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. 2010 Jul;148(1):110-8.
doi: 10.1016/j.surg.2009.12.006. Epub 2010 Feb 4.

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

Robert S Crawford  1 , Hassan Albadawi, Marvin D Atkins, John E Jones, Hyung-Jin Yoo, Mark F Conrad, W Gerald Austen Jr, Michael T Watkins
Affiliations

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

Robert S Crawford et al. Surgery. 2010 Jul.

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.

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Figures

Figure 1
Figure 1. Percent Injured Skeletal Muscle Fibers
PJ34 treated mice had substantially fewer injured fibers than LR treated mice after 24 hours reperfusion (*p=0.0004).
Figure 2
Figure 2. Photomicrographs of Reperfused Skeletal Muscle (200X)
PJ34 and LR treated skeletal muscle. There are normal polygonal muscle fibers evident in the sham skeletal muscle. In contrast, there are edematous skeletal muscle fibers (arrow) and clusters of injured fibers (outlined) evident in the photomicrograph. The bar indicates 100 microns.
Figure 3
Figure 3. ATP levels in Reperfused Skeletal Muscle
Absolute levels of ATP were markedly preserved in the PJ34 treated vs LR treated mice by 24 hours reperfusion (*p=0.002).
Figure 4
Figure 4. Cytokine/Chemokine Levels in Skeletal Muscle
(A) Keratinocyte Chemoattractant Protein (KC) levels were markedly reduced at 24 hours reperfusion in PJ34 treated mice (*p=0.04). (B) Macrophage Inflammatory Protein-2 levels in reperfused skeletal muscle were also significantly reduced in the PJ34 treated mice (p=0.014).
Figure 5
Figure 5. Myeloperoxidase Levels in Skeletal Muscle
Myeloperoxidase levels were markedly reduced in PJ34 treated mice as compared to LR treated mice by 24 hours reperfusion.
Figure 6
Figure 6. PAR expression following Hind Limb IR injury
A Treatment with PJ34 resulted in decreased levels of PAR accumulation in skeletal muscle as compared to LR treated mice at 3 but not 24 hours reperfusion(*p<0.01).
Figure 7
Figure 7. Representative PAR Immunoblots
Murine skeletal muscle from LR and PJ34 treated mice exposed to 3 hours reperfusion(A) and 24 hours reperfusion(B). Each lane represents a sample from an individual mouse.
See this image and copyright information in PMC

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