The role of EphA2 signaling in lipopolysaccharide-induced lung injury

Abstract

Purpose: Eph-Ephrin signaling mediates various cellular processes including vasculogenesis, angiogenesis, cell migration, axon guidance, fluid homeostasis and repair after injury. Although previous studies demonstrate that stimulation of EphA receptor induces increased vascular permeability and inflammatory response in lung injury, the detailed mechanisms of EphA2 signaling are unknown. The aim of this study is to evaluate the role and related signal pathways of EphA2 signaling in the lipopolysaccharide (LPS)-induced lung injury model.

Materials and Methods: We studied three experimental mice groups. These were PBS + IgG (IgG instillation after PBS exposure), LPS + IgG group (IgG instillation after LPS exposure) and LPS+ EphA2 mAb group (EphA2 monoclonal antibody instillation postreatment after LPS exposure). The cell numbers and protein concentration in the bronchoalveolar lavage fluid (BALF), changes in histopathology and the expression of several signal pathway proteins including PI3K-Akt-NFkB,Src, Erk, E-cadherin and mTOR signaling were compared among three groups.

Results: We report that acute LPS exposure significantly upregulated Epha2 and EphrinA1 expression. Inhibiting EphA2 receptor by intranasal EphA2 mAb instillation attenuated lung injury and reduced cell counts and protein concentration of BALF (all, P < 0.05). EphA2 mAb posttreatment downregulated the expression of PI3K 110γ, phospho-Akt, phosphor-NFkB, Erk1/Erk2, phospho-Src and phospho-S6K. In addition, inhibiting EphA2 receptor augmented the expression of E- cadherin protein related to cell-cell adhesions.

Conclusion: The present data suggest that EphA2 receptor may be an unrecognized contributor modulating several signal pathways including PI3K-Akt-NFkB, Src-NFkB, E-cadherin in cell-cell adhesions and mTOR in LPS- induced lung injury. Further studies are needed to verify the potential of EphA2 receptor inhibitor as a novel therapeutic agent in LPS-induced lung injury.