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

Robert S. Crawford, Hassan Albadawi, Marvin D. Atkins, John E. Jones, Hyung Jin Yoo, Mark F. Conrad, W. Gerald Austen, Michael T. Watkins

Research output: Contribution to journalArticle

14 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)110-118
Number of pages9
JournalSurgery
Volume148
Issue number1
DOIs
StatePublished - Jul 1 2010

ASJC Scopus subject areas

  • Surgery

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    Crawford, R. S., Albadawi, H., Atkins, M. D., Jones, J. E., Yoo, H. J., Conrad, M. F., Austen, W. G., & Watkins, M. T. (2010). Postischemic poly (ADP-ribose) polymerase (PARP) inhibition reduces ischemia reperfusion injury in a hind-limb ischemia model. Surgery, 148(1), 110-118. https://doi.org/10.1016/j.surg.2009.12.006