The growth factor progranulin attenuates neuronal injury induced by cerebral ischemia-reperfusion through the suppression of neutrophil recruitment.
The growth factor progranulin attenuates neuronal injury induced by cerebral ischemia-reperfusion through the suppression of neutrophil recruitment.
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DOI：
10.1186/1742-2094-10-105
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发表时间：
2013-08-23
影响因子：
9.3
通讯作者：
Hara H
中科院分区：
文献类型：
--
作者：
Egashira Y;Suzuki Y;Azuma Y;Takagi T;Mishiro K;Sugitani S;Tsuruma K;Shimazawa M;Yoshimura S;Kashimata M;Iwama T;Hara H
为了改善缺血性脑卒中患者的临床预后，脑缺血再灌注（I/R）损伤是需要克服的主要问题之一。炎症反应被认为是脑缺血后脑损伤的主要原因，而I/R加剧了这些反应。本研究旨在探讨颗粒蛋白前体（PGRN）对小鼠脑缺血再灌注损伤的可能改善作用。在体内I/R诱导4周龄雄性ddY小鼠2小时的MCAO（大脑中动脉闭塞），随后22小时的再灌注。我们评估了PGRN在I/R脑中的表达，重组PGRN（r-PGRN）治疗的功效及其对I/R损伤的治疗时间窗。MCAO后2小时，通过脑室内给予1.0 ng r-PRGN或PBS。免疫荧光染色和Western blotting检测肿瘤组织中中性粒细胞浸润、肿瘤坏死因子（TNF）-α、基质金属蛋白酶-9（MMP-9）的表达及核因子-κB（NF-κB）的磷酸化。我们还研究了中性粒细胞趋化性和细胞间粘附分子-1（ICAM-1）的表达在体外炎症模型中使用分离的中性粒细胞和内皮细胞。我们发现PGRN在I/R小鼠脑中的表达降低。在MCAO后2小时的r-PGRN治疗导致梗死体积的减小和脑肿胀的减少;这分别导致MCAO后24小时和7天的神经学评分的改善和死亡率的降低。免疫组织化学、蛋白质印迹法和明胶酶谱法也证实了r-PGRN治疗抑制了中性粒细胞募集到I/R脑中，这导致NF-κB和MMP-9活化的减少。在体外炎症模型中，PGRN可抑制TNF-α诱导的内皮细胞中性粒细胞趋化性和ICAM-1的表达。PGRN对I/R诱导的炎症具有改善作用，这些作用可能是由于抑制中性粒细胞募集到I/R脑中。
To improve the clinical outcome of patients who suffered ischemic stroke, cerebral ischemia-reperfusion (I/R) injury is one of the major concerns that should be conquered. Inflammatory reactions are considered a major contributor to brain injury following cerebral ischemia, and I/R exacerbates these reactions. The aim of this study was to investigate the possible ameliorative effects of progranulin (PGRN) against I/R injury in mice. In vivo I/R was induced in four-week-old male ddY mice by 2 h of MCAO (middle cerebral artery occlusion) followed by 22 h of reperfusion. We evaluate expression of PGRN in I/R brain, efficacy of recombinant-PGRN (r-PGRN) treatment and its therapeutic time-window on I/R injury. Two hours after MCAO, 1.0 ng of r-PRGN or PBS was administered via intracerebroventricular. We assess neutrophil infiltration, expression of tumor necrosis factor (TNF)-α, matrix metalloproteinase-9 (MMP-9) and phosphorylation of nuclear factor-κB (NF-κB) by immunofluorescense staining and Western blotting. We also investigate neutrophil chemotaxis and intercellular adhesion molecule-1 (ICAM-1) expression in vitro inflammation models using isolated neutrophils and endothelial cells. We found that expression of PGRN was decreased in the I/R mouse brain. r-PGRN treatment at 2 h after MCAO resulted in a reduction in the infarct volume and decreased brain swelling; this led to an improvement in neurological scores and to a reduction of mortality rate at 24 h and 7 d after MCAO, respectively. Immunohistochemistry, Western blotting, and gelatin zymography also confirmed that r-PGRN treatment suppressed neutrophil recruitment into the I/R brain, and this led to a reduction of NF-κB and MMP-9 activation. In the in vitro inflammation models, PGRN suppressed both the neutrophil chemotaxis and ICAM-1 expression caused by TNF-α in endothelial cells. PGRN exerted ameliorative effects against I/R-induced inflammation, and these effects may be due to the inhibition of neutrophil recruitment into the I/R brain.
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影响因子：
37.8
作者：
Roger VL;Go AS;Lloyd-Jones DM;Benjamin EJ;Berry JD;Borden WB;Bravata DM;Dai S;Ford ES;Fox CS;Fullerton HJ;Gillespie C;Hailpern SM;Heit JA;Howard VJ;Kissela BM;Kittner SJ;Lackland DT;Lichtman JH;Lisabeth LD;Makuc DM;Marcus GM;Marelli A;Matchar DB;Moy CS;Mozaffarian D;Mussolino ME;Nichol G;Paynter NP;Soliman EZ;Sorlie PD;Sotoodehnia N;Turan TN;Virani SS;Wong ND;Woo D;Turner MB;American Heart Association Statistics Committee and Stroke Statistics Subcommittee
通讯作者：
American Heart Association Statistics Committee and Stroke Statistics Subcommittee
影响因子：
4
作者：
Bateman, Andrew;Bennett, Hugh P. J.
通讯作者：
Bennett, Hugh P. J.
影响因子：
64.8
作者：
Cruts, Marc;Gijselinck, Ilse;Van Broeckhoven, Christine
通讯作者：
Van Broeckhoven, Christine
影响因子：
5.3
作者：
McColl, Barry W.;Rothwell, Nancy J.;Allan, Stuart M.
通讯作者：
Allan, Stuart M.
影响因子：
3.5
作者：
Alkayed, Feras;Kashimata, Masanori;Azuma, Yukio
通讯作者：
Azuma, Yukio