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Mechanisms and Interventions on Acute Lower Limb Ischemia/Reperfusion Injury: A Review and Insights from Cell to Clinical Investigations

  • Poon Apichartpiyakul
    Affiliations
    Department of Surgery, Vascular Surgery Unit, Clinical Surgical Research Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
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  • Krekwit Shinlapawittayatorn
    Affiliations
    Department of Physiology, Cardiac Electrophysiology Unit, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand

    Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand

    Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai, Thailand
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  • Kittipan Rerkasem
    Affiliations
    Department of Surgery, Vascular Surgery Unit, Clinical Surgical Research Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
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  • Siriporn C. Chattipakorn
    Affiliations
    Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand

    Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai, Thailand
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  • Nipon Chattipakorn
    Correspondence
    Correspondence to: Nipon Chattipakorn, MD, PhD, Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand
    Affiliations
    Department of Physiology, Cardiac Electrophysiology Unit, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand

    Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand

    Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai, Thailand
    Search for articles by this author

      Background

      This review aims to highlight mechanistic insights on skeletal muscle ischemia/reperfusion injury (IRI), a potentially life-threatening complication after acute lower limb ischemia. Lower limb IRI produces a wide spectrum of manifestations, ranging from local skeletal muscle necrosis to multi-organ failure. There is increasing evidence from both in vitro and in vivo reports to demonstrate several promising interventions that have successfully reduced IRI in skeletal muscle ischemic models. However, clinical studies to confirm their benefits are still lacking.

      Methods

      We conducted a comprehensive search of English literature listed in the PubMed database (All related published articles shown in PubMed until September 2020 have been included in this review), using the following keywords: acute limb ischemia, acute arterial occlusion, compartment syndrome, ischemic reperfusion injury, revascularization, and hypoxic reoxygenation.

      Results

      A total of 58 articles pertinent to acute limb ischemia models were identified. The underlying mechanisms associated with IRI in skeletal muscle are due to excessive mitochondrial production of reactive oxygen species (ROS), cellular apoptosis and activation of inflammatory cascades. Several therapeutic interventions including both pharmacological and nonpharmacological treatments have been investigated and some showed promising results. These interventions include anti-oxidation, anti-inflammation, anti-hypertension, controlled-reperfusion, and ischemic preconditioning. Further clinical studies are needed to warrant their use in a clinical setting for lower limb IRI treatment.

      Conclusions

      This review comprehensively summarizes the mechanisms underlying IRI in lower limb ischemia. The reports currently available regarding the potential therapeutic interventions against lower limb IRI from in vitro, in vivo and clinical studies are presented and discussed. These findings may provide mechanistic insights for devising the strategies to improve the clinical outcomes in IRI patients in the near future. Further clinical studies are needed to warrant their use in a clinical setting for lower limb IRI treatment.
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