Akt1 is critical for acute inflammation and histamine-mediated vascular leakage
Akt1 is critical for acute inflammation and histamine-mediated vascular leakage
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DOI：
10.1073/pnas.0904073106
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发表时间：
2009-08-25
影响因子：
11.1
通讯作者：
Sessa, William C.
中科院分区：
文献类型：
--
作者：
Di Lorenzo, Annarita;Fernandez-Hernando, Carlos;Sessa, William C.
Akt1 与细胞代谢、存活迁移和基因表达有关；然而，人们对特定 Akt 同工型在体内炎症过程中的作用知之甚少。因此，我们通过使用 Akt1 或 Akt2 缺陷的小鼠直接探索了 Akt1 和 Akt2 亚型在急性炎症模型中的作用。与 Akt2(-/-) 和 WT 对照相比，Akt1(-/-) 小鼠的水肿明显减轻，炎症的减轻与中性粒细胞和单核细胞浸润的显着减少有关。 Akt1 的缺失并不影响体外白细胞功能，骨髓移植实验表明宿主 Akt1 调节白细胞迁移到发炎组织中。此外，与WT小鼠相比，Akt1(-/-)小鼠中角叉菜胶诱导的水肿以及缓激肽和组胺的直接渗透性作用显着降低。这些发现得到了体外实验的支持，表明 Akt1 缺乏或一氧化氮合酶阻断可显着降低组胺刺激的微血管内皮细胞跨内皮电阻变化。总的来说，这些结果表明 Akt1 对于急性炎症是必需的，并且主要通过调节血管通透性发挥其作用，导致水肿和白细胞外渗。
Akt1 is implicated in cell metabolism, survival migration, and gene expression; however, little is known about the role of specific Akt isoforms during inflammation in vivo. Thus, we directly explored the roles of the isoforms Akt1 and Akt2 in acute inflammation models by using mice deficient in either Akt1 or Akt2. Akt1(-/-) mice showed a markedly reduced edema versus Akt2(-/-) and WT controls, and the reduced inflammation was associated with a dramatic decrease in neutrophil and monocyte infiltration. The loss of Akt1 did not affect leukocyte functions in vitro, and bone marrow transplant experiments suggest that host Akt1 regulates leukocyte emigration into inflamed tissues. Moreover, carrageenan-induced edema and the direct propermeability actions of bradykinin and histamine were reduced dramatically in Akt1(-/-) versus WT mice. These findings are supported by in vitro experiments showing that Akt1 deficiency or blockade of nitric oxide synthase markedly reduces histamine-stimulated changes in transendothelial electrical resistance of microvascular endothelial cells. Collectively, these results suggest that Akt1 is necessary for acute inflammation and exerts its actions primarily via regulation of vascular permeability, leading to edema and leukocyte extravasation.