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1.  Inhalation of Carbon Monoxide Reduces Skeletal Muscle Injury Following Hind Limb Ischemia Reperfusion Injury in Mice 
American Journal of Surgery  2012;203(4):488-495.
Introduction
The purpose of this study was to determine if inhaled carbon monoxide (CO) can ameliorate skeletal muscle injury, modulate endogenous heme oxygenase-1 (HO) expression, improve indices of tissue integrity and inflammation following hind limb ischemia reperfusion(IR).
Methods
C57BL6 mice inhaling CO (250ppm) or room air were subjected to 1.5 hrs of ischemia followed by limb reperfusion for either 3 or 6 hours (total treatment time of 4.5 or 7.5 hrs). After the initial period of reperfusion, all mice breathed only room air until 24 hours after the onset of ischemia. Mice were sacrificed at either the end of CO treatment or at 24 hours reperfusion. Skeletal muscle was subjected to histologic and biochemical analysis.
Results
CO treatment for 7.5 hours protected skeletal muscle from histologic and structural evidence of skeletal muscle injury. Serum and tissue cytokines were significantly reduced (p<0.05) in mice treated with CO for 7.5 hours. Tubulin, Heme Oxygenase, and ATP levels were higher in CO treated mice.
Conclusions
Inhaled CO protected muscle from structural injury and energy depletion following IR.
doi:10.1016/j.amjsurg.2011.05.005
PMCID: PMC3315834  PMID: 22450026
Carbon Monoxide; Reperfusion Injury; Heme Oxygenase; Skeletal Muscle
2.  Tourniquet-induced acute ischemia-reperfusion injury in mouse skeletal muscles: involvement of superoxide 
European journal of pharmacology  2010;650(1):328-334.
Although arterial limb tourniquet is one of the first-line treatments to prevent exsanguinating hemorrhage in both civilian pre-hospital and battlefield casualty care, prolonged application of a limb tourniquet can lead to serious ischemia-reperfusion injury. However, the underlying pathomechanisms of tourniquet-induced ischemia-reperfusion injury are still poorly understood. Using a murine model of acute limb ischemia-reperfusion, we investigated if acute limb ischemia-reperfusion injury is mediated by superoxide overproduction and mitochondrial dysfunction. Hind limbs of C57/BL6 mice were subjected to 3 h ischemia and 4 h reperfusion via placement and release of a rubber tourniquet at the greater trochanter. Approximately 40% gastrocnemius muscle suffered infarction in this model. Activities of mitochondrial electron transport chain complexes including complex I, II, III, and IV in gastrocnemius muscle were decreased in the ischemia-reperfusion group compared to sham. Superoxide production was increased while activity of manganese superoxide dismutase (MnSOD, the mitochondria-targeted SOD isoform) was decreased in the ischemia-reperfusion group compared to sham group. Pretreatment with tempol (a SOD mimetic, 50 mg/kg) or co-enzyme Q10 (50 mg/kg) not only decreased the superoxide production, but also reduced the infarct size and normalized mitochondrial dysfunction in the gastrocnemius muscle. Our results suggest that tourniquet-induced skeletal muscle ischemia-reperfusion injuries including infarct size and mitochondrial dysfunction may be mediated via the superoxide over-production and reduced antioxidant activity. In the future, this murine ischemia-reperfusion model can be adapted to mechanistically evaluate anti-ischemic molecules in tourniquet-induced skeletal muscle injury.
doi:10.1016/j.ejphar.2010.10.037
PMCID: PMC3008320  PMID: 21036124
Infarct size; Ischemia-reperfusion injury; Mitochondria; Superoxide; Tourniquet
3.  Post Ischemic PARP Inhibition Reduces Ischemia Reperfusion Injury in a Hind-Limb Ischemia Model 
Surgery  2010;148(1):110-118.
INTRODUCTION
These experiments were designed to determine whether systemic post ischemic administration of PJ34, a Poly ADP-ribose polymerase inhibitor, decreased tissue injury and inflammation following hind limb ischemia reperfusion (I/R).
METHODS
C57BL6 mouse limbs were subjected to 1.5 hrs ischemia followed by 24 hours reperfusion. The treatment group (PJ) received intraperitoneal PJ34 (30 mg/Kg) immediately before, 15 minutes and 2 hours into reperfusion. Control group (CG) received Lactated Ringers alone at the same time intervals as PJ34 administration. Skeletal muscle levels of 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 vs. CG (Absolute ATP: 4.7 ± 0.35 vs. 2.3 ± 0.15 ng/mg tissue, p=0.002). Levels of MIP-2, KC and MPO were lower in PJ vs. CG (MIP-2: 1.4±0.34 vs. 3.67±0.67 pg/mg protein, p=0.014; KC: 4.97±0.97 vs. 12.65±3.05 pg/mg protein, p=0.037, MPO: 46.27±10.53 vs. 107.34±13.58 ng/mg protein, p=0.008). Muscle fiber injury was markedly reduced in PJ vs. CG (4.25±1.9% vs 22.68±3.0% total fibers, p=0.0004).
CONCLUSION
Systemic post ischemic 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.
doi:10.1016/j.surg.2009.12.006
PMCID: PMC2886175  PMID: 20132957
Basic science; skeletal muscle; cytokines; inflammation; vascular disease
4.  Postischemic Treatment With Ethyl Pyruvate Prevents Adenosine Triphosphate Depletion, Ameliorates Inflammation, and Decreases Thrombosis in a Murine Model of Hind-Limb Ischemia and Reperfusion 
The Journal of trauma  2011;70(1):103-110.
Introduction
Experiments were designed to investigate the effects of ethyl pyruvate (EP) in a murine model of hind-limb ischemia-reperfusion (IR) injury.
Methods
C57BL6 mice underwent 90 minutes of unilateral ischemia followed by 24 hours of reperfusion using two treatment protocols. For the preischemic treatment (pre-I) protocol, mice (n = 6) were given 300 mg/kg EP before ischemia, followed by 150 mg/kg of EP just before reperfusion and at 6 hours and 12 hours after reperfusion. In a postischemic treatment (post-I) protocol, mice (n = 7) were treated with 300 mg/kg EP at the end of the ischemic period, then 15 minutes later, and 2 hours after reperfusion and 150 mg/kg of EP at 4 hours, 6 hours, 10 hours, 16 hours, and 22 hours after reperfusion. Controls mice for both protocols were treated with lactated Ringers alone at time intervals identical to EP. Skeletal muscle levels of adenosine triphosphate (ATP), interleukin-1β, keratinocyte chemoattractant protein, and thrombin antithrombin-3 complex were measured. Skeletal muscle architectural integrity was assessed microscopically.
Results
ATP levels were higher in mice treated with EP compared with controls under the both treatment protocols (p = 0.02). Interleukin-1β, keratinocyte chemoattractant protein, thrombin antithrombin-3 complex (p < 0.05), and the percentage of injured fibers (p < 0.0001) were significantly decreased in treated versus control mice under the both protocols.
Conclusion
Muscle fiber injury and markers of tissue thrombosis and inflammation were reduced, and ATP was preserved with EP in pre-I and post-I protocols. Further investigation of the efficacy of EP to modulate IR injury in a larger animal model of IR injury is warranted.
doi:10.1097/TA.0b013e3182031ccb
PMCID: PMC3056773  PMID: 21217488
Ischemia-reperfusion; Inflammation; Skeletal muscle; cytokines
5.  A Functional Murine Model of Hind Limb Demand Ischemia 
Annals of vascular surgery  2010;24(4):532-537.
Introduction
To date murine models of treadmill exercise have been used to study general exercise physiology and angiogenesis in ischemic hind limbs. The purpose of these experiments was to develop a murine model of demand ischemia in an ischemic limb to mimic claudication in humans. The primary goal was to determine whether treadmill exercise reflected a hemodynamic picture which might be consistent with the hyperemic response observed in humans.
Methods
Aged hypercholesterolemic ApoE null mice ( ApoE−/−, n=13) were subjected to Femoral Artery Ligation (FAL), and allowed to recover from the acute ischemic response. Peripheral perfusion of the hind limbs at rest was determined by serial evaluation using laser Doppler imaging (LDI) on days 0, 7, and 14 following FAL. During the duration of the experiments, the mice were also assessed on an established 5 point clinical ischemic score which assessed the degree of digital amputation, necrosis, and cyanosis as compared to the non ischemic contralateral limb. After stabilization of the LDI ratio (ischemic limb flux/contralateral non ischemic limb flux) and clinical ischemic score, mice underwent two days of treadmill training (10 min @ 10 m/min, incline of 10°) followed by 60 minutes daily treadmill exercise (13 m/min, incline of 10°) through day 25. An evaluation of pre-exercise and post exercise perfusion using LDI was performed on two separate occasions following the onset of daily exercise. During the immediate 15 minute post exercise evaluation, LDI scanning was obtained in quadruplicate, to allow identification of peak flux ratios. Statistical analysis included unpaired t-tests and ANOVA.
Results
After FAL, the LDI Flux ratio reached a nadir between days one and two, then stabilized by day 14 and remained stable through day 25. The clinical ischemic score stabilized at day 7, and remained stable throughout the rest of the experiment. Based on stabilization of both the clinical ischemic score and LDI ratio, exercise training began on day 15. The peak 15 minute post exercise LDI ratio increased significantly as compared to pre-exercise ratio on day 17 (0.48+0.04 vs. 0.34± 0.04, p<0.05) and day 25 (0.37±0.03 vs. 0.27±0.03, p<0.01). Within 2 hours of exercise, the LDI ratio returned to pre-exercise levels on both day 17 and 25.
Conclusions
Clinical and hemodynamic stabilization of limb perfusion is evident by 14 days after FAL. FAL followed by demand ischemia results in a reversible relative hyperemic response similar to those observed in exercising human claudicants. A murine model of FAL associated with demand ischemia may be a useful model to evaluate the metabolic, inflammatory and flow related changes associated with claudication in humans.
doi:10.1016/j.avsg.2009.12.003
PMCID: PMC2909630  PMID: 20363101

Results 1-5 (5)