Background: Ischemia-reperfusion injury (IRI) secondary to acute limb ischemia is a complex clinical phenomenon induced by a variety of pathologies, including arterial embolization, arterial thrombosis, vascular trauma, advanced peripheral vascular disease, traumatic crush injuries, and/or prolonged tourniquet application. The restoration of blood flow and oxygen to the limb after an ischemic period, while necessary, is ultimately the driving force of IRI. The exaggerated inflammation, oxidative stress, and tissue damage caused by IRI often lead to limb dysfunction, limb loss, multi-organ failure, and/or death. While no gold-standard therapy currently exists, various in vitro and in vivo models have been developed to explore potential therapeutic strategies. Currently, pharmacological agents with anti-inflammatory and/or antioxidant properties, as well as non-pharmacological strategies, have been investigated, and some agents show promise in mitigating the effects of lower extremity ischemia-reperfusion injury (IRI). Purpose: In this review article, we provide a comprehensive overview of the pathophysiology of IRI, discuss the local and systemic effects of IRI, and examine the experimental models used to investigate IRI. We also outline the current in vitro and in vivo pharmacological and non-pharmacological interventions studied to reduce IRI.

Cardiovascular disease remains the leading cause of morbidity and mortality worldwide, with atherosclerosis and maladaptive vascular remodeling serving as central drivers of clinical events. Mechanistic investigation of arterial disease processes relies heavily on experimental animal models that permit precise control of vascular injury, hemodynamic forces, and ischemic stress. Over the past several decades, murine and rat models have become indispensable tools for studying endothelial dysfunction, intimal hyperplasia, flow-mediated remodeling, and ischemia–reperfusion injury. Each model reproduces distinct aspects of human vascular pathology while offering unique technical and biological advantages. This review summarizes commonly used murine and rat models of arterial disease, emphasizing the biological mechanisms they study, the surgical techniques used, pathophysiology, experimental endpoints, advantages, and limitations.

Acute limb ischemia (ALI) is a medical emergency that can be due to prolonged tourniquet application, peripheral arterial disease, arterial embolization, and/or arterial thrombosis. To prevent associated morbidity and mortality, ischemia time should be minimized by urgent or emergent revascularization. However, revascularization can lead to ischemia-reperfusion injury (IRI), a devastating complication that can cause limb loss, multi-organ failure, and/or death. Currently, management of IRI largely relies on preventative measures and supportive care. In Part 2 of this two-part review article, we will briefly review the pathophysiology of IRI discussed in Part 1, and then discuss contemporary interventions to perfuse an acutely ischemic limb, clinical strategies that have been used to reduce and/or prevent IRI, and lastly, randomized controlled trials that have investigated pharmacological interventions to neutralize or mitigate IRI toxicity.