Dissecting the role of vascular endothelial BMP9 signaling in lung transplantation

Primary Graft Dysfunction (PGD) has a 30% prevalence post lung transplantation (LTx) and is the leading cause of morbidity and mortality. The mechanisms that contribute to PGD are complex. However, the process of ischemia reperfusion injury (IRI) and degree of injury to the lung microvasculature are known contributors to PGD development. Despite significantly worsening short and long-term survival outcomes, there are currently no FDA approved therapies for PGD. Injury to the microvascular beds leads to dysfunctional and activated vascular endothelial cells which are pro-inflammatory, lack barrier integrity, and improperly regulate immune cell extravasation [17,18]. Bone morphogenetic protein 9 (BMP9) is a critical lung microvascular homeostasis and quiescent factor. Loss of BMP9 signaling has been shown to promote lung pathology in a number of lung acute and chronic diseases. Whether BMP signaling plays a role in the acute lung injury seen in LTx PGD has not been previously investigated. Here we present novel preliminary data showing that BMP signaling is significantly downregulated as a consequence of IRI, using in vitro and in vivo models of LTx. We further demonstrate that exogenous augmentation of circulating BMP9 significantly reduces post-LTx IRI. Based on these novel data, the important role that BMP signaling plays in endothelial homeostasis, and protective effects that exogenous BMP9 therapy yields in other experimental lung injuries, we hypothesize that impaired microvascular BMP signaling promotes lung endothelial injury and the development of primary graft dysfunction. Our overarching goal is to mechanistically dissect and define how BMP microvascular homeostasis pathway is impacted by lung transplantation and develop pathway-specific novel pharmacotherapeutic interventions. SA. 1. Determine the mechanisms by which BMP signaling contributes to primary graft dysfunction and SA. 2. Explore the therapeutic potential of modulating the BMP9 signaling axis as a means to improve LTx outcomes. We hypothesize that augmentation of BMPR2 signaling will promote protection from IRI and the development of PGD. On completion of these studies, our short-term goal will provide novel insights into the role of the BMP signaling pathway in endothelial injury and LTx. These proposed studies will further support our long-term goal to provide important information that could contribute to the establishment of tailored BMP signaling pathway interventions that could serve as novel pharmacotherapeutic strategy to improve early lung transplant outcomes. Based on the literature, these therapies may translate to significantly improved long-term allograft survival. Project Number: 1F31HL176117-01 | Fiscal Year: 2024 | NIH Institute/Center: National Heart Lung and Blood Institute (NHLBI) | Principal Investigator: Blake Gill | Institution: NORTHWESTERN UNIVERSITY AT CHICAGO, CHICAGO, IL | Award Amount: $44,187 | Activity Code: F31 | Study Section: Special Emphasis Panel[ZRG1 F10A-R (08)] View on NIH RePORTER: https://reporter.nih.gov/project-details/1F31HL17611701