Simultaneous C5 and CD14 inhibition limits inflammation and organ dysfunction in pig polytrauma

Frontiers in Immunology, vol. 13, pp. 952267

Abstract

Dysfunctional complement activation and Toll-like receptor signaling immediately after trauma are associated with development of trauma-induced coagulopathy and multiple organ dysfunction syndrome. We assessed the efficacy of the combined inhibition therapy of complement factor C5 and the TLR co-receptor CD14 on thrombo-inflammation and organ damage in an exploratory 72-h polytrauma porcine model, conducted under standard surgical and intensive care management procedures. Twelve male pigs were subjected to polytrauma, followed by resuscitation (ATLS® guidelines) and operation of the femur fracture (intramedullary nailing technique). The pigs were allocated to combined C5 and CD14 inhibition therapy group (n=4) and control group (n=8). The therapy group received intravenously C5 inhibitor (RA101295) and anti-CD14 antibody (rMil2) 30 min post-trauma. Controls received saline. Combined C5 and CD14 inhibition reduced the blood levels of the terminal complement complex (TCC) by 70% (p=0.004), CRP by 28% (p=0.004), and IL-6 by 52% (p=0.048). The inhibition therapy prevented the platelet consumption by 18% and TAT formation by 77% (p=0.008). Moreover, the norepinephrine requirements in the treated group were reduced by 88%. The inhibition therapy limited the organ damage, thereby reducing the blood lipase values by 50% (p=0.028), LDH by 30% (p=0.004), AST by 33%, and NGAL by 30%. Immunofluorescent analysis of the lung tissue revealed C5b-9 deposition on blood vessels in five from the untreated, and in none of the treated animals. In kidney and liver, the C5b-9 deposition was similarly detected mainly the untreated as compared to the treated animals. Combined C5 and CD14 inhibition limited the inflammatory response, the organ damage, and reduced the catecholamine requirements after experimental polytrauma and might be a promising therapeutic approach.

Authors 15

1. Ludmila Lupu

   Universität Ulm · University Hospital Ulm

   Affiliation as printed

   Institute of Clinical and Experimental Trauma Immunology, University Hospital Ulm, Ulm, Germany

2. Klemens Horst Aachen Department of Orthopedics, Trauma and Reconstructive Surgery

   RWTH Aachen University

   Affiliation as printed

   Department of Orthopedics, Trauma and Reconstructive Surgery, Rheinisch-Westfalische Technische Hochschule (RWTH) Aachen University, Aachen, Germany

3. Johannes Greven Aachen Department of Orthopedics, Trauma and Reconstructive Surgery

   RWTH Aachen University

   Affiliation as printed

   Department of Orthopedics, Trauma and Reconstructive Surgery, Rheinisch-Westfalische Technische Hochschule (RWTH) Aachen University, Aachen, Germany

4. Ümit Mert Aachen Department of Orthopedics, Trauma and Reconstructive Surgery

   RWTH Aachen University

   Affiliation as printed

   Department of Orthopedics, Trauma and Reconstructive Surgery, Rheinisch-Westfalische Technische Hochschule (RWTH) Aachen University, Aachen, Germany

5. Judith Krey Ludviksen

   Nordland Hospital Trust · Nordland Hospital

   Affiliation as printed

   Research Laboratory, Nordland Hospital Bodø, Bodø, Norway

6. Kristin Pettersen

   Nordland Hospital Trust · Nordland Hospital

   Affiliation as printed

   Research Laboratory, Nordland Hospital Bodø, Bodø, Norway

7. Corinna Lau

   Nordland Hospital Trust · Nordland Hospital

   Affiliation as printed

   Research Laboratory, Nordland Hospital Bodø, Bodø, Norway

8. Yang Li

   Universität Ulm · University Hospital Ulm

   Affiliation as printed

   Institute of Clinical and Experimental Trauma Immunology, University Hospital Ulm, Ulm, Germany

9. Annette Palmer

   Universität Ulm · University Hospital Ulm

   Affiliation as printed

   Institute of Clinical and Experimental Trauma Immunology, University Hospital Ulm, Ulm, Germany

10. Xing Zhang Aachen Department of Orthopedics, Trauma and Reconstructive Surgery

    RWTH Aachen University

    Affiliation as printed

    Department of Orthopedics, Trauma and Reconstructive Surgery, Rheinisch-Westfalische Technische Hochschule (RWTH) Aachen University, Aachen, Germany

11. Benjamin Mayer

    Universität Ulm

    Affiliation as printed

    Institute of Epidemiology and Medical Biometry, Ulm University, Ulm, Germany

12. Martijn van Griensven

    Maastricht University

    Affiliation as printed

    Department Cell Biology-Inspired Tissue Engineering (cBITE), MERLN Institute for Technology-Inspired Regenerative Medicine, Maastricht University, Maastricht, Netherlands

13. Markus Stefan Huber-Lang

    Universität Ulm · University Hospital Ulm

    Affiliation as printed

    Institute of Clinical and Experimental Trauma Immunology, University Hospital Ulm, Ulm, Germany

14. Frank Hildebrand Aachen Department of Orthopedics, Trauma and Reconstructive Surgery

    RWTH Aachen University

    Affiliation as printed

    Department of Orthopedics, Trauma and Reconstructive Surgery, Rheinisch-Westfalische Technische Hochschule (RWTH) Aachen University, Aachen, Germany

15. Tom Eirik Mollnes corresponding

    Oslo University Hospital · University of Oslo · Norwegian University of Science and Technology · Nordland Hospital Trust · Nordland Hospital

    Affiliation as printed

    Center of Molecular Inflammation Research, Norwegian University of Science and Technology, Trondheim, Norway

    Department of Immunology, Oslo University Hospital, and University of Oslo, Oslo, Norway

    Research Laboratory, Nordland Hospital Bodø, Bodø, Norway