Abstract
Rationale: Pulmonary endothelial permeability contributes to the high-permeability pulmonary edema that characterizes acute respiratory distress syndrome. Circulating BMP9 (bone morphogenetic protein 9) is emerging as an important regulator of pulmonary vascular homeostasis.Objectives:To determine whether endogenous BMP9 plays a role in preserving pulmonary endothelial integrity and whether loss of endogenous BMP9 occurs during 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. The 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 from endotoxemic mice.Measurements and 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 treatment (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 circulating BMP9 concentrations were markedly reduced, the causes of which include a transient reduction in hepatic BMP9 mRNA expression and increased elastase activity in plasma. In human patients with sepsis (N = 10), circulating concentratons of BMP9 were also markedly reduced (P < 0.0001).Conclusions: Endogenous circulating BMP9 is a pulmonary endothelial-protective factor, downregulated during inflammation. Exogenous BMP9 offers a potential therapy to prevent increased pulmonary endothelial permeability in lung injury.
Highlights
Endothelial dysfunction, inflammation and increased capillary permeability play central roles in the pathobiology of sepsis and the acute respiratory distress syndrome (ARDS)(1)
After neutralizing anti-bone morphogeneic protein 9 (BMP9) antibody was administered by intraperitoneal injection on day 0 and day 2, lung interstitial fluid accumulation was evaluated at day 3 using the EB dye extravasation assay [8](Figure 1A)
Mice treated with anti-BMP9 antibody exhibited significantly higher levels of interstitial fluid accumulation in their lungs compared with mice treated with isotype control IgG (Figure 1B)
Summary
Endothelial dysfunction, inflammation and increased capillary permeability play central roles in the pathobiology of sepsis and the acute respiratory distress syndrome (ARDS)(1). Previous studies have identified important signaling pathways and protein-protein interactions within inter-endothelial junctions that regulate endothelial barrier function[2]. Such knowledge has not yet resulted in approved drugs that target the increased vascular permeability present in sepsis and ARDS[1], conditions associated with an unacceptably high mortality. Adenoviral delivery of BMP9 has been shown to prevent retinal vascular permeability in diabetic mice[9] Despite such evidence suggesting that augmentation of BMP9 signaling might prevents endothelial hyperpermeability, the role of the endogenous BMP9 in the maintainence of endothelial barrier function, and the mechanisms involved, has not been investigated
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