1. Modulation of the hepatic RANK-RANKL-OPG axis by combined C5 and CD14 inhibition in a long-term polytrauma model
- Author
-
Yang Li, Klemens Horst, Johannes Greven, Ümit Mert, Ludmila Lupu, Annette Palmer, Lena Doerfer, Qun Zhao, Xing Zhang, Rebecca Halbgebauer, Anita Ignatius, Ingo Marzi, Martijn van Griensven, Elizabeth Balmayor, Frank Hildebrand, Tom Eirik Mollnes, and Markus Huber-Lang
- Subjects
polytrauma ,RANK-RANKL-OPG pathway ,immunomodulation ,complement ,CD14 ,Immunologic diseases. Allergy ,RC581-607 - Abstract
BackgroundPolytrauma and hemorrhagic shock can lead to direct and indirect liver damage involving intricate pathophysiologic mechanisms. While hepatic function has been frequently highlighted, there is minimal research on how the receptor activator of the NF-κB (RANK)/RANK ligand (RANKL)/osteoprotegerin (OPG) system is regulated in the liver following trauma. Furthermore, cross-talking complement and toll-like-receptor (TLR) systems can contribute to the posttraumatic response. Therefore, we investigated the hepatic consequences of polytrauma focusing on the RANK-RANKL-OPG axis, and evaluated the effects of a dual blockade of complement factor C5 and TLR-cofactor CD14 on hepatic features.MethodsThe established pig model of polytrauma (PT) and hemorrhagic shock included pulmonary contusion, hepatic dissection, and bilateral femur fractures, surgically addressed either by external fixation (Fix ex) or intramedullary nailing (Nail). Four groups were investigated: 1) sham animals; 2) PT treated by Fix ex (Fix ex); 3) PT by Nail (Nail); or 4) PT by Nail plus combined C5/CD14 inhibition (Nail+Therapy). Serum samples were obtained between 0 - 72 h, and liver samples at 72 h after PT. Liver tissues were histologically scored and subjected to RT-qPCR-analyses, immunohistochemistry and ELISAs to evaluate the posttraumatic hepatic response with a focus on the RANK-RANKL-OPG system.ResultsFollowing PT, the liver injury score of the Nail+Therapy group was significantly lower than in the Fix ex or Nail group without immunomodulation (p
- Published
- 2024
- Full Text
- View/download PDF