Effects of Glutamine on the Inflammatory Response and Tissue Injury in a Hindlimb Ischemic Reperfusion Mice Model(3/3)

Ischemic reperfusion (IR) injury often occurs in trauma patients suffering from critical limb ischemia. Tissue damage during IR is a result of direct cellular damage by the reactive oxygen species, produced by endothelial cells and activated leukocytes, as well as the intense inflammatory responses that occur both locally and systemically. IR can be divided into two phases. The early injury phase occurs just few minutes after reperfusion up to 4 h. In the late phase of injury between 6 and 24 h from reperfusion, an evolving inflammatory process occurs, often leading to the development of excessive systemic inflammatory response syndrome and remote organ failure. In this study, we wish to explore the applicability of a specific nutrient, glutamine (GLN), in the prevention or therapy of early and late IR. Numerous studies showed that GLN supplementation protected against organ damage, and decreased mortality in an infected animal model. Our studies conducted previously also found that GLN exerts a more balanced T cell response and attenuates inflammatory reaction in sepsis and colitis conditions. However, studies concerning the effect of GLN on IR injury are rare. Most studies treated GLN before limb ischemia which is not applicable in clinical situation. Endothelial progenitor cells (EPC) are unique cells circulate in the blood with the ability to differentiate into endothelial cells and can contribute to vascular repair in IR. The transcription factor hypoxia-inducible factor (HIF)-1 is a key regulator responsible for the induction of genes that facilitate vasculogenesis in IR. IR results in lower circulating EPC and HIF activation. At present, no study investigated the effects of nutrients on changes of EPC or HIF in IR. Therefore, we propose to carry out this study in 3 consecutive years. In the 1st year, we attempt to assess the effect of GLN on leukocyte adhesion molecule expression and local skeleton muscle damage in early IR. In the 2nd year, influences of GLN on circulating EPC and remote organ injury will be investigated in late IRI. In the 3rd year, an in vitro study will be performed to evaluate the effect of GLN on the vascular endothelial cell adhesion molecule expression and HIF activation in a hypoxia condition. The results of this study may provide basic information for the clinical application of GLN in patients with critical limb ischemia.