Project Details
Projekt
The lung-bone axis after major trauma: insights into organ crosstalk and tissue regeneration
Subject Area
Orthopaedics, Traumatology, Reconstructive Surgery
Term
since 2022
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 465409392
Thoracic trauma and long bone fractures are common injuries in trauma patients and are major contributors to post-traumatic complications such as acute respiratory distress syndrome (ARDS), systemic inflammation, and impaired fracture healing. Organ crosstalk, the systemic interaction between tissues and organs, has emerged as a key mechanism in trauma pathophysiology. Research indicates that pulmonary injuries can negatively influence fracture healing, potentially via systemic inflammation, suggesting the existence of a so-called lung-bone axis. However, the underlying biomolecular mechanisms and potential therapeutic approaches remain largely unexplored. Extracellular vesicles (EVs), particles secreted by various cells, have gained attention as mediators in organ crosstalk. EVs carry bioactive cargoes including proteins and microRNAs (miRNAs), and their abundance and composition correlate with trauma severity and the post-traumatic immune response, as well as organ-specific responses. Prior work, including studies by our group, has demonstrated differential EV-miRNA expression in trauma models, as well as links to ARDS and fracture healing outcomes. The proposed project aims to characterize and functionally evaluate the role of EVs in mediating the lung-bone axis after trauma, with a focus on different cell types (pulmonary alveolar epithelial cells and bone marrow derived mesenchymal stem cells) as well as the exposure to differential oxygen concentrations (normoxia 21% O₂ vs. hypoxia 2% O₂). Hypoxia frequently occurs after thoracic trauma and may modulate EV secretion and cargo, influencing both local pulmonary regeneration and distant fracture healing. These EVs will then be applied in a translational air-liquid-interface model of lung injury to further explore their regenerative potential. Lastly, the most regenerative EV subsets will be applied by means of nebulization in a rat model of chest trauma and concomitant femoral fracture to investigate their therapeutic application and potential. Thereby, the immunomodulatory and regenerative potential of EVs will be leveraged using readily available and already clinically applied nebulization equipment. Therefore, to gain insights into the lung-bone axis, we defined three hypotheses: H1: EVs derived from pulmonary alveolar epithelial cells and bone marrow-derived mesenchymal stem cells under normoxic conditions will exhibit reduced pro-inflammatory and increased regenerative cargo profiles compared to those from hypoxic cultures. Cooperation partners: Central Project, UA-3. H2: Normoxia-derived EVs will attenuate inflammation and fibrosis in an in vitro lung injury model while enhancing regenerative responses. Cooperation partners: AU-3. H3: In an in vivo rat trauma model, local nebulization of normoxic EVs will reduce lung injury, dampen systemic inflammation, and improve fracture healing outcomes. Cooperation partners: F-2, U-1, UA-3
DFG Programme
Research Units
Subproject of
FOR 5417:
Translational Polytrauma Research to Provide Diagnostic and Therapeutic Tools for Improving Outcomes
International Connection
Netherlands
Cooperation Partner
Professor Dr. Martijn van Griensven, Ph.D.
