Erythropoietin-producing hepatoma receptor tyrosine kinase A2 modulation associates with protective effect of prone position in ventilator-induced lung injury

Byung Hoon Park, Mi Hwa Shin, Ivor S. Douglas, Kyung Soo Chung, Joo Han Song, Song Yee Kim, Eun Young Kim, Ji Ye Jung, Young Ae Kang, Joon Chang, Young Sam Kim, Moo Suk Park

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4 Citations (Scopus)


The erythropoietin-producing hepatoma (Eph) receptor tyrosine kinase A2 (EphA2) and its ligand, ephrinA1, play a pivotal role in inflammation and tissue injury by modulating the epithelial and endothelial barrier integrity. Therefore, EphA2 receptor may be a potential therapeutic target for modulating ventilator-induced lung injury (VILI). To support this hypothesis, here, we analyzed EphA2/ephrinA1 signaling in the process of VILI and determined the role of EphA2/ephrinA1 signaling in the protective mechanism of prone positioning in a VILI model. Wild-type mice were ventilated with high (24 ml/kg; positive end-expiratory pressure, 0 cm; 5 h) tidal volume in a supine or prone position. Anti-EphA2 receptor antibody or IgG was administered to the supine position group. Injury was assessed by analyzing the BAL fluid, lung injury scoring, and transmission electron microscopy. Lung lysates were evaluated using cytokine/chemokine ELISA and Western blotting of EphA2, ephrinA1, PI3Kg, Akt, NF-kB, and P70S6 kinase. EphA2/ephrinA1 expression was higher in the supine high tidal volume group than in the control group, but it did not increase upon prone positioning or anti-EphA2 receptor antibody treatment. EphA2 antagonism reduced the extent of VILI and downregulated the expression of PI3Kg, Akt, NF-kB, and P70S6 kinase. These findings demonstrate that EphA2/ephrinA1 signaling is involved in the molecular mechanism of VILI and that modulation of EphA2/ehprinA1 signaling by prone position or EphA2 antagonism may be associated with the lung-protective effect. Our data provide evidence for EphA2/ehprinA1 as a promising therapeutic target for modulating VILI.

Original languageEnglish
Pages (from-to)519-529
Number of pages11
JournalAmerican Journal of Respiratory Cell and Molecular Biology
Issue number4
Publication statusPublished - 2018 Apr

Bibliographical note

Publisher Copyright:
Copyright © 2018 by the American Thoracic Society.

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology


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