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Novel Synthetic, Host-defense Peptide Protects Against Organ Injury/Dysfunction in a Rat Model of Severe Hemorrhagic Shock

Yamada, Noriaki, MD, PhD*; Martin, Lukas B., MD*,†; Zechendorf, Elisabeth, MSc; Purvis, Gareth S. D., BSc*; Chiazza, Fausto, PhD; Varrone, Barbara, MSc; Collino, Massimo, PhD; Shepherd, Joanna, MD§; Heinbockel, Lena, PhD; Gutsmann, Thomas, PhD; Correa, Wilmar, PhD; Brandenburg, Klaus, PhD; Marx, Gernot, MD; Schuerholz, Tobias, MD||; Brohi, Karim, MD§; Thiemermann, Christoph, MD, PhD*

doi: 10.1097/SLA.0000000000002186
ORIGINAL ARTICLES

Objective: To evaluate (1) levels of the host-defense/antimicrobial peptide LL-37 in patients with trauma and hemorrhagic shock (HS) and (2) the effects of a synthetic host-defense peptide; Pep19-4LF on multiple organ failure (MOF) associated with HS.

Background: HS is a common cause of death in severely injured patients. There is no specific therapy that reduces HS-associated MOF.

Methods: (1) LL-37 was measured in 47 trauma/HS patients admitted to an urban major trauma center. (2) Male Wistar rats were submitted to HS (90 min, target mean arterial pressure: 27–32 mm Hg) or sham operation. Rats were treated with Pep19-4LF [66 (n = 8) or 333 μg/kg · h (n = 8)] or vehicle (n = 12) for 4 hours following resuscitation.

Results: Plasma LL-37 was 12-fold higher in patients with trauma/HS compared to healthy volunteers. HS rats treated with Pep19-4LF (high dose) had a higher mean arterial pressure at the end of the 4-hour resuscitation period (79 ± 4 vs 54 ± 5 mm Hg) and less renal dysfunction, liver injury, and lung inflammation than HS rats treated with vehicle. Pep19-4LF enhanced (kidney/liver) the phosphorylation of (1) protein kinase B and (2) endothelial nitric oxide synthase. Pep19-4LF attenuated the HS-induced (1) translocation of p65 from cytosol to nucleus, (2) phosphorylation of IκB kinase on Ser176/180, and (3) phosphorylation of IκBα on Ser32/36 resulting in inhibition of nuclear factor kappa B and formation of proinflammatory cytokines. Pep19-4LF prevented the release of tumor necrosis factor alpha caused by heparan sulfate in human mononuclear cells by binding to this damage-associated molecular pattern.

Conclusions: Trauma-associated HS results in release of LL-37. The synthetic host-defense/antimicrobial peptide Pep19-4LF attenuates the organ injury/dysfunction associated with HS.

*William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom

Department of Intensive Care and Intermediate Care, University Hospital RWTH Aachen, Aachen, Germany

Department of Drug Science and Technology, University of Turin, Turin, Italy

§Barts Centre for Trauma Sciences, Blizard Institute, Queen Mary University of London, London, United Kingdom

Division of Biophysics, Forschungszentrum Borstel, Borstel, Germany

||Department of Anaesthesia and Intensive Care, University of Rostock, Rostock, Germany.

Reprints: Dr Lukas B. Martin, MD, Centre for Translational Medicine and Therapeutics, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK. E-mail: lmartin@ukaachen.de.

N. Y. and L. M. contributed equally to this work.

N.Y. was supported by Gifu University Hospital Advanced Critical Care Center. L.M. has received a grant by the Deutsche Forschungsgemeinschaft (DFG, MA 7082/1–1). G.P. has received a grant by the British Heart Foundation (FS/13/58/30648). This work was supported, in part, by the University of Turin (ex-60% 2015 A and B) and by the William Harvey Research Foundation and forms part of the research themes contributing to the translational research portfolio of Barts and the London Cardiovascular Biomedical Research Unit. This work also contributes to the Organ Protection research theme of the Barts Centre for Trauma Sciences supported by the Barts and The London Charity (Award 753/1722).

K.B. has a patent for the structure of the synthetic antimicrobial peptide 19-4LF (Brandenburg Antiinfektiva, Borstel, Germany): Patent-No: PCT/EP2009/002565. K.B. and L.H. are chief scientific officer and T.S. is chief medical officer of Brandenburg Antiinfektiva GmbH. All the other authors declare no conflicts of interest.

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