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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Immunol. | doi: 10.3389/fimmu.2019.01920

Midkine is elevated after multiple trauma and acts directly on human cardiomyocytes by altering their functionality and metabolism

Ina Lackner1, Birte Weber1, Meike Baur1,  Melanie Haffner-Luntzer2, Tim Eiseler3,  Giorgio Fois4, Florian Gebhard1,  Borna Relja5,  Ingo Marzi5, Roman Pfeifer6,  Sascha Halvachizadeh6, Miriam Lipiski7,  Nikola Cesarovic7, Hans-Christoph Pape6 and  Miriam Kalbitz8*
  • 1Clinic for Trauma, Hand, Plastic and Reconstructive Surgery, Ulm University Medical Center, Germany
  • 2Institute of Orthopedic Research and Biomechanics, Trauma Research Center Ulm, Ulm University Medical Center, Germany
  • 3Department of Internal Medicine I, Faculty of Medicine, University of Ulm, Germany
  • 4Institute of General Physiology, Faculty of Medicine, University of Ulm, Germany
  • 5Department of Trauma, Hand and Reconstructive Surgery, University Hospital Frankfurt, Germany
  • 6Department of Traumatology, University Hospital Zurich, Switzerland
  • 7Department of Surgical Research, University Hospital of Zurich, Switzerland
  • 8Department of Trauma, Hand, Plastic and Reconstructive Surgery, Ulm University Medical Center, Germany

Background and Purpose: Post-traumatic cardiac dysfunction often occurs in multiply injured patients (ISS 16). Next to direct cardiac injury, post-traumatic cardiac dysfunction is mostly induced by the release of inflammatory biomarkers. One of those is the heparin-binding factor Midkine, which is elevated in humans after fracture, burn injury and traumatic spinal cord injury. Midkine is associated with cardiac pathologies but the exact role of Midkine in the development of those diseases is ambiguous. The systemic profile of Midkine after multiple trauma, its effects on cardiomyocytes and the association with post-traumatic cardiac dysfunction remain unknown.
Experimental Approach: Midkine levels were investigated in blood plasma of multiply injured humans and pigs. Furthermore, human cardiomyocytes (iPS) were cultured in presence/absence of Midkine and analysed regarding viability, apoptosis, calcium handling, metabolic alterations and oxidative stress. Finally, the Midkine filtration capacity of the therapeutic blood absorption column CytoSorb300 was tested with recombinant Midkine or plasma from multiply injured patients.
Key Results: Midkine levels were significantly increased in blood plasma of multiply injured humans and pigs. Midkine acts on human cardiomyocytes, altering their mitochondrial respiration and calcium handling in vitro. CytoSorb300 filtration reduced Midkine concentration ex vivo and in vitro depending on the dosage.
Conclusion and Implications: Midkine is elevated in human and porcine plasma after multiple trauma, affecting the functionality and metabolism of human cardiomyocytes in vitro. If the application of CytoSorb300 filtration for patients after multiple trauma is a promising therapeutic approach to prevent post-traumatic cardiac dysfunction requires further examination.

Keywords: polytrauma, Cardiac dysfunction, Fracture treatment, damage associate molecular pattern (DAMP), Toll like receptor (TLR), Toll like receptor signaling, prevention cardiac injury, CytoSorb®

Received: 29 Apr 2019; Accepted: 29 Jul 2019.

Copyright: © 2019 Lackner, Weber, Baur, Haffner-Luntzer, Eiseler, Fois, Gebhard, Relja, Marzi, Pfeifer, Halvachizadeh, Lipiski, Cesarovic, Pape and Kalbitz. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Miriam Kalbitz, Department of Trauma, Hand, Plastic and Reconstructive Surgery, Ulm University Medical Center, Ulm, Germany, miriam.kalbitz@uniklinik-ulm.de