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

Ann Surg. 2018 Aug;268(2):348-356. doi: 10.1097/SLA.0000000000002186.

Abstract

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 Ser, and (3) phosphorylation of IκBα on Ser 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Infective Agents / therapeutic use*
  • Antimicrobial Cationic Peptides / blood*
  • Biomarkers / blood
  • Case-Control Studies
  • Cathelicidins
  • Combined Modality Therapy
  • Humans
  • Male
  • Multiple Organ Failure / etiology
  • Multiple Organ Failure / prevention & control*
  • Peptides / therapeutic use*
  • Protective Agents / therapeutic use*
  • Rats
  • Rats, Wistar
  • Resuscitation
  • Shock, Hemorrhagic / blood
  • Shock, Hemorrhagic / complications
  • Shock, Hemorrhagic / diagnosis
  • Shock, Hemorrhagic / drug therapy*
  • Treatment Outcome
  • Wounds and Injuries / complications*

Substances

  • Anti-Infective Agents
  • Antimicrobial Cationic Peptides
  • Biomarkers
  • Pep19-4LF
  • Peptides
  • Protective Agents
  • Cathelicidins