Biliverdin reductase-A attenuated GMH-induced inflammatory response in the spleen by inhibiting toll-like receptor-4 through eNOS/NO pathway.
Biliverdin reductase-A attenuated GMH-induced inflammatory response in the spleen by inhibiting toll-like receptor-4 through eNOS/NO pathway.
复制标题
DOI：
10.1186/s12974-018-1155-z
复制
发表时间：
2018-04-20
影响因子：
9.3
通讯作者：
Zhang JH
中科院分区：
文献类型：
--
作者：
Zhang Y;Ding Y;Lu T;Zhang Y;Xu N;McBride DW;Tang J;Zhang JH
脑出血是早产儿常见的神经系统疾病，发病率和死亡率都很高。脾脏通过调节外周免疫细胞在炎症反应中发挥重要作用，导致继发性脑损伤。本研究探讨了胆绿素还原酶-A（BLVRA）在胶原酶GMH模型新生儿脾反应和脑损伤中的机制作用。评估神经学结局和脾脏重量。分别定量脾和脑中的神经元产生和浸润。在脾和脑组织中进行Western印迹以测量Toll样受体4和促炎细胞因子的蛋白水平。BLVRA治疗减轻了GMH诱导的发育迟缓，并在GMH后1天和3天减弱了脾萎缩。定量分析显示，脾脏储存的外周免疫细胞动员到循环中，并在GMH后浸润到脑中，这被BLVRA给药所消除，导致脾脏炎症反应降低。此外，我们发现，BLVRA刺激的eNOS/NO信号的调节钝化了Toll样受体4（TLR 4）信号。eNOS产生的NO部分地将BLVRA转运到细胞核中，在那里BLVRA抑制TLR 4的表达。我们揭示了BLVRA依赖的信号通路通过eNOS/NO/TLR 4通路调节GMH应答的脾脏炎症。
Germinal matrix hemorrhage (GMH) is a common neurologic event with high morbidity and mortality in preterm infants. Spleen has been reported to play a critical role in inflammatory responses by regulating peripheral immune cells which contributes to secondary brain injury. The current study investigated the mechanistic role of biliverdin reductase-A (BLVRA) in the splenic response and brain damage in neonates following a collagenase GMH model. Neurological outcomes and splenic weights were assessed. Neutrophil production and infiltration were quantitated in the spleen and brain, respectively. Western blot was performed in both splenic and brain tissues to measure protein levels of toll-like receptor 4 and proinflammatory cytokines. BLVRA treatment alleviated GMH-induced developmental delay and attenuated splenic atrophy at 1 and 3 days after GMH. Quantification analysis showed that spleen-stored peripheral immune cells mobilized into circulation and infiltrated in the brain following GMH, which was abrogated by BLVRA administration, resulting in reduced splenic inflammatory response. Furthermore, we showed that regulation of eNOS/NO signaling by BLVRA stimulation blunted toll-like receptor-4 (TLR4) signal. The eNOS-generated NO, in part, translocated BLVRA into the nucleus, where BLVRA inhibited TLR4 expression. We revealed a BLVRA-dependent signaling pathway in modulating the splenic inflammation in response to GMH via the eNOS/NO/TLR4 pathway.
登录
查看更多内容
影响因子：
12.4
作者：
Ferenbach, David A.;Ramdas, Vasudev;Kluth, David C.
通讯作者：
Kluth, David C.
影响因子：
5.7
作者：
Doré, S;Sampei, K;Snyder, SH
通讯作者：
Snyder, SH
急性脾辐射可减少大鼠局灶性缺血性中风模型中的脑损伤。
影响因子：
6.9
作者：
Ostrowski, Robert P.;Schulte, Reinhard W.;Nie, Ying;Ling, Ted;Lee, Timothy;Manaenko, Anatol;Gridley, Daila S.;Zhang, John H.
通讯作者：
Zhang, John H.
影响因子：
4.4
作者：
Offner, Halina;Subramanian, Sandhya;Hurn, Patricia D.
通讯作者：
Hurn, Patricia D.
影响因子：
5.3
作者：
Into, Takeshi;Inomata, Megumi;Matsushita, Kenji
通讯作者：
Matsushita, Kenji