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

Abstract

RationalePulmonary 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.ObjectiveTo 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.MethodsA 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 ResultsSubacute 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.ConclusionsEndogenous 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.Short summaryScientific Knowledge on the SubjectIncreased 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 FieldHere 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.

Tregs-derived interleukin 35 attenuates endothelial proliferation through STAT1 in pulmonary hypertension

“…The Interleukin-12 family was discovered in 2007, and Interleukin-35 is a new member of it (7). Recent studies have investigated the connection between impaired immune regulation and pulmonary endothelium, which is required for pulmonary vascular local homeostasis (26). Under physiological conditions, IL-35 expression was absent or present only at very low levels in the cardiovascular system.…”

It Takes Two to Tango: Endothelial TGFβ/BMP Signaling Crosstalk with Mechanobiology

“…These results in summary showed that BMP2/4/6 induce EC permeability, likely resulting in reduced cell–cell tension. In contrast, BMP9/ALK1 signaling prevents vascular permeability and was recently shown to prevent the leakiness of the inflamed lung microvasculature [ 193 ]. BMP9-ALK1 signaling facilitates cell–cell contacts and balances the interdependency between apico-basal and lateral forces [ 194 ]; Figure 4 b,c.…”

BMP9 in Acute Respiratory Distress Syndrome: Decades of BMP Studies in Vascular Biology Paying Off?

“…In this issue of Journal , Li and colleagues (pp. 1419–1430 ) show the power of this approach, adapting findings originally produced for pulmonary hypertension to acute respiratory distress syndrome (ARDS), a much more common problem than PAH, with an estimated 190,000 cases per year in the United States ( 9 , 10 ). They show in mice that blocking BMP9 leads to pulmonary vascular leak comparable to adding LPS, that BMP9 regulates genes involved in endothelial cell integrity, and that giving BMP9 to mice prevents vascular injury with inhaled LPS in mice.…”