SPRED2 deficiency may lead to lung ischemia-reperfusion injury via ERK1/2 signaling pathway activation.

Abstract

Inflammatory changes during lung ischemia-reperfusion injury (IRI) are related to the activation of the extracellular signal-regulated kinase (ERK)1/2 signaling pathway. Sprouty-related EVH1 (enabled/vasodilator-stimulated phosphoprotein homology 1)-domain-containing proteins (SPREDs) are known inhibitors of ERK1/2 signaling. The role of SPRED2 in lung IRI was examined in a left hilar clamp mouse model. C57BL/6 wild-type (WT) and Spred2-/- mice were used in the left hilar clamp model. Experimental groups underwent 30min of left hilar clamping followed by 1h of reperfusion. U0126, an ERK1/2 inhibitor, was administered to Spred2-/- mice with reperfused lungs. The partial pressures of oxygen of the Spred2-/- mice after reperfusion were significantly worse than those of WT mice (p < 0.01). Spred2-/- mice displayed more severe injuries than WT mice with increased neutrophil infiltration observed by a histological evaluation and flow cytometry (p < 0.001). This severe inflammation was inhibited by U0126. In addition, the rate of ERK1 activation was significantly higher in the lungs of Spred2-/- mice after reperfusion than in WT mice according to a Western blot analysis (p < 0.05). The activation of the ERK1/2 signaling pathway influences the severity of lung IRI, causing inflammation with neutrophil infiltration. SPRED2 may be a promising target for the suppression of lung IRI.