Circulating BMP9 Protects the Pulmonary Endothelium during Inflammation-induced Lung Injury in Mice

Area of Science:

• Pulmonary vascular biology
• Endothelial function
• Acute lung injury

Background:

• Pulmonary endothelial permeability is a hallmark of acute respiratory distress syndrome (ARDS).
• Bone morphogenetic protein 9 (BMP9) is an emerging regulator of pulmonary vascular homeostasis.
• The role of endogenous BMP9 in maintaining pulmonary endothelial integrity and its modulation during inflammatory conditions like LPS challenge requires investigation.

Purpose of the Study:

• To investigate the role of endogenous BMP9 in maintaining pulmonary endothelial integrity.
• To determine if BMP9 levels decrease during lipopolysaccharide (LPS)-induced inflammation.
• To evaluate the therapeutic potential of exogenous BMP9 in preventing lung injury.

Main Methods:

• Administered BMP9-neutralizing antibody to mice to assess effects on lung vascular permeability, edema, and neutrophil extravasation.
• Utilized transcript analysis in human lung endothelial cells to explore underlying mechanisms.
• Evaluated BMP9 administration in a murine model of inhaled LPS-induced acute lung injury.
• Measured BMP9 levels in plasma from endotoxemic mice and human sepsis patients.

Main Results:

• Neutralization of endogenous BMP9 increased lung vascular permeability, interstitial edema, and neutrophil extravasation in mice.
• BMP9 modulated gene expression pathways related to vascular permeability and endothelial integrity in lung endothelial cells.
• BMP9 administration protected against LPS-induced lung injury and edema.
• Endogenous BMP9 concentrations were significantly reduced in endotoxemic mice and human sepsis patients, linked to decreased hepatic BMP9 mRNA and increased plasma elastase activity.
• Reduced BMP9 levels were observed in sepsis patients.

Conclusions:

• Endogenous BMP9 acts as a protective factor for pulmonary endothelium, preserving vascular integrity.
• BMP9 levels are downregulated during inflammatory responses, contributing to increased vascular permeability.
• Exogenous BMP9 administration demonstrates therapeutic potential for preventing and treating lung injury characterized by increased pulmonary endothelial permeability.