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Abstract
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, NFkB, 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.
Keywords: erythropoietin-producing hepatoma receptor tyrosine kinase A2; ephrinA1; prone position; mechanical ventilation; lung injury
Mechanical ventilation (MV) remains an important life-supportive modality in the intensive care setting. This therapy, however, can cause or exacerbate lung damage by a variety of mechanisms referred to as ventilator-induced lung injury (VILI) (1). In addition to barotrauma, volutrauma, and atelectrauma caused by the cyclic overdistension of lung architecture at the tissue level, injurious mechanical forces can trigger biotrauma at the cellular level; biotrauma is characterized by an influx of inflammatory cells, epithelial and endothelial cell damage, impaired edema clearance, and apoptosis (2). VILI can propagate the injury to extrapulmonary organs, resulting in multiple system organ dysfunction and increased morbidity and mortality (3).
Although low tidal volume reduces the mortality rate associated with VILI in patients with acute...