Influence of age and alcohol intoxication on fracture healing and the regenerative potential after trauma-hemorrhage in a murine model
Final Report Abstract
Polytrauma, the simultaneous occurrence of severe injuries at different body sites, on average leads to a loss of 32 life years and is the primary cause of death for individuals under 50 years of age. Survivors often suffer long-term disabilities, with only about half being able to return to work after two years. Fractures and trauma-hemorrhage (TH) frequently occur together, with uncontrolled blood loss being the second most common cause of death. Challenges for polytrauma patients manifest in disrupted fracture healing due to tissue hypoperfusion and impaired inflammatory phase of fracture healing. The influence of trauma-hemorrhage on fracture healing is particularly relevant in individuals over 70 years old, who often experience long bone fractures from falls. Osteoporosis increases the risk of pseudarthrosis, associated with higher morbidity and mortality. The project investigates the impact of TH on fracture healing in young and old mice with and without alcohol intoxication. In the first funding phase, the effects of severe blood loss on fracture healing and underlying signaling pathways were examined. Results indicated impaired fracture healing after TH and fracture in male mice, manifested in biomechanical, histological, and signaling changes. In the second funding phase, the influence of age and alcohol intoxication on fracture healing and regenerative potential was explored. Mice were divided into different age and treatment groups. Advanced age led to lower bone mineralization and a reduced number of osteoclasts in the fracture gap. Older mice exhibited increased susceptibility to organ damage in the liver and lungs after trauma. Alcohol had anti-inflammatory effects, especially in young mice, influencing various molecular mechanisms. Age-dependent changes in immune response and heightened inflammatory reactions were observed. Pathway analyses revealed that NF- kappaB and Wnt/β-Catenin in the liver and lungs were influenced by alcohol. Reduced activity of circulating neutrophils and monocytes after alcohol exposure could impact healing. The results provide comprehensive insights into the complex interactions among trauma, hemorrhage, age, and alcohol on fracture healing, organ regeneration, and the underlying mechanisms at the cellular and molecular levels.
Link to the final report
https://doi.org/10.26068/mhhrpm/20250108-000
Publications
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Severe Hemorrhagic Shock Leads to a Delayed Fracture Healing and Decreased Bone Callus Strength in a Mouse Model. Clinical Orthopaedics & Related Research, 475(11), 2783-2794.
Bundkirchen, Katrin; Macke, Christian; Reifenrath, Janin; Schäck, Luisa Marilena; Noack, Sandra; Relja, Borna; Naber, Philipp; Welke, Bastian; Fehr, Michael; Krettek, Christian & Neunaber, Claudia
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Hemorrhagic shock alters fracture callus composition and activates the IL6 and RANKL/OPG pathway in mice. Journal of Trauma and Acute Care Surgery, 85(2), 359-366.
Bundkirchen, Katrin; Macke, Christian; Angrisani, Nina; Schäck, Luisa M.; Noack, Sandra; Fehr, Michael; Krettek, Christian & Neunaber, Claudia
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The Impact of Acute or Chronic Alcohol Intake on the NF-κB Signaling Pathway in Alcohol-Related Liver Disease. International Journal of Molecular Sciences, 21(24), 9407.
Nowak, Aleksander J. & Relja, Borna
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Acute Intoxication With Alcohol Reduces Trauma-Induced Proinflammatory Response and Barrier Breakdown in the Lung via the Wnt/β-Catenin Signaling Pathway. Frontiers in Immunology, 13.
Noack, Laurens; Bundkirchen, Katrin; Xu, Baolin; Gylstorff, Severin; Zhou, Yuzhuo; Köhler, Kernt; Jantaree, Phatcharida; Neunaber, Claudia; Nowak, Aleksander J. & Relja, Borna
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Fracture Healing in Elderly Mice and the Effect of an Additional Severe Blood Loss: A Radiographic and Biomechanical Murine Study. Bioengineering, 10(1), 70.
Bundkirchen, Katrin; Ye, Weikang; Nowak, Aleksander J.; Lienenklaus, Stefan; Welke, Bastian; Relja, Borna & Neunaber, Claudia
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Impact of age on liver damage, inflammation, and molecular signaling pathways in response to femoral fracture and hemorrhage. Frontiers in Immunology, 14 2023, 8, 24)).
Meng, Fanshuai; Zhou, Yuzhuo; Wagner, Alessa; Bülow, Jasmin Maria; Köhler, Kernt; Neunaber, Claudia; Bundkirchen, Katrin & Relja, Borna
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Age-related exacerbation of lung damage after trauma is associated with increased expression of inflammasome components. Frontiers in Immunology, 14 (2024, 1, 11)).
Zhou, Yuzhuo; Meng, Fanshuai; Köhler, Kernt; Bülow, Jasmin Maria; Wagner, Alessa; Neunaber, Claudia; Bundkirchen, Katrin & Relja, Borna
