Calpain inhibitor I reduces the activation of nuclear factor‐κΒ and organ injury/dysfunction in hemorrhagic shock
Calpain inhibitor I reduces the activation of nuclear factor‐κΒ and organ injury/dysfunction in hemorrhagic shock
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钙蛋白酶抑制剂 I 减少失血性休克中核因子-κB 的激活和器官损伤/功能障碍
DOI：
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发表时间：
2001
期刊：
影响因子：
--
通讯作者：
C. Thiemermann
中科院分区：
文献类型：
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作者：
M. McDonald;H. Mota;A. Paul;S. Cuzzocrea;M. Abdelrahman;S. Harwood;R. Plevin;P. Chatterjee;M. Yaqoob;C. Thiemermann
有有限的证据表明，抑制胞质半胱氨酸蛋白酶钙蛋白酶的活性，减少缺血/再灌注损伤。与出血性休克相关的多器官损伤至少部分是由于靶器官的缺血（在出血期间）和再灌注（在复苏期间）。本实验观察了钙蛋白酶抑制剂I对麻醉大鼠失血性休克相关器官损伤（肾、肝、胰、肺、肠）和功能障碍（肾）的影响。出血和失血复苏导致钙蛋白酶活性（心脏）、NF-κB活化（肾脏）、iNOS和考克斯-2表达（肾脏）增加，以及多器官损伤和功能障碍的发生，所有这些均被钙蛋白酶抑制剂I（10 mg/kg i. p.）减弱，在出血前30分钟给药。Chymostatin是一种丝氨酸蛋白酶抑制剂，不能阻止NF-κB的激活，对失血性休克引起的器官损伤/衰竭没有影响。用钙蛋白酶抑制剂I预处理（1 h）小鼠巨噬细胞或大鼠主动脉平滑肌细胞（用内毒素活化）可减弱活化的NF-κB与DNA的结合以及IκBα、I κ B β和IκBε的降解。用L-NIL选择性抑制iNOS活性可减轻循环衰竭和肝损伤，而用SC 58635选择性抑制考克斯-2活性可减轻失血性休克引起的肾功能障碍和肝损伤。因此，我们提供证据证明钙蛋白酶抑制剂I减轻失血性休克中循环衰竭以及器官损伤和功能障碍的机制包括：1）抑制钙蛋白酶活性，2）抑制NF-κB的活化，从而阻止NF-κB依赖性基因的表达，3）阻止iNOS的表达，4）阻止考克斯-2的表达。抑制钙蛋白酶活性可能是治疗失血性休克的一种新的治疗方法。McDonald，M. C.的方法，莫塔-菲利佩，H.，保罗，A.，Cuzzocrea，S.，Abdelrahman，M.，Harwood，S.，普列文河，Chatterjee，P.K.，Yaqoob，M. M.，蒂默曼角钙蛋白酶抑制剂I可降低失血性休克中核因子-κB的活化和器官损伤/功能障碍。FASEB J. 15，171-186（2001）
There is limited evidence that inhibition of the activity of the cytosolic cysteine protease calpain reduces ischemia/reperfusion injury. The multiple organ injury associated with hemorrhagic shock is due at least in part to ischemia (during hemorrhage) and reperfusion (during resuscitation) of target organs. Here we investigate the effects of calpain inhibitor I on the organ injury (kidney, liver, pancreas, lung, intestine) and dysfunction (kidney) associated with hemorrhagic shock in the anesthetized rat. Hemorrhage and resuscitation with shed blood resulted in an increase in calpain activity (heart), activation of NF‐κB (kidney), expression of iNOS and COX‐2 (kidney), and the development of multiple organ injury and dysfunction, all of which were attenuated by calpain inhibitor I (10 mg/kg i.p.), administered 30 min prior to hemorrhage. Chymostatin, a serine protease inhibitor that does not prevent the activation of NF‐κB, had no effect on the organ injury/failure caused by hemorrhagic shock. Pretreatment (for 1 h) of murine macrophages or rat aortic smooth muscle cells (activated with endotoxin) with calpain inhibitor I attenuated the binding of activated NF‐κB to DNA and the degradation of IκBα, IKBβ, and IκBε. Selective inhibition of iNOS activity with L‐NIL reduced the circulatory failure and liver injury, while selective inhibition of COX‐2 activity with SC58635 reduced the renal dysfunction and liver injury caused by hemorrhagic shock. Thus, we provide evidence that the mechanisms by which calpain inhibitor I reduces the circulatory failure as well as the organ injury and dysfunction in hemorrhagic shock include 1) inhibition of calpain activity, 2) inhibition of the activation of NF‐κB and thus prevention of the expression of NFκB‐dependent genes, 3) prevention of the expression of iNOS, and 4) prevention of the expression of COX‐2. Inhibition of calpain activity may represent a novel therapeutic approach for the therapy of hemorrhagic shock.—McDonald, M. C., Mota‐Filipe, H., Paul, A., Cuzzocrea, S., Abdelrahman, M., Harwood, S., Plevin, R., Chatterjee, P. K., Yaqoob, M. M., Thiemermann, C. Calpain inhibitor I reduces the activation of nuclear factor‐κB and organ injury/dysfunction in hemorrhagic shock. FASEB J. 15, 171–186 (2001)
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影响因子：
--
作者：
Crofford, LJ;Tan, B;Hla, T
通讯作者：
Hla, T
氯喹可减轻失血性休克引起的免疫抑制并降低败血症的易感性。
DOI：
10.1001/archsurg.1992.01420010084012
发表时间：
1992
期刊：
Archives of surgery (Chicago, Ill. : 1960)
影响因子：
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作者：
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DOI：
10.1016/s0021-9258(19)50326-x
发表时间：
1993-06
期刊：
The Journal of biological chemistry
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作者：
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通讯作者：
J. Sirois;L. Daniel;Simmons;Joanne;Richards
丝氨酸和半胱氨酸蛋白酶抑制剂通过干扰诱导型 NO 合酶基因的转录来防止活化的巨噬细胞产生一氧化氮。
DOI：
10.1006/bbrc.1995.2523
发表时间：
1995
期刊：
Biochemical and biophysical research communications.
影响因子：
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作者：
Griscavage,JM;Wilk,S;Ignarro,LJ
通讯作者：
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DOI：
10.1073/pnas.88.16.7233
发表时间：
1991-08-01
影响因子：
11.1
作者：
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通讯作者：
LYNCH, G