The early responses of VEGF and its receptors during acute lung injury: implication of VEGF in alveolar epithelial cell survival

INTRODUCTION The function of the vascular endothelial growth factor (VEGF) system in acute lung injury (ALI) is controversial. We hypothesized that the role of VEGF in ALI may depend upon the stages of pathogenesis of ALI. METHODS To determine the responses of VEGF and its receptors during the early onset of ALI, C57BL6 mice were subjected to intestinal ischemia or sham operation for 30 minutes followed by intestinal ischemia-reperfusion (IIR) for four hours under low tidal volume ventilation with 100% oxygen. The severity of lung injury, expression of VEGF and its receptors were assessed. To further determine the role of VEGF and its type I receptor in lung epithelial cell survival, human lung epithelial A549 cells were treated with small interference RNA (siRNA) to selectively silence related genes. RESULTS IIR-induced ALI featured interstitial inflammation, enhancement of pulmonary vascular permeability, increase of total cells and neutrophils in the bronchoalveolar lavage (BAL), and alveolar epithelial cell death. In the BAL, VEGF was significantly increased in both sham and IIR groups, while the VEGF and VEGF receptor (VEGFR)-1 in the lung tissues were significantly reduced in these two groups. The increase of VEGF in the BAL was correlated with the total protein concentration and cell count. Significant negative correlations were observed between the number of VEGF or VEGFR-1 positive cells, and epithelial cells undergoing cell death. When human lung epithelial A549 cells were pre-treated with 50 nM of siRNA either against VEGF or VEGFR-1 for 24 hours, reduced VEGF and VEGFR-1 levels were associated with reduced cell viability. CONCLUSION These results suggest that VEGF may have dual roles in ALI: early release of VEGF may increase pulmonary vascular permeability; reduced expression of VEGF and VEGFR-1 in lung tissue may contribute to the death of alveolar epithelial cells.