Involvement of VEGFR1 signaling in LPS-induced lung injury in mice

<p>Acute respiratory distress syndrome (ARDS) is characterized by lung edema induced by increases in pulmonary vascular permeability. VEGF regulates vascular permeability; however, little is known about the role of VEGF receptor 1 (VEGFR1), a receptor for VEGF, in ARDS. Here, we examined the involvement of VEGFR1 signaling in the pathology of ARDS. ARDS was created by intra-tracheal injection of LPS to male VEGFR1 tyrosine kinase knock-out mice (TKKO) and wild-type mice (WT). Compared with WT, TKKO displayed increased lung injury histological scores and BALF levels of total protein, inflammatory cytokines (TNF, IL-1, and IL-6), and chemokine (CXCL2). VEGFR1 was expressed in the macrophages in the lung. Flow cytometry analysis of both genotypes demonstrated that alveolar macrophages were decreasing with time after LPS injection, and instead, recruited macrophages and neutrophils with higher extension were increased. Neutrophils in TKKO were greater than WT. The deletion of macrophages with clodronate liposomes (CL) in both genotypes attenuated lung injury scores and total protein, which was associated with reduced alveolar and recruited macrophages and neutrophils. But the magnitude of reduced levels of injury scores, total protein, cytokines, chemokines, and neutrophil accumulation was lower in CL-treated TKKO than that in CL-treated WT. These results suggested that attenuated acute lung injury through VEGFR1 signaling might be caused by inhibiting accumulation of neutrophils induced by cytokines and chemokines produced from macrophages.</p>