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Original Investigation | Association of VA Surgeons

Association Between MC-2 Peptide and Hepatic Perfusion and Liver Injury Following Resuscitated Hemorrhagic Shock

Paul J. Matheson, PhD1,2,3; Rafael Fernandez-Botran, PhD3,4; Jason W. Smith, MD, PhD2,3; Samuel A. Matheson, BS2; Cynthia D. Downard, MD, MMSc2; Craig J. McClain, MD1,4; Richard N. Garrison, MD1,2,3
[+] Author Affiliations
1Robley Rex Veteran’s Affairs Medical Center, Louisville, Kentucky
2Department of Surgery, University of Louisville, Louisville, Kentucky
3Department of Physiology and Biophysics, University of Louisville, Louisville, Kentucky
4Department of Medicine, University of Louisville, Louisville, Kentucky
JAMA Surg. 2016;151(3):265-272. doi:10.1001/jamasurg.2015.4050.
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Importance  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.

Design, Setting, and Participants  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.

Main Outcomes and Measures  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 __mL/min/100g and _mL/min/100g at baseline to __mL/min/100g and __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 and Relevance  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.

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Figure 1.
Experimental Protocol

The protocol was carried out to 4 hours postresuscitation (PR). Rats were hemorrhaged (H) to 40% of their baseline (BL) mean arterial pressure (MAP) and maintained at this pressure for 60 minutes by infusion or withdrawal of shed blood as needed. For resuscitation (R), shed blood was returned over 5 minutes, followed by infusion of 2 equal volumes of lactated Ringers (LR) solution over 25 minutes. This hemorrhagic shock model carries a mortality of 27% at 24 hours postresuscitation.5 MC-2 was given (50 mg/kg, intravenously [IV]) at the time of return of shed blood.

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Figure 2.
Heart Rate, Mean Arterial Pressure, and Effective Hepatic Blood Flow for Each Group

Effective hepatic blood flow was stable across the entire protocol in the sham and sham+MC-2 groups. In the hemorrhagic shock (HS)/conventional resuscitation (CR) groups, EHBF was decreased during the period of shock and restored by resuscitation (RES) in both the HS/CR groups. However, EHBF decreased incrementally over the 4 hour post RES period. HS/CR+MC-2 increased EHBF compared to HS/CR alone at 3 hours and 4-hours postresuscitation. P values calculated by 2-way analysis of variance and Tukey-Kramer honestly significant difference test.

aP < .05 vs baseline (BL).

bP < .05 vs sham.

cP < .05 vs sham+MC-2.

dP < .05 vs HS/CR.

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Figure 3.
Hematoxylin-eosin–Stained Liver Samples From the Groups

There were no differences evident in injury score between the sham and sham+MC-2 groups, and all samples were graded as no or minimal injury. In the hemorrhagic shock (HS)/conventional resuscitation (CR) group, focal and centrilobular necrosis is evident, while in the HS/CR+MC-2 group, most samples were graded as focal necrosis. Original magnification is ×10.

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