麩醯胺及魚油乳劑對小鼠後肢缺血再灌流所造成肌肉及遠端器官損傷的保護作用

急性肢體缺血常發生於創傷或肢體重建手術，缺血的組織再重新獲得血液灌流是維持組織生理功能所必需，但當缺血組織再灌流血液時會引致大量自由基產生，自由基及其引發的免疫細胞活化，會造成細胞膜損傷、細胞凋亡、組織壞死、並使器官組織喪失其功能，通常也伴隨全身性的發炎反應，並造成遠端器官的傷害。營養支持對肢體缺血再灌流的重症病人非常重要，但理想的營養素配方組成目前仍有待研發。本研究介入兩種特殊營養素，來探討這些營養素對缺血再灌流引致的白血球活化及缺血肌肉與遠端器關損傷的影響。本研究共分為兩個部分，第一部分以尾靜脈注射之方式在小鼠後肢缺血90分鐘，血液再灌流之前注入麩醯胺 (glutamine, GLN)，在灌流4及24小時後觀察血液及組織的變化。結果顯示，GLN的給予可在再灌流的早期和晚期低肌肉發炎反應介質基因表現、血中巨噬細胞比例及血中Interleukin-6 的濃度，肺的組織切片也顯示其受損較為輕微。此結果顯示在缺血組織再灌流之前立即給予GLN，可降低缺血再灌流引致的發炎反應，並減輕局部和遠端器官的損傷。第二部分則是在小鼠後肢缺血再灌流之前給予富含n-3多元不飽和脂肪酸(PUFA)的魚油脂肪乳劑，來探討n-3 PUFA對缺血再灌流引致的細胞激素分泌及白血球活化的影響，希望能了解魚油乳劑介入對再灌流後血中各不同白血球的分佈，以及巨噬細胞極化轉變(polarization switch)的影響。結果顯示，在再灌流後24小時，在魚油給予的組別局部和全身性發炎反應介質的表現量較低，同時血中發炎性Ly6ChiCCR2hi單核球的百分比，及肌肉中M1/M2的比例均較生理食鹽水組為低，顯示魚油給予的組別發炎反應較為減輕。這兩個實驗的結果可提供臨床上肢體缺血病人利用GLN和n-3 PUFA做為營養支持的重要參考依據。

關鍵字

缺血再灌流；麩醯胺；魚油乳劑；肺組織損傷；發炎介質

並列摘要

Acute ischemia of limb is a frequent clinical entity that may be encountered in the practice of traumatic surgery or reconstructive. Ischemic reperfusion (IR) injury often occurs in trauma patients suffering from critical limb ischemia. Re-establishment of blood flow to ischemic tissue is necessary to maintain metabolic requirements of the tissue; however, the reperfusionof oxygenated blood to ischemic tissue may induce local tissue and remote organ injury. For critical patients with IR injury, nutrition support is essential and the optimal formulation is still being investigated. In this study, we administered 2 specific nutrients to investigate the possible protective effect of the nutrients on IR-induced leukocyte activation and the affected muscle as well as distant organ injury. There are 2 parts in this study. The first part involves administering intravenous glutamine (GLN) to C57BL6 mice after 90 minutes of ischemia just before reperfusion in a murine unilateral hind limb IR model. The results showed that IRinduced muscle inflammatory mediator expression, blood macrophage percentage, and plasma interleukin-6 levels all declined at either early or late phases of reperfusion when GLN was administered. These findings suggest that GLN administration immediately after sublethal limb ischemia reduces the inflammatory response and offer tissue protection both locally and systemically. The second part of this study investigated the effects of an n-3 polyunsaturated fatty acid (PUFA) containing fish oil (FO) lipid emulsion on the modulation of cytokine/chemokine expressions and alteration of leukocytes activation in order to understand the recruitment pattern of various leukocyte subpopulations and the status of macrophage polarization switch during the period after reperfusion. The results showed FO pretreatment suppressed the local and systemic expression of several IR-induced proinflammatory mediators. Additionally, FO-pretreated group had lower blood Ly6ChiCCR2hi monocyte percentage and muscle M1/M2 ratio than the saline group at 24 h after reperfusion. The results of these 2 experiments may provide some evidence for the clinical application of GLN and n-3 PUFA in patients with critical limb ischemia.

並列關鍵字

ischemia reperfusion injury ； glutamine ； fish oil lipid emulsion ； remote lung

參考文獻

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麩醯胺及魚油乳劑對小鼠後肢缺血再灌流所造成肌肉及遠端器官損傷的保護作用

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