2型肺泡上皮细胞中缺氧诱导因子-1α的激活是肺挫伤后急性炎症的主要驱动因素。
Activation of hypoxia-inducible factor-1α in type 2 alveolar epithelial cell is a major driver of acute inflammation following lung contusion.
作者信息
Suresh Madathilparambil V, Ramakrishnan Sadeesh Kumar, Thomas Bivin, Machado-Aranda David, Bi Yu, Talarico Nicholas, Anderson Erik, Yatrik Shah M, Raghavendran Krishnan
机构信息
1Department of Surgery, University of Michigan Medical School, Ann Arbor, MI. 2Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI. 3Department of Internal Medicine, Division of Gastroenterology, University of Michigan Medical School, Ann Arbor, MI.
出版信息
Crit Care Med. 2014 Oct;42(10):e642-53. doi: 10.1097/CCM.0000000000000488.
OBJECTIVE
Lung contusion is a major risk factor for the development of acute respiratory distress syndrome. Hypoxia-inducible factor-1α is the primary transcription factor that is responsible for regulating the cellular response to changes in oxygen tension. We set to determine if hypoxia-inducible factor-1α plays a role in the pathogenesis of acute inflammatory response and injury in lung contusion.
DESIGN
Nonlethal closed-chest unilateral lung contusion was induced in a hypoxia reporter mouse model and type 2 cell-specific hypoxia-inducible factor-1α conditional knockout mice. The mice were killed at 5-, 24-, 48-, and 72-hour time points, and the extent of systemic and tissue hypoxia was assessed. In addition, injury and inflammation were assessed by measuring bronchoalveolar lavage cells (flow cytometry and cytospin), albumin (permeability injury), and cytokines (inflammation). Isolated type 2 cells from the hypoxia-inducible factor-1α conditional knockout mice were isolated and evaluated for proinflammatory cytokines following lung contusion. Finally, the role of nuclear factor-κB and interleukin-1β as intermediates in this interaction was studied.
RESULTS
Lung contusion induced profound global hypoxia rapidly. Increased expression of hypoxia-inducible factor-1α from lung samples was observed as early as 60 minutes, following the insult. The extent of lung injury following lung contusion was significantly reduced in conditional knockout mice at all the time points, when compared with the wild-type littermate mice. Release of proinflammatory cytokines, such as interleukin-1β, interleukin-6, macrophage inflammatory protein-2, and keratinocyte chemoattractant, was significantly lower in conditional knockout mice. These actions are in part mediated through nuclear factor-κB. Hypoxia-inducible factor-1α in lung epithelial cells was shown to regulate interleukin-1β promoter activity.
CONCLUSION
Activation of hypoxia-inducible factor-1α in type 2 cell is a major driver of acute inflammation following lung contusion.
目的
肺挫伤是急性呼吸窘迫综合征发生的主要危险因素。缺氧诱导因子-1α是负责调节细胞对氧张力变化反应的主要转录因子。我们旨在确定缺氧诱导因子-1α是否在肺挫伤的急性炎症反应和损伤的发病机制中起作用。
设计
在缺氧报告基因小鼠模型和2型细胞特异性缺氧诱导因子-1α条件性敲除小鼠中诱导非致死性闭胸单侧肺挫伤。在5小时、24小时、48小时和72小时时间点处死小鼠，评估全身和组织缺氧程度。此外，通过测量支气管肺泡灌洗细胞（流式细胞术和细胞离心涂片）、白蛋白（通透性损伤）和细胞因子（炎症）来评估损伤和炎症。从缺氧诱导因子-1α条件性敲除小鼠中分离出2型细胞，并在肺挫伤后评估促炎细胞因子。最后，研究核因子-κB和白细胞介素-1β作为这种相互作用中间体的作用。
结果
肺挫伤迅速导致严重的全身性缺氧。在损伤后60分钟，最早观察到肺样本中缺氧诱导因子-1α的表达增加。与野生型同窝小鼠相比，条件性敲除小鼠在所有时间点肺挫伤后的肺损伤程度均显著降低。条件性敲除小鼠中促炎细胞因子如白细胞介素-1β、白细胞介素-6、巨噬细胞炎性蛋白-2和角质形成细胞趋化因子的释放显著降低。这些作用部分通过核因子-κB介导。肺上皮细胞中的缺氧诱导因子-1α被证明可调节白细胞介素-1β启动子活性。
结论
2型细胞中缺氧诱导因子-1α的激活是肺挫伤后急性炎症的主要驱动因素。
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