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The role of EphA2/ephrinA1 pathway in hyperoxia-induced lung injury

Other Titles
 고산소유발 폐 손상에서 EphA2/ephrinA1 신호전달의 역할 
 College of Medicine (의과대학) 
 Dept. of Internal Medicine (내과학교실) 
Issue Date
Background: Oxygen therapy is an essential treatment for patients with acute respiratory distress syndrome. However, the inevitable development of hyperoxia-induced lung injury (HALI) may worsen patient prognosis. EphA2/ephrinA1 receptor-ligand signaling regulates the cytoskeleton and cell adhesion in various diseases and embryogenesis. We investigated whether EphA2/ephrinA1 signaling was associated with HALI in the present study. Methods: Male wild-type C57BL/6J mice (20-24 g; Orient Bio) were exposed to >95% O2 in a Plexiglass chamber. To evaluate the association between changes in EphA2/ephrinA1 signaling and exposure time on HALI, analysis was performed at 24 hr, 48 hr, and 72 hr compared with normoxia (21% O2 room air). To analyze the effect of an EphA2 monoclonal antibody (mAb, 8 µg via tail vein, pretreatment), the mice were sacrificed at 72 hr after hyperoxia exposure. Total cell counts, protein concentration measurements, and cytokine Luminex® assays (Biotech®, Minneapolis, USA) were performed on bronchoalveolar lavage (BAL) fluid. Western blotting, immunohistochemical (IHC), and immunofluorescence (IF) staining were performed on mouse lung tissue. To analyze the effect of the EphA2 mAb on survival, animal survival was observed by placing the mice in normoxic conditions after 72 hr of hyperoxia exposure. Results: With increasing exposure to hyperoxia, the expression of phosphorylated EphA2 in mouse lung tissue significantly increased, and protein leakage and cytokine activation (IL-1β, TNF-α, IL-6, and MIP-2) in BAL fluid were increased (p<0.05). In addition, the expression of tight or adherens junctions proteins, such as ZO-2 and VE-cadherin, was disrupted due to hyperoxia. In the HALI mouse model, compared with phosphate-buffered saline (PBS), the EphA2 mAb attenuated cytokine activation (IL-10 and TNFα) in BAL fluid and lung injury scores (p<0.05). The EphA2 mAb attenuated oxygen stress and abrogated the degradation of tight junction or adherens junction proteins, which was accompanied by a decrease in the expression of the antiapoptotic protein Bcl-2 (p<0.05). Furthermore, the EphA2 mAb improved the survival of HALI mice (p=0.045). Conclusion: EphA2/ephrinA1 signaling is significantly associated with HALI. EphA2 mAb treatment prevented alveolar-endothelial barrier damage and improved survival.
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1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 3. Dissertation
Yonsei Authors
Jung, Kyung Soo(정경수) ORCID logo https://orcid.org/0000-0003-1604-8730
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