chaoyang District, Beijing 100029, PR China; National Center for Respiratory Medicine, No 2, East Yinghua Road, Chaoyang District, Beijing 100029, PR China; Institute of Respiratory Medicine, Chinese Academy of Medical Sciences, No 2, East Yinghua Road, Chaoyang District, Beijing 100029, PR China; National Clinical Research Center for Respiratory Diseases, No 2, East Yinghua Road, Chaoyang District, Beijing 100029, PR China; WHO Collaborating Centre for Tobacco Cessation and Respiratory Diseases Prevention, No 2, East Yinghua Road, Chaoyang District, Beijing 100029, PR China. Electronic address: xiajingen_00632@163.com.
PMID: 39617220 DOI: 10.1016/j.ijbiomac.2024.138238
Abstract

Whether LincRNA erythroid prosurvival (LncEPS) reduces VILI remains unclear. A GSE200932 microarray was used to screen differentially expressed genes (DEGs). A VILI mouse model was constructed by mechanical ventilation (MV), with or without TAK242 or SN50 pretreatment. Airway transfection with adeno-associated virus (AAV) was used to overexpress lncEPS in alveolar macrophages (AMs). Lung tissues were collected to assess pathological injury and macrophage polarization. NLRP3 inflammasome, TLR4/NF-κB pathway activation and heat shock protein family A member 5 (HSPA5) in lung tissue and AMs wre evaluated. LncEPS localization and regulatory changes were assessed using in situ hybridization and RT-PCR. Lung tissues after lncEPS overexpression were subjected to transcriptomics. Chromatin isolation and mass spectrometry (MS) were performed to identify proteins interacting with lncEPS. GSE200932 microarray showed that the DEGs were related to NF-κB pathway, Toll-like Receptor pathway and NOD-like Receptor pathway. TAK242 or SN50 treatment increased polarization of M2 macrophages and decreased NLRP3 inflammasome activation by inhibiting TLR4/NF-κB pathway in VILI. Inhibition of TLR4/NF-κB pathway upregulated lncEPS expression in AMs. Overexpression of lncEPS increased polarization of M2 macrophages and decreased NLRP3 inflammasome activation, eventually alleviating VILI in mice. Mechanistically, lncEPS bound to HSPA5 and downregulated its expression to inhibit inflammatory response.

Keywords

Long noncoding RNA lncEPS; TLR4/NF-κB pathway; Ventilator-induced lung injury.

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