title: Association Between MC-2 Peptide and Hepatic Perfusion and Liver Injury Following Resuscitated Hemorrhagic Shock.
abstract: OBJECTIVE
  Hemorrhagic shock (HS) due to trauma remains a major cause of morbidity and mortality in the United States, despite continuing progression of advanced life support and treatment. Trauma is the third most common cause of death worldwide and is the leading cause of death in the 1- to 44-year-old age group. Hemorrhagic shock often progresses to multiple organ failure despite conventional resuscitation (CR) that restores central hemodynamics.
  
  
  OBJECTIVE
  To examine whether MC-2 would bind glycosaminoglycans to decrease proinflammatory cytokines' influence in the liver, minimize organ edema, prevent liver injury, and improve hepatic perfusion. MC-2, a synthetic octapeptide derived from the heparin-binding domain of murine interferon gamma (IFN-γ), binds glycosaminoglycans to modulate serum and interstitial cytokine levels and activity.
  
  
  METHODS
  A controlled laboratory study of 3y male Sprague-Dawley rats that were randomized to 4 groups of 8 each: sham, sham+MC-2 (50 mg/kg), HS/CR, or HS/CR+MC-2 (HS = 40% of baseline mean arterial pressure for 60 minutes; CR = return of shed blood and 2 volumes of saline). The study began in March, 2013.
  
  
  METHODS
  Effective hepatic blood flow (EHBF) by galactose clearance, wet-dry weights, cytokines, histopathology, complete metabolic panel, and complete blood cell count were performed at 4 hours after CR.
  
  
  RESULTS
  MC-2 partially reversed the HS/CR-induced hepatic hypoperfusion at 3 and 4 hours postresuscitation compared with HS/CR alone. Effective hepatic blood flow decreased during the HS period from a mean (SD) of 7.4 (0.3) mL/min/100 g and 7.5 (0.5) mL/min/100g at baseline to 3.7 (0.4) mL/min/100g and 5.9 (0.5) mL/min/100g for the HS/CR and HS/CR+MC-2 groups, respectively (P <.05). Effective hepatic blood flow remained constant in the sham groups throughout the experimental protocol. Organ edema was increased in the ileum and liver in the HS/CR vs sham group, and MC-2 decreased edema in the ileum vs the HS/CR group. MC-2 in HS also decreased levels of alanine aminotransferase, zonula occludens-1, and interleukin-1β compared with HS/CR alone.
  
  
  CONCLUSIONS
  MC-2 was associated with decreased liver injury, enhanced effective hepatic blood flow, decreased cytokines, and prevention of edema formation in the ileum when administered with CR following HS. These data suggest that the MC-2 peptide could be a potential therapeutic approach to target cytokine and chemokine interactions, which might limit multiple organ failure and decrease mortality in hemorrhagic shock.
authors.affiliation: Robley Rex Veteran's Affairs Medical Center, Louisville, Kentucky2Department of Surgery, University of Louisville, Louisville, Kentucky3Department of Physiology and Biophysics, University of Louisville, Louisville, Kentucky.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Matheson
authors.affiliation: Department of Physiology and Biophysics, University of Louisville, Louisville, Kentucky4Department of Medicine, University of Louisville, Louisville, Kentucky.
authors.forename: Rafael
authors.initials: R
authors.lastname: Fernandez-Botran
authors.affiliation: Department of Surgery, University of Louisville, Louisville, Kentucky3Department of Physiology and Biophysics, University of Louisville, Louisville, Kentucky.
authors.forename: Jason W
authors.initials: JW
authors.lastname: Smith
authors.affiliation: Department of Surgery, University of Louisville, Louisville, Kentucky.
authors.forename: Samuel A
authors.initials: SA
authors.lastname: Matheson
authors.affiliation: Department of Surgery, University of Louisville, Louisville, Kentucky.
authors.forename: Cynthia D
authors.initials: CD
authors.lastname: Downard
authors.affiliation: Robley Rex Veteran's Affairs Medical Center, Louisville, Kentucky4Department of Medicine, University of Louisville, Louisville, Kentucky.
authors.forename: Craig J
authors.initials: CJ
authors.lastname: McClain
authors.affiliation: Robley Rex Veteran's Affairs Medical Center, Louisville, Kentucky2Department of Surgery, University of Louisville, Louisville, Kentucky3Department of Physiology and Biophysics, University of Louisville, Louisville, Kentucky.
authors.forename: Richard N
authors.initials: RN
authors.lastname: Garrison
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000097:blood; D004195:Disease Models, Animal; D007371:Interferon-gamma / Q000097:blood*; D008102:Liver Circulation / Q000502:physiology*; D017093:Liver Failure / Q000097:blood* / Q000209:etiology / Q000503:physiopathology; D008297:Male; D010446:Peptide Fragments / Q000097:blood*; D010477:Perfusion / Q000009:adverse effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012039:Regional Blood Flow / Q000502:physiology; D012151:Resuscitation / Q000009:adverse effects*; D012771:Shock, Hemorrhagic / Q000150:complications / Q000628:therapy*
chemical_list: D015415:Biomarkers; C506054:MC2 peptide; D010446:Peptide Fragments; D007371:Interferon-gamma