| Abstract: | 缺血性心臟病及缺血性中風是最常發生以及造成死亡的疾病，臨床上治療缺血性疾病最主要的策略是恢復梗塞缺血區域血流，但是當血流再灌注時會產生大量的自由基或活性氧，惡化缺血區域的細胞損傷，造成缺血再灌注損傷，導致不可回復的細胞損傷，及嚴重的功能損傷。我們先前的研究發現缺血前投予lumbrokinase能夠透過調控TLR4/NF-κB訊息傳遞路徑抑制發炎反應，有效的減少心肌缺血再灌注損傷，本研究進一步探討缺血後投予lumbrokinase對於減少缺血再灌注損傷的治療效果。
本研究中，我們利用結紮大鼠心臟的左冠狀動脈造成心肌缺血再灌注損傷及結紮小鼠大腦的中大腦動脈造成局部大腦缺血再灌注損傷的兩種動物模式，評估缺血後投予lumbrokinase對於治療心肌缺血再灌注損傷及局部大腦缺血再灌注損傷的效果及機制。研究結果發現，在大鼠心肌缺血再灌注損傷的模式中，缺血二十分鐘後由靜脈注射10 ?g/kg lumbrokinase會藉由活化Sirt1調控下游訊息傳遞路徑，增加細胞自噬作用並降低缺血再灌注損傷引起的氧化壓力、細胞凋亡及發炎反應，進而減少心肌細胞損傷程度、心律不整及心臟收縮功能障礙，達到保護心臟對抗心肌缺血再灌注損傷的效果。而在小鼠局部大腦缺血再灌注損傷的模式中，缺血二十分鐘後由腹腔注射1 mg/kg lumbrokinase會透過降低內質網壓力，減少缺血再灌注損傷引起的細胞凋亡、細胞自噬作用，以及減少發炎體的形成及發炎反應，進而減少大腦梗塞的體積，並改善運動及感覺功能損傷，達到保護大腦對抗局部大腦缺血再灌注損傷的作用。
本研究證明lumbrokinase可以保護心臟及大腦對抗缺血再灌注損傷，能夠透過不同機制降低缺血再灌注損傷引起的病理機制，減少缺血再灌注傷害造成的心肌及大腦損傷程度，並改善心臟功能及神經功能，是一個很有潛力的心臟保護劑及神經保護劑。
Ischemic heart disease and ischemic stroke are the most common and the major cause of death. In clinical, the mainly strategy for treatment ischemic diseases is restoring blood flow to the ischemic zone. However, reperfusion will generate a large amount of free radicals or reactive oxygen species, which will exacerbate the cell damage in the ischemic region and induce ischemia-reperfusion (I-R) injury to cause irreversible cell damage and severe functional impairment. Our previous study found that pre- treatment with lumbrokinase could effectively attenuate myocardial I-R injury by inhibiting the inflammatory effect through TLR4/NF-κB signaling pathway. In this study, we investigated the therapeutic effect of post-ischemic administration of lumbrokinase on I-R injury.
Two animal models were used in this study, myocardial I-R injury caused by ligation of the left anterior descending coronary artery in rats and the focal cerebral I-R injury induced by occlusion of the middle cerebral artery in mice. In addition, this study explored the underlying mechanism of post-ischemic treatment with lumbrokinase on myocardial I-R injury and focal cerebral I-R injury. Results showed that post-ischemic treatment with 10 μg/kg lumbrokinase, which intravenous injected 20 minutes after ischemia, significantly attenuated myocardial damage, arrhythmias and improved systolic dysfunction in rats subjected to myocardial I-R injury. Post-ischemic treatment with lumbrokinase protected the heart against myocardial I-R injury by activating Sirt1 signaling pathway, thereby enhancing autophagic flux and reducing oxidative damage, inflammation and apoptosis. In the other hand, post-ischemic treatment with 1 mg/kg lumbrokinase, which intraperitoneal injected 20 minutes after focal cerebral ischemia, significantly attenuated infarct volume, and improved the neurological function in mice subjected to focal cerebral I-R injury. Post-ischemic treatment with lumbrokinase protected the brain against focal cerebral I-R injury by decreasing endoplasmic reticulum stress, thereby reducing apoptosis, autophagy, and reducing inflammasome formation and inflammation.
This study demonstrated that lumbrokinase protect heart and brain against I-R injury by different dose. In addition, lumbrokinase reduced the myocardial and brain damage after I-R injury, by improving cardiac function and neurological function by regulating different mechanisms and reducing the I-R-injury-induced pathological mechanism. Lumbrokinase is a potential cardioprotective and neuroprotective agent from myocardial and focal cerebral I-R injury. |
