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), which carries a high mortality. Circulating bone morphogeneic protein 9 (BMP9) is emerging as an important regulator of pulmonary vascular homeostasis. Objective: To determine whether endogenous circulating BMP9 plays a role in preserving pulmonary endothelial integrity, and whether loss of endogenous BMP9 occurs during LPS-induced
... ing LPS-induced lung inflammation and permeability. Methods: A BMP9-neutralizing antibody was administrated to healthy adult mice and lung vasculature was examined. Inhaled LPS was used as a murine model of acute lung injury to evaluate the impact of BMP9 in vivo. Levels of BMP9 were measured in plasma from patients with sepsis and endotoxemic mice. Potential mechanisms were delineated by transcript analysis in human primary lung endothelial cells. Main Results: Subacute neutralization of endogenous circulating BMP9 in mice resulted in increased lung vascular permeability, interstitial edema and neutrophil extravasation. In mice exposed to LPS, BMP9 levels were markedly reduced, due to a temporary reduction in hepatic BMP9 mRNA expression and increased elastase activity in plasma. Augmentation of BMP9 signalling with exogenous BMP9 in LPS-challenged mice prevented lung injury and edema. In human sepsis patients, circulating levels of BMP9 were also markedly reduced. In lung endothelial cells, BMP9 regulated a programme of gene expression controlling vascular permeability including AQP1 (encoding aquaporin-1), KDR (encoding VEGFR2), TEK (encoding Tie2), and pathways involved in cell membrane integrity. Conclusions: Endogenous circulating BMP9 is a pulmonary endothelial protective factor, down-regulated during inflammation. Supplementation with exogenous BMP9 offers a potential therapy to prevent increased pulmonary endothelial permeability in the setting of lung injury.