Circulating BMP9 protects the pulmonary endothelium during inflammation-induced lung injury in mice

Rationale: Pulmonary endothelial permeability contributes to the high-permeability pulmonary edema that characterizes acute respiratory distress syndrome (ARDS). Circulating bone morphogeneic protein 9 (BMP9) is emerging as an important regulator of pulmonary vascular homeostasis. Objective: To determine whether endogenous BMP9 plays a role in preserving pulmonary endothelial integrity, and whether loss of endogenous BMP9 occurs during lipopolysacharride (LPS) challenge. Methods: A BMP9-neutralizing antibody was administrated to healthy adult mice and lung vasculature was examined. Potential mechanisms were delineated by transcript analysis in human lung endothelial cells. Impact of BMP9 administration was evaluated in a murine acute lung injury model induced by inhaled LPS. Levels of BMP9 were measured in plasma from patients with sepsis and endotoxemic mice. Main Results: Subacute neutralization of endogenous BMP9 in mice (N=12) resulted in increased lung vascular permeability (P=0.022), interstitial edema (P=0.0047) and neutrophil extravasation (P=0.029) compared with IgG control (N=6). In pulmonary endothelial cells, BMP9 regulated transcriptome pathways implicated in vascular permeability and cell membrane integrity. Augmentation of BMP9 signaling in mice (N=8) prevented inhaled LPS-induced lung injury (P=0.0027) and edema (P<0.0001). In endotoxemic mice (N=12), endogenous BMP9 levels were markedly reduced, due to a transient reduction in hepatic BMP9 mRNA expression and increased elastase activity in plasma. In human sepsis patients (N=10), circulating levels of BMP9 were also markedly reduced (P<0.0001). Conclusions: Endogenous circulating BMP9 is a pulmonary endothelial protective factor, down-regulated during inflammation. Exogenous BMP9 offers a potential therapy to prevent increased pulmonary endothelial permeability in lung injury.