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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Akt1 is critical for acute inflammation and histamine-mediated vascular leakage
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Akt1 is critical for acute inflammation and histamine-mediated vascular leakage

机译：Akt1对于急性炎症和组胺介导的血管渗漏至关重要

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摘要

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 micro-vascular 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.
机译：Akt1与细胞代谢，存活迁移和基因表达有关。然而，人们对体内炎症过程中特定Akt亚型的作用了解甚少。因此，我们通过使用缺乏Akt1或Akt2的小鼠直接探索了亚型Akt1和Akt2在急性炎症模型中的作用。与Akt2〜（-/-）和WT对照相比，Akt1〜（-/-）小鼠表现出明显的水肿减少，并且炎症减少与中性粒细胞和单核细胞浸润的急剧减少有关。 Akt1的丢失不会在体外影响白细胞的功能，骨髓移植实验表明宿主Akt1调节白细胞向发炎组织的迁移。此外，与WT小鼠相比，Akt1〜（-/-）小鼠中角叉菜胶引起的水肿以及缓激肽和组胺的直接通透作用明显降低。这些发现得到了体外实验的支持，这些实验表明Akt1缺乏或一氧化氮合酶的阻断显着降低了组胺刺激的微血管内皮细胞跨内皮电阻的变化。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渗透性而发挥其作用，从而导致水肿和白细胞外渗。

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  • 作者

    Annarita Di Lorenzo; Carlos Fernandez-Hernando; Giuseppe Cirino; William C. Sessa;

  • 作者单位

    Department of Pharmacology and Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT 06520;

    Department of Pharmacology and Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT 06520;

    Department of Pharmacology, Faculty of Pharmacy, University of Naples 'Federico II,' Naples, Italy;

    Department of Pharmacology, Faculty of Pharmacy, University of Naples 'Federico II,' Naples, Italy;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

    endothelium; nitric oxide;

    机译：内皮一氧化氮;

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