2. Academic Validation
  3. Inhibition the ubiquitination of ENaC and Na,K-ATPase with erythropoietin promotes alveolar fluid clearance in sepsis-induced acute respiratory distress syndrome

Inhibition the ubiquitination of ENaC and Na,K-ATPase with erythropoietin promotes alveolar fluid clearance in sepsis-induced acute respiratory distress syndrome

  • Biomed Pharmacother. 2024 Mar 21:174:116447. doi: 10.1016/j.biopha.2024.116447.
Ye Gao 1,  Fei Cao 2,  Xinyi Tian 1,  Qianping Zhang 3,  Congcong Xu 1,  Bowen Ji 1,  Ye-An Zhang 1,  Linan Du 1,  Jun Han 1,  Li Li 1,  Siyu Zhou 1,  Yuqiang Gong 1,  Binyu Ying 1,  Fang Gao-Smith 4,  Shengwei Jin 5
Affiliations

Affiliations

  • 1 Department of Anaesthesia, Pain and Critical Care, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China; Key Laboratory of Pediatric Anesthesiology, Ministry of Education, Wenzhou Medical University, Zhejiang, China; Laboratory of Anesthesiology of Zhejiang Province, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Zhejiang, China.
  • 2 Department of Anaesthesia, Pain and Critical Care, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China; Key Laboratory of Pediatric Anesthesiology, Ministry of Education, Wenzhou Medical University, Zhejiang, China; Laboratory of Anesthesiology of Zhejiang Province, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Zhejiang, China; Department of Anesthesiology, Sun Yat-sen University Cancer Center, Guangzhou, China.
  • 3 Department of Anaesthesia, Pain and Critical Care, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
  • 4 Department of Anaesthesia, Pain and Critical Care, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China; Key Laboratory of Pediatric Anesthesiology, Ministry of Education, Wenzhou Medical University, Zhejiang, China; Laboratory of Anesthesiology of Zhejiang Province, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Zhejiang, China; Centre for Translational Inflammation Research, Institute of Inflammation and Aging, University of Birmingham, Birmingham, United Kingdom. Electronic address: f.g.smith@bham.ac.uk.
  • 5 Department of Anaesthesia, Pain and Critical Care, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China; Key Laboratory of Pediatric Anesthesiology, Ministry of Education, Wenzhou Medical University, Zhejiang, China; Laboratory of Anesthesiology of Zhejiang Province, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Zhejiang, China. Electronic address: jsw@wmu.edu.cn.
PMID: 38518606 DOI: 10.1016/j.biopha.2024.116447
Abstract

Sepsis-induced acute respiratory distress syndrome (ARDS) causes significant fatalities worldwide and lacks pharmacological intervention. Alveolar fluid clearance (AFC) plays a pivotal role in the remission of ARDS and is markedly impaired in the pathogenesis of ARDS. Here, we demonstrated that erythropoietin could effectively ameliorate lung injury manifestations and lethality, restore lung function and promote AFC in a rat model of lipopolysaccharide (LPS)-induced ARDS. Moreover, it was proven that EPO-induced restoration of AFC occurs through triggering the total protein expression of ENaC and Na,K-ATPase channels, enhancing their protein abundance in the membrane, and suppressing their ubiquitination for degeneration. Mechanistically, the data indicated the possible involvement of EPOR/JAK2/STAT3/SGK1/Nedd4-2 signaling in this process, and the pharmacological inhibition of the pathway markedly eliminated the stimulating effects of EPO on ENaC and Na,K-ATPase, and subsequently reversed the augmentation of AFC by EPO. Consistently, in vitro studies of alveolar epithelial cells paralleled with that EPO upregulated the expression of ENaC and Na,K-ATPase, and patch-clamp studies further demonstrated that EPO substantially strengthened sodium ion currents. Collectively, EPO could effectively promote AFC by improving ENaC and Na,K-ATPase protein expression and abundance in the membrane, dependent on inhibition of ENaC and Na,K-ATPase ubiquitination, and resulting in diminishing LPS-associated lung injuries.

Keywords

ENaC; Na,K-ATPase; acute respiratory distress syndrome; alveolar fluid clearance; erythropoietin; ubiquitination.

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