Proteasome inhibition prolongs survival during lethal hemorrhagic shock in rats.
Proteasome inhibition prolongs survival during lethal hemorrhagic shock in rats.
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蛋白酶体抑制可延长大鼠致死性出血性休克期间的生存。
DOI：
10.1097/ta.0b013e31827d5db2
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发表时间：
2013-02
期刊：
影响因子：
--
通讯作者：
Majetschak M
中科院分区：
文献类型：
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作者：
Bach HH 4th;Laporte HM;Wong YM;Gamelli RL;Majetschak M
一些证据表明，真核生物中主要的非溶酶体蛋白酶蛋白酶蛋白酶蛋白酶参与各种疾病过程的病理生理学，包括缺血再灌注损伤和创伤。最近，我们证明了26S蛋白酶体的活性受到三磷酸腺苷（ATP）的负调控，缺血时蛋白酶体的激活有助于心肌损伤。然而，在失血性休克期间，ATP对组织蛋白酶体活性的调节以及蛋白酶体作为药物靶点的潜力尚不清楚。因此，我们评估了组织蛋白酶体肽酶活性的调节和蛋白酶体抑制剂硼替佐米在失血性休克大鼠模型中的作用。系列1包括动物（n = 20）出血至平均动脉压30mmHg长达45分钟。系列2包括动物出血至平均动脉血压30 mm Hg，持续30分钟，随后给予硼替佐米（0.4 mg/kg）或载药（每组n =5）和液体复苏，直至75分钟。系列3包括出血40%血容量的动物，随后每15分钟出血2%血容量，直到死亡。出血发生15分钟后给予硼替佐米（0.4 mg/kg）或对照药（每组n = 6-7）。持续监测生命体征。分析心脏、肺和胸肌的蛋白酶体肽酶活性和ATP、泛素蛋白偶联物和细胞因子（肿瘤坏死因子α、白细胞介素6和白细胞介素10）的水平。在系列1中，在失血性休克期间，组织提取物中的蛋白酶体肽酶活性与组织ATP浓度的降低成正比。在正常组织提取物中也可检测到蛋白酶体肽酶活性随着ATP测定浓度的降低而活化。在系列2中，全身给药硼替佐米抑制组织蛋白酶体活性，但不影响生理反应。在系列3中，硼替佐米抑制组织蛋白酶体活性，增加内源性泛素蛋白偶联物，并将生存时间从对照组的48.5分钟延长至85分钟（p = 0.0012）。硼替佐米治疗不影响组织细胞因子水平。蛋白酶体的活化与严重失血性休克的病理生理有关。在致死性失血性休克期间，蛋白酶体的药理学抑制可能提供生存优势。
Several lines of evidence suggest that proteasomes, the major nonlysosomal proteases in eukaryotes, are involved in the pathophysiology of various disease processes, including ischemia-reperfusion injury and trauma. Recently, we demonstrated that 26S proteasome activity is negatively regulated by adenosine triphosphate (ATP) and that proteasome activation during ischemia contributes to myocardial injury. The regulation of tissue proteasome activity by ATP and the potential of proteasomes as drug targets during hemorrhagic shock, however, are unknown. Thus, we evaluated the regulation of tissue proteasome peptidase activity and the effects of the proteasome inhibitor bortezomib in rat models of hemorrhagic shock. Series 1 includes animals (n = 20) hemorrhaged to a mean arterial blood pressure of 30mmHg for up to 45minutes. Series 2 includes animals hemorrhaged to a mean arterial blood pressure of 30 mm Hg for 30 minutes, followed by bortezomib (0.4 mg/kg) or vehicle administration (n =5 per group) and fluid resuscitation until 75 minutes. Series 3 includes animals that underwent 40% blood volume hemorrhage, followed by 2% blood volume hemorrhage every 15 minutes until death. Bortezomib (0.4 mg/kg) or vehicle were administered 15 minutes after the onset of hemorrhage (n = 6–7 per group). Vital signs were continuously monitored. The heart, lung, and pectoral muscle were analyzed for proteasome peptidase activities and levels of ATP, ubiquitin-protein conjugates, and cytokines (tumor necrosis factorα, interleukin 6, and interleukin 10). In Series 1, proteasome peptidase activities in tissue extracts increased proportional to the decrease in tissue ATP concentrations during hemorrhagic shock. Activation of proteasome peptidase activity with decreases of the ATP assay concentration was also detectable in normal tissue extracts. In Series 2, systemic administration of bortezomib inhibited tissue proteasome activities but did not affect the physiologic response. In Series 3, bortezomib inhibited tissue proteasome activities, increased endogenous ubiquitin-protein conjugates, and prolonged survival time from treatment from 48.5 minutes in the control group to 85 minutes (p = 0.0012). Bortezomib treatment did not affect tissue cytokine levels. Proteasome activation contributes to the pathophysiology of severe hemorrhagic shock. Pharmacologic inhibition of the proteasome may provide a survival advantage during lethal hemorrhagic shock.