title: Novel Synthetic, Host-defense Peptide Protects Against Organ Injury/Dysfunction in a Rat Model of Severe Hemorrhagic Shock.
abstract: 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.
  
  
  
  HS is a common cause of death in severely injured patients. There is no specific therapy that reduces HS-associated MOF.
  
  
  
  (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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom.
authors.forename: Noriaki
authors.initials: N
authors.lastname: Yamada
authors.affiliation: 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.
authors.forename: Lukas B
authors.initials: LB
authors.lastname: Martin
authors.affiliation: Department of Intensive Care and Intermediate Care, University Hospital RWTH Aachen, Aachen, Germany.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Zechendorf
authors.affiliation: William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom.
authors.forename: Gareth S D
authors.initials: GSD
authors.lastname: Purvis
authors.affiliation: Department of Drug Science and Technology, University of Turin, Turin, Italy.
authors.forename: Fausto
authors.initials: F
authors.lastname: Chiazza
authors.affiliation: Department of Drug Science and Technology, University of Turin, Turin, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Varrone
authors.affiliation: Department of Drug Science and Technology, University of Turin, Turin, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Collino
authors.affiliation: Barts Centre for Trauma Sciences, Blizard Institute, Queen Mary University of London, London, United Kingdom.
authors.forename: Joanna
authors.initials: J
authors.lastname: Shepherd
authors.affiliation: Division of Biophysics, Forschungszentrum Borstel, Borstel, Germany.
authors.forename: Lena
authors.initials: L
authors.lastname: Heinbockel
authors.affiliation: Division of Biophysics, Forschungszentrum Borstel, Borstel, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Gutsmann
authors.affiliation: Division of Biophysics, Forschungszentrum Borstel, Borstel, Germany.
authors.forename: Wilmar
authors.initials: W
authors.lastname: Correa
authors.affiliation: Division of Biophysics, Forschungszentrum Borstel, Borstel, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Brandenburg
authors.affiliation: Department of Intensive Care and Intermediate Care, University Hospital RWTH Aachen, Aachen, Germany.
authors.forename: Gernot
authors.initials: G
authors.lastname: Marx
authors.affiliation: Department of Anaesthesia and Intensive Care, University of Rostock, Rostock, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Schuerholz
authors.affiliation: Barts Centre for Trauma Sciences, Blizard Institute, Queen Mary University of London, London, United Kingdom.
authors.forename: Karim
authors.initials: K
authors.lastname: Brohi
authors.affiliation: William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom.
authors.forename: Christoph
authors.initials: C
authors.lastname: Thiemermann
mesh_terms: D000818:Animals; D000890:Anti-Infective Agents / Q000627:therapeutic use*; D023181:Antimicrobial Cationic Peptides / Q000097:blood*; D015415:Biomarkers / Q000097:blood; D016022:Case-Control Studies; D003131:Combined Modality Therapy; D006801:Humans; D008297:Male; D009102:Multiple Organ Failure / Q000209:etiology / Q000517:prevention & control*; D010455:Peptides / Q000627:therapeutic use*; D020011:Protective Agents / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D012151:Resuscitation; D012771:Shock, Hemorrhagic / Q000097:blood / Q000150:complications / Q000175:diagnosis / Q000188:drug therapy*; D016896:Treatment Outcome; D014947:Wounds and Injuries / Q000150:complications*; D054804:Cathelicidins
chemical_list: D000890:Anti-Infective Agents; D023181:Antimicrobial Cationic Peptides; D015415:Biomarkers; C000634107:Pep19-4LF; D010455:Peptides; D020011:Protective Agents; D054804:Cathelicidins