Surgery
Volume 148, Issue 1 , Pages 110-118, July 2010

Postischemic poly (ADP-ribose) polymerase (PARP) inhibition reduces ischemia reperfusion injury in a hind-limb ischemia model

  • Robert S. Crawford, MD

      Affiliations

    • Division of Vascular and Endovascular Surgery, Massachusetts General Hospital, Boston, MA
    • Harvard Medical School, Boston, MA
    • ,
  • Hassan Albadawi, MD

      Affiliations

    • Division of Vascular and Endovascular Surgery, Massachusetts General Hospital, Boston, MA
    • Harvard Medical School, Boston, MA
    • ,
  • Marvin D. Atkins, MD

      Affiliations

    • Division of Vascular and Endovascular Surgery, Massachusetts General Hospital, Boston, MA
    • Harvard Medical School, Boston, MA
    • ,
  • John E. Jones, MD

      Affiliations

    • Division of Vascular and Endovascular Surgery, Massachusetts General Hospital, Boston, MA
    • Harvard Medical School, Boston, MA
    • ,
  • Hyung-Jin Yoo, MA

      Affiliations

    • Division of Vascular and Endovascular Surgery, Massachusetts General Hospital, Boston, MA
    • ,
  • Mark F. Conrad, MD

      Affiliations

    • Division of Vascular and Endovascular Surgery, Massachusetts General Hospital, Boston, MA
    • Harvard Medical School, Boston, MA
    • ,
  • W. Gerald Austen Jr., MD

      Affiliations

    • Division of Plastic and Reconstructive Surgery of the General Surgical Services, Massachusetts General Hospital, Boston, MA
    • Harvard Medical School, Boston, MA
    • ,
  • Michael T. Watkins, MD

      Affiliations

    • Division of Vascular and Endovascular Surgery, Massachusetts General Hospital, Boston, MA
    • Harvard Medical School, Boston, MA
    • Corresponding Author InformationReprint requests: Michael T. Watkins, MD, Division of Vascular and Endovascular Surgery, Massachusetts General Hospital, 15 Parkman Street, WAC 440, Boston, MA 02114.

Accepted 7 December 2009. published online 04 February 2010.

Background

Several experiments were designed to determine whether the systemic, postischemic administration of PJ34,which is a poly-adenosine diphosphate (ADP)-ribose polymerase inhibitor, decreased tissue injury and inflammation after hind-limb ischemia reperfusion (I/R).

Methods

C57BL6 mouse limbs were subjected to 1.5 h ischemia followed by 24-h reperfusion. The treatment group (PJ) received intraperitoneal PJ34 (30 mg/kg) immediately before reperfusion, as well as 15 min and 2 h into reperfusion. The control group (CG) received lactated Ringer's alone at the same time intervals as PJ34 administration. The skeletal muscle levels of adenosine triphosphate (ATP), macrophage inflammatory protein-2 (MIP-2), keratinocyte derived chemokine (KC), and myeloperoxidase (MPO) were measured. Quantitative measurement of skeletal muscle tissue injury was assessed by microscopic analysis of fiber injury.

Results

ATP levels were higher in limbs of PJ versus CG mice (absolute ATP: 4.7 ± 0.35 vs 2.3 ± 0.15-ng/mg tissue, P = .002). The levels of MIP-2, KC, and MPO were lower in PJ versus CG mice (MIP-2: 1.4 ± 0.34 vs 3.67 ± 0.67-pg/mg protein, P = .014; KC: 4.97 ± 0.97 vs 12.65 ± 3.05-pg/mg protein, P = .037; MPO: 46.27 ± 10.53 vs 107.34 ± 13.58-ng/mg protein, P = .008). Muscle fiber injury was markedly reduced in PJ versus CG mice (4.25 ± 1.9% vs 22.68 ± 3.0% total fibers, P = .0004).

Conclusion

Systemic postischemic administration of PJ34 preserved skeletal muscle energy levels, decreased inflammatory markers, and preserved tissue viability post-I/R. These results support PARP inhibition as a viable treatment for skeletal muscle I/R in a clinically relevant post hoc scenario.

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 Supported by the Pacific Vascular Research Foundation, the American Diabetes Association, the Geneen Fund at the Massachusetts General Hospital, and Grant 1R01AR055843 from the National Institutes of Health.

PII: S0039-6060(09)00798-3

doi:10.1016/j.surg.2009.12.006

Surgery
Volume 148, Issue 1 , Pages 110-118, July 2010

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