Endothelial Sash1 is required for alveolar surfactant production through nitric oxide signaling

Sash1 acts as a scaffold in TLR4 signaling. We generated Sash1-/- mice, which die in the perinatal period due to respiratory distress. Constitutive or endothelial-restricted Sash1 loss leads to a reduction of surfactant-associated protein synthesis. We show that Sash1 interacts with β-arrestin 1 downstream of the TLR4 pathway to activate Akt and eNOS in microvascular endothelial cells. Generation of nitric oxide downstream of Sash1 in endothelial cells activated cGMP in adjacent alveolar type 2 cells to induce transcription of surfactant genes. Thus we identify a critical cell nonautonomous function for Sash1 in embryonic development in which endothelial Sash1 affects alveolar type 2 cells and promotes pulmonary surfactant production through nitric oxide signaling. Lack of pulmonary surfactant is a major cause of respiratory distress and mortality in preterm infants, and these findings identify the endothelium as a potential target for therapy. E18.5 lung endothelial cells from wild-type compared to Sash1-knockout