Localised release of matrix metallopeptidase 8 in fatal cerebral malaria.
Localised release of matrix metallopeptidase 8 in fatal cerebral malaria.
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DOI：
10.1002/cti2.1263
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发表时间：
2021
影响因子：
5.8
通讯作者：
Cunnington AJ
中科院分区：
文献类型：
--
作者：
Georgiadou A;Naidu P;Walsh S;Kamiza S;Barrera V;Harding SP;Moxon CA;Cunnington AJ
脑型疟疾（CM）是恶性疟原虫疟疾的一种并发症，其中进行性脑肿胀与寄生虫的隔离和脑微血管内皮屏障功能受损有关。为了验证基质金属肽酶8 （MMP8）在视网膜内的局部释放与CM微血管泄漏有关的假设，我们在一项病例对照研究中检测了它的表达及其与血管外纤维蛋白原泄漏的关系，该研究来自13名马拉维儿童的死后视网膜样本，这些儿童一生中符合CM的临床病例定义。病例中有7名儿童在尸检中被发现患有“真CM”（寄生虫在脑血管中被隔离），而对照组中有6名儿童因其他原因死亡（“假CM”，血管中没有寄生虫被隔离）。我们使用免疫荧光显微镜和独立评分，由两名对CM状态不知情的评估者进行评估，以评估MMP8表达、血管外纤维蛋白原作为血管泄漏的指标及其在视网膜微血管中的共定位。在“真CM”受试者中，MMP8染色总是与被隔离的寄生虫相关，中位数为88% （IQR = 74-91%）的毛细血管显示MMP8染色，而在“假CM”受试者中，这一比例为14% (IQR = 3.8-24%) （P值= 0.001）。“真CM”受试者中41% （IQR = 28-49%）的毛细血管显示血管外纤维蛋白原泄漏和MMP8染色共定位，而“假CM”受试者中1.8%的毛细血管显示共定位（IQR = 0-3.9%， P值= 0.01）。在没有MMP8染色的情况下，血管渗漏很少见。基质金属肽酶8在马拉维疟疾视网膜病变儿童视网膜毛细血管中广泛表达，并与血管渗漏密切相关。我们的研究结果表明MMP8是CM血管内皮屏障破坏的一个原因，这可能导致致命的脑肿胀。为了验证基质金属肽酶8 （MMP8）在视网膜内的局部释放与脑疟疾（CM）微血管泄漏有关的假设，我们在13名马拉维儿童死后视网膜样本的病例对照研究中检测了其表达及其与血管外纤维蛋白原泄漏的关系。MMP8在CM视网膜病变儿童视网膜毛细血管中广泛表达，与血管渗漏密切相关。我们的研究结果提示MMP8参与CM的血管内皮屏障破坏，这可能导致致命的脑肿胀。
Cerebral malaria (CM) is a complication of Plasmodium falciparum malaria, in which progressive brain swelling is associated with sequestration of parasites and impaired barrier function of the cerebral microvascular endothelium. To test the hypothesis that localised release of matrix metallopeptidase 8 (MMP8) within the retina is implicated in microvascular leak in CM, we examined its expression and association with extravascular fibrinogen leak in a case–control study of post‐mortem retinal samples from 13 Malawian children who met the clinical case definition of CM during life. Cases were seven children who were found on post‐mortem examination to have ‘true‐CM’ (parasite sequestration in brain blood vessels), whilst controls were six children who had alternative causes of death (‘faux‐CM’, no parasite sequestration in blood vessels). We used immunofluorescence microscopy and independent scoring, by two assessors blinded to the CM status, to assess MMP8 expression, extravascular fibrinogen as an indicator of vascular leak and their co‐localisation in the retinal microvasculature. In ‘true‐CM’ subjects, MMP8 staining was invariably associated with sequestered parasites and a median of 88% (IQR = 74–91%) of capillaries showed MMP8 staining, compared with 14% (IQR = 3.8–24%) in ‘faux‐CM’ (P‐value = 0.001). 41% (IQR = 28–49%) of capillaries in ‘true‐CM’ subjects showed co‐localisation of extravascular fibrinogen leak and MMP8 staining, compared with 1.8% of capillaries in ‘faux‐CM’ (IQR = 0–3.9%, P‐value = 0.01). Vascular leak was rare in the absence of MMP8 staining. Matrix metallopeptidase 8 was extensively expressed in retinal capillaries of Malawian children with malarial retinopathy and strongly associated with vascular leak. Our findings implicate MMP8 as a cause of the vascular endothelial barrier disruption in CM, which may precipitate fatal brain swelling. To test the hypothesis that localised release of matrix metallopeptidase 8 (MMP8) within the retina is implicated in microvascular leak in cerebral malaria (CM), we examined its expression and association with extravascular fibrinogen leak in a case‐control study of post‐mortem retinal samples from 13 Malawian children. MMP8 was extensively expressed in retinal capillaries of children with CM retinopathy and strongly associated with vascular leak. Our findings implicate MMP8 in the vascular endothelial barrier disruption in CM, which may precipitate fatal brain swelling.
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影响因子：
6.4
作者：
Dietmann, Anelia;Helbok, Raimund;Kremsner, Peter G.
通讯作者：
Kremsner, Peter G.
影响因子：
17.1
作者：
Lee HJ;Georgiadou A;Walther M;Nwakanma D;Stewart LB;Levin M;Otto TD;Conway DJ;Coin LJ;Cunnington AJ
通讯作者：
Cunnington AJ
DOI：
10.1016/j.trstmh.2008.11.003
发表时间：
2009-07
影响因子：
2.2
作者：
Maude RJ;Dondorp AM;Abu Sayeed A;Day NP;White NJ;Beare NA
通讯作者：
Beare NA
影响因子：
6.4
作者：
Feintuch, Catherine Manix;Saidi, Alex;Daily, Johanna P.
通讯作者：
Daily, Johanna P.
影响因子：
6.4
作者：
Beare, Nicholas A. V.;Harding, Simon P.;Molyneux, Malcolm E.
通讯作者：
Molyneux, Malcolm E.