Exogenous BMP9 therapy ameliorates primary graft dysfunction post lung transplantation

Abstract

Primary graft dysfunction (PGD) is a leading cause of early mortality after lung transplantation and is driven by ischemia-reperfusion injury (IRI), which destabilizes the pulmonary endothelium. Bone morphogenetic protein 9 (BMP9), a vascular quiescence factor of the TGF superfamily, maintains endothelial homeostasis through ALK-1/BMPR2-mediated signaling. Herein, this work identified a previously unrecognized suppression of BMP9 signaling during early reperfusion in a murine orthotopic lung transplant model. Allograft transcriptomic profiling revealed rapid downregulation of BMP9 pathway components, including Bmpr2, Acvrl1, Smad5, and Eng. Recombinant BMP9 administered at reperfusion enhanced Id1 expression in pulmonary endothelium, reduced neutrophil infiltration, preserved vascular barrier function, and improved oxygenation. In vitro, BMP9 attenuated proinflammatory cytokine release following simulated cold ischemia-reperfusion injury in human lung endothelial cells. Plasma from lung transplant recipients, regardless of PGD status, had impaired BMP9-induced ID1 expression in endothelial cells, with the most profound suppression observed in patients with interstitial lung disease. These findings implicate transient loss of BMP9 signaling as a key feature of transplant-induced vascular injury and support the therapeutic potential of BMP9 supplementation to restore endothelial homeostasis and improve early graft outcomes.