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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 
 American Journal of Respiratory Cell and Molecular Biology, Vol.58(4) : 519-529, 2018 
Journal Title
 American Journal of Respiratory Cell and Molecular Biology 
Issue Date
ephrinA1 ; erythropoietin-producing hepatoma receptor tyrosine kinase A2 ; lung injury ; mechanical ventilation ; prone position
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, PI3Kgamma, Akt, NF-kappaB, 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 PI3Kgamma, Akt, NF-kappaB, 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.
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1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
Kang, Young Ae(강영애) ORCID logo https://orcid.org/0000-0002-7783-5271
Kim, Song Yee(김송이) ORCID logo https://orcid.org/0000-0001-8627-486X
Kim, Young Sam(김영삼) ORCID logo https://orcid.org/0000-0001-9656-8482
Kim, Eun Young(김은영) ORCID logo https://orcid.org/0000-0002-3281-5744
Park, Moo Suk(박무석) ORCID logo https://orcid.org/0000-0003-0820-7615
Song, Joo Han(송주한)
Shin, Mi Hwa(신미화) ORCID logo https://orcid.org/0000-0003-2215-8629
Chang, Joon(장준) ORCID logo https://orcid.org/0000-0003-4542-6841
Jung, Kyung Soo(정경수) ORCID logo https://orcid.org/0000-0003-1604-8730
Jung, Ji Ye(정지예) ORCID logo https://orcid.org/0000-0003-1589-4142
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