ABSTRACT
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 BMP9 plays a role in preserving pulmonary endothelial integrity, and whether loss of endogenous BMP9 occurs during lipopolysacharride (LPS)-induced lung inflammation and permeability.
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 primary lung endothelial cells. Impact of BMP9 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 resulted in increased lung vascular permeability, interstitial edema and neutrophil extravasation. In lung endothelial cells, BMP9 regulated a programme of gene expression and pathways controlling vascular permeability and cell membrane integrity. Augmentation of BMP9 signalling in mice with exogenous BMP9 prevented inhaled LPS-caused lung injury and edema. In endotoxemic mice, 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, circulating levels of BMP9 were also markedly reduced.
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.
Scientific Knowledge on the Subject Increased pulmonary endothelial permeability is a major factor in the development of acute respiratory distress syndrome (ARDS). Evidence is emerging that circulating BMP9, secreted from the liver, might protect the pulmonary endothelium from injury. For example, loss of BMP9 levels or signalling receptor contributes to the development of pulmonary arterial hypertension. The role of endogenous BMP9 in endothelial permeability remains unclear.
What This Study Adds to the Field Here we show that subacute neutralization of endogenous BMP9 leads to lung vascular injury, including enhanced permeability and neutrophil extravasation. BMP9 levels were markedly reduced in the setting of inflammation in mice and humans. Conversely, exogenous supplementation of BMP9 protected the lung from LPS-induced injury. This study suggests that exogenous BMP9 could offer a novel approach to prevent increased pulmonary endothelial permeability in the setting of lung injury and ARDS.
Competing Interest Statement
Prof Morrell, and Drs Wei Li and Paul Upton are co-founders and scientific advisers to Morphogen-IX.
Footnotes
↵* Joint senior authors
Conflict of Interest: WL and PDU are founders and consultants to Morphogen-IX. NWM is a founder and CEO of Morphogen-IX.
Funding: This work was supported by the following grants: British Heart Foundation grants (PG/17/1/32532 to WL and NWM, PG/17/58/33134 to WL, NWM and CS, CH/09/001/25945 and RG/13/4/30107 to NWM), MRC grant (MR/K020919/1 to NWM), British Lung Foundatin grant (BLF COPD10/5 to AMC), and National Institutes of Health Grants (P01-HL108801 to RMB, R01-HL131910 to PBY and R42-HL132742 to PBY). KML was supported by a Wellcome Trust Clinical Research Fellowship (102706/Z/13/Z). Infrastructre support was provided by the Cambridge NIHR Biomedical Research Centre.