title: Inhibition of EphA2/EphrinA1 signal attenuates lipopolysaccharide-induced lung injury.
abstract: Eph-Ephrin signalling mediates various cellular processes, including vasculogenesis, angiogenesis, cell migration, axon guidance, fluid homoeostasis and repair after injury. Although previous studies have demonstrated that stimulation of the EphA receptor induces increased vascular permeability and inflammatory response in lung injury, the detailed mechanisms of EphA2 signalling are unknown. In the present study, we evaluated the role of EphA2 signalling in mice with lipopolysaccharide (LPS)-induced lung injury. Acute LPS exposure significantly up-regulated EphA2 and EphrinA1 expression. Compared with LPS+IgG mice (IgG instillation after LPS exposure), LPS+EphA2 mAb mice [EphA2 monoclonal antibody (mAb) instillation posttreatment after LPS exposure] had attenuated lung injury and reduced cell counts and protein concentration of bronchoalveolar lavage fluid (BALF). EphA2 mAb posttreatment down-regulated the expression of phosphoinositide 3-kinases (PI3K) 110γ, phospho-Akt, phospho-NF-κB p65, phospho-Src and phospho-S6K in lung lysates. In addition, inhibiting the EphA2 receptor augmented the expression of E-cadherin, which is involved in cell-cell adhesion. Our study identified EphA2 receptor as an unrecognized modulator of several signalling pathways-including PI3K-Akt-NF-kB, Src-NF-κB, E-cadherin and mTOR-in LPS-induced lung injury. These results suggest that EphA2 receptor inhibitors may function as novel therapeutic agents for LPS-induced lung injury.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Chuncheon Sacred Heart Hospital, Hallym University Medical Center, Chuncheon-si, Gangwon-do, 200-704, Republic of Korea.
authors.forename: Ji Young
authors.initials: JY
authors.lastname: Hong
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Institute of Chest Disease, Severance Hospital, Yonsei University College of Medicine, Seodaemun-gu, Seoul 120-752, Republic of Korea.
authors.forename: Mi Hwa
authors.initials: MH
authors.lastname: Shin
authors.affiliation: Division of Pulmonary Sciences and Critical Care Medicine, Denver Health Medical Center, University of Colorado School of Medicine, Denver, CO 80204, U.S.A.
authors.forename: Ivor S
authors.initials: IS
authors.lastname: Douglas
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Institute of Chest Disease, Severance Hospital, Yonsei University College of Medicine, Seodaemun-gu, Seoul 120-752, Republic of Korea.
authors.forename: Kyung Soo
authors.initials: KS
authors.lastname: Chung
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Institute of Chest Disease, Severance Hospital, Yonsei University College of Medicine, Seodaemun-gu, Seoul 120-752, Republic of Korea.
authors.forename: Eun Young
authors.initials: EY
authors.lastname: Kim
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Institute of Chest Disease, Severance Hospital, Yonsei University College of Medicine, Seodaemun-gu, Seoul 120-752, Republic of Korea.
authors.forename: Ji Ye
authors.initials: JY
authors.lastname: Jung
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Institute of Chest Disease, Severance Hospital, Yonsei University College of Medicine, Seodaemun-gu, Seoul 120-752, Republic of Korea.
authors.forename: Young Ae
authors.initials: YA
authors.lastname: Kang
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Institute of Chest Disease, Severance Hospital, Yonsei University College of Medicine, Seodaemun-gu, Seoul 120-752, Republic of Korea.
authors.forename: Se Kyu
authors.initials: SK
authors.lastname: Kim
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Institute of Chest Disease, Severance Hospital, Yonsei University College of Medicine, Seodaemun-gu, Seoul 120-752, Republic of Korea.
authors.forename: Joon
authors.initials: J
authors.lastname: Chang
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Institute of Chest Disease, Severance Hospital, Yonsei University College of Medicine, Seodaemun-gu, Seoul 120-752, Republic of Korea.
authors.forename: Young Sam
authors.initials: YS
authors.lastname: Kim
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Institute of Chest Disease, Severance Hospital, Yonsei University College of Medicine, Seodaemun-gu, Seoul 120-752, Republic of Korea pms70@yuhs.ac.
authors.forename: Moo Suk
authors.initials: MS
authors.lastname: Park
mesh_terms: D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D036382:Ephrin-A1 / Q000378:metabolism*; D006801:Humans; D008070:Lipopolysaccharides / Q000009:adverse effects*; D008168:Lung / Q000378:metabolism; D055370:Lung Injury / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D036104:Receptor, EphA2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D036382:Ephrin-A1; D008070:Lipopolysaccharides; D036104:Receptor, EphA2
keywords: EphA2; EphrinA1; acute lung injury; lipopolysaccharide