TY - JOUR
T1 - Postischemic poly (ADP-ribose) polymerase (PARP) inhibition reduces ischemia reperfusion injury in a hind-limb ischemia model
AU - Crawford, Robert S.
AU - Albadawi, Hassan
AU - Atkins, Marvin D.
AU - Jones, John E.
AU - Yoo, Hyung Jin
AU - Conrad, Mark F.
AU - Austen, W. Gerald
AU - Watkins, Michael T.
N1 - Funding Information:
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 .
PY - 2010/7
Y1 - 2010/7
N2 - 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.
AB - 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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U2 - 10.1016/j.surg.2009.12.006
DO - 10.1016/j.surg.2009.12.006
M3 - Article
C2 - 20132957
AN - SCOPUS:77953292779
SN - 0039-6060
VL - 148
SP - 110
EP - 118
JO - Surgery
JF - Surgery
IS - 1
ER -