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首页> 外文期刊>Journal of Cerebral Blood Flow and Metabolism: Official Journal of the International Society of Cerebral Blood Flow and Metabolism >Transforming growth factor-beta signaling alters substrate permeability and tight junction protein expression at the blood-brain barrier during inflammatory pain.
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Transforming growth factor-beta signaling alters substrate permeability and tight junction protein expression at the blood-brain barrier during inflammatory pain.

机译:在炎症性疼痛期间,转化生长因子-β信号转导会改变底物通透性和血脑屏障处紧密连接蛋白的表达。

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Our laboratory has shown that peripheral inflammatory pain induced by lambda-carrageenan (CIP) can increase blood-brain barrier (BBB) permeability and alter tight junction (TJ) protein expression leading to changes in BBB functional integrity. However, the intracellular signaling mechanisms involved in this pathophysiologic response have not been elucidated. Transforming growth factor (TGF)-beta signaling pathways are known to regulate vascular integrity and permeability. Therefore, we examined the function of TGF-beta signaling at the BBB in rats subjected to CIP. During CIP, serum TGF-beta1 and protein expression of the TGF-beta receptor activin receptor-like kinase-5 (ALK5) were reduced. Brain permeability to (14)C-sucrose was increased and expression of TJ proteins (i.e., claudin-5, occludin, zonula occluden (ZO-1)) were also altered after 3 h CIP. Pharmacological inhibition of ALK5 with the selective inhibitor SB431542 further enhanced brain uptake of (14)C-sucrose, increased TJ protein expression (i.e., claudin-3, claudin-5, occludin, ZO-1), and decreased nuclear expression of TGF-beta/ALK5 signaling molecules (i.e., Smad2, Smad3), which suggests a role for TGF-beta/ALK5 signaling in the regulation of BBB integrity. Interestingly, administration of exogenous TGF-beta1 before CIP activated the TGF-beta/ALK5 pathway and reduced BBB permeability to (14)C-sucrose. Taken together, our data show that TGF-beta/ALK5 signaling is, in part, involved in the regulation of BBB functional integrity.
机译:我们的实验室表明,λ-角叉菜胶(CIP)引起的周围性炎性疼痛可增加血脑屏障(BBB)的通透性并改变紧密连接(TJ)的蛋白表达,从而导致BBB功能完整性的改变。然而,尚未阐明参与这种病理生理反应的细胞内信号传导机制。已知转化生长因子(TGF)-β信号通路可调节血管完整性和通透性。因此,我们检查了CIP大鼠在BBB处TGF-β信号转导的功能。在CIP期间,血清TGF-beta1和TGF-beta受体激活素受体样激酶5(ALK5)的蛋白表达降低。 CIP后3小时,大脑对(14)C-蔗糖的通透性增加,TJ蛋白(即claudin-5,occludin,zonula occluden(ZO-1))的表达也发生了变化。用选择性抑制剂SB431542抑制ALK5的药理作用进一步增强了大脑对(14)C-蔗糖的摄取,增加了TJ蛋白表达(即claudin-3,claudin-5,occludin,ZO-1),并降低了TGF-β的核表达。 β/ ALK5信号分子(即Smad2,Smad3)提示TGF-β/ ALK5信号在调节BBB完整性中起作用。有趣的是,在CIP之前施用外源性TGF-beta1激活了TGF-beta / ALK5途径,并降低了BBB对(14)C-蔗糖的渗透性。综上所述,我们的数据表明,TGF-beta / ALK5信号传导部分参与了BBB功能完整性的调节。

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