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The Journal of Heart and Lung Transplantation
International Society for Heart and Lung Transplantation.

Venovenous extracorporeal membrane oxygenation promotes alveolar epithelial recovery by activating Hippo/YAP signaling after lung injury

  • Author Footnotes
    # These authors contributed equally to this work.
    Jian Huang
    Footnotes
    # These authors contributed equally to this work.
    Affiliations
    Department of Cardiac Surgery, Lanzhou University Second Hospital, Lanzhou University, Lanzhou, Gansu, China

    Second Clinical Medical College, Lanzhou University, Lanzhou, Gansu, China
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  • Author Footnotes
    # These authors contributed equally to this work.
    Rongzhi Zhang
    Footnotes
    # These authors contributed equally to this work.
    Affiliations
    Department of Anesthesiology, Lanzhou University Second Hospital, Lanzhou University, Lanzhou, Gansu, China
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  • Author Footnotes
    # These authors contributed equally to this work.
    Kerong Zhai
    Footnotes
    # These authors contributed equally to this work.
    Affiliations
    Department of Cardiac Surgery, Lanzhou University Second Hospital, Lanzhou University, Lanzhou, Gansu, China

    Second Clinical Medical College, Lanzhou University, Lanzhou, Gansu, China
    Search for articles by this author
  • Jian Li
    Affiliations
    Second Clinical Medical College, Lanzhou University, Lanzhou, Gansu, China
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  • Min Yao
    Affiliations
    Second Clinical Medical College, Lanzhou University, Lanzhou, Gansu, China
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  • Shilin Wei
    Affiliations
    Department of Cardiac Surgery, Lanzhou University Second Hospital, Lanzhou University, Lanzhou, Gansu, China

    Second Clinical Medical College, Lanzhou University, Lanzhou, Gansu, China
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  • Xingdong Cheng
    Affiliations
    Department of Cardiac Surgery, Lanzhou University Second Hospital, Lanzhou University, Lanzhou, Gansu, China

    Second Clinical Medical College, Lanzhou University, Lanzhou, Gansu, China
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  • Jianbao Yang
    Affiliations
    Department of Thoracic Surgery, Lanzhou University Second Hospital, Lanzhou University, Lanzhou, Gansu, China
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  • Bingren Gao
    Affiliations
    Department of Cardiac Surgery, Lanzhou University Second Hospital, Lanzhou University, Lanzhou, Gansu, China
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  • Xiangyang Wu
    Affiliations
    Department of Cardiac Surgery, Lanzhou University Second Hospital, Lanzhou University, Lanzhou, Gansu, China
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  • Yongnan Li
    Correspondence
    Reprint requests: Yongnan Li, MD, PhD, Department of Cardiac Surgery, Lanzhou University Second Hospital, No. 80 Cuiyingmen, Chengguan District, 730030, Lanzhou, China. Telephone: +86-152-106-12927. Fax: +86-931-894-2279.
    Affiliations
    Department of Cardiac Surgery, Lanzhou University Second Hospital, Lanzhou University, Lanzhou, Gansu, China

    Cuiying Biomedical Research Center, Lanzhou University Second Hospital, Lanzhou University, Lanzhou, Gansu, China

    Laboratory of Extracorporeal Life Support, Lanzhou University Second Hospital, Lanzhou University, Lanzhou, Gansu, China
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  • Author Footnotes
    # These authors contributed equally to this work.

      Background

      The preferred configuration for bridging patients with respiratory failure while awaiting lung transplantation is venovenous extracorporeal membrane oxygenation (VV ECMO). However, the protective effect of VV ECMO on the lung, as well as the underlying mechanisms, are still unknown.

      Methods

      We investigated the role of VV ECMO in preventing lung injury in vivo using a rat model. Additionally, the effects of Hippo/YAP signaling on alveolar epithelial type II cells (AT2)-mediated alveolar epithelial recovery in VV ECMO rats were also investigated. In the bronchoalveolar lavage fluid (BALF) and lung tissue, RNA sequencing, lung injury, edema, and cytokine expression were evaluated.

      Results

      VV ECMO significantly improved severe hypoxemia, reduced lung edema, and inflammatory response, and altered alveolar epithelial function, as indicated by reduced protein concentrations in BALF. This was associated with Hippo/YAP signaling activation, according to RNA sequencing analysis. Furthermore, we discovered that after VV ECMO, AT2 cells proliferated and differentiated, and this increase in AT2 cell activity was correlated to the increased nuclear expression of YAP, which is critical for alveolar epithelial recovery from lung injury. During VV ECMO, verteporfin-induced YAP inhibition and the loss of the oxygenator delayed lung alveolar epithelial recovery and led to a prolonged inflammatory response.

      Conclusions

      These findings suggest that VV ECMO protects against lung injury by activating the Hippo/YAP signaling pathway. Strategies aimed at increasing YAP activity in AT2 cells could thus aid alveolar epithelial recovery, making VV ECMO easier for lung transplantation.

      KEYWORDS

      Abbreviations:

      VV ECMO (venovenous extracorporeal membrane oxygenation), AT2 (alveolar epithelial type II cells), BALF (bronchoalveolar lavage fluid), AT1 (alveolar epithelial type I), TEAD (transcriptional enhanced associate domain), TNF-α (Tumor necrosis factor-α), IL-6 (interleukin-6), VP (YAP inhibitor), BCA (Bicinchoninic Acid)
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