Netrin-1 Dampens Pulmonary Inflammation during Acute Lung Injury
Netrin-1 Dampens Pulmonary Inflammation during Acute Lung Injury
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DOI：
10.1164/rccm.200905-0717oc
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发表时间：
2010-04-15
影响因子：
24.7
通讯作者：
Rosenberger, Peter
中科院分区：
文献类型：
--
作者：
Mirakaj, Valbona;Thix, Cyril A.;Rosenberger, Peter
基本原理：急性肺损伤（acute lung injury，ALI）是一种以低氧血症和中性粒细胞弥漫性浸润为特征的炎症性疾病。中性粒细胞的迁移和外渗是通过积极的指导线索，如趋化因子。最近的工作已经确定了神经元的指导蛋白netrin-1是一个负的指导线索白细胞迁移，并持有potential.Objectives：为了测试肺netrin-1在急性肺损伤的作用。研究方法：在体外和体内急性炎症期间评估肺netrin-1表达;使用pGL 4荧光素酶报告基因研究netrin-1启动子。在野生型、Ntn 1（+/-）和A2 BAR（-/-）动物中通过LPS吸入和机械通气诱导ALI。外源性netrin-1被用来评估其对肺部inflammation.Measurements和主要结果的影响：野生型动物表现出肺netrin-1的抑制LPS吸入后。体外研究证实了netrin-1的抑制作用。在假定netrin-1启动子的研究确定了一个核因子-κ B依赖的机制参与这种镇压。与Ntn 1（+/+）动物相比，Ntn 1（+/-）动物在LPS吸入后表现出增加的炎症变化。用netrin-1重建抑制了肺泡腔中中性粒细胞的浸润和细胞因子的产生。这种作用依赖于腺苷2b受体。netrin-1控制肺部炎症的重要性可以在呼吸机诱导的肺injury.Conclusions模型中得到证实：ALI期间肺netrin-1水平被抑制。这导致明显的肺损伤、中性粒细胞浸润增加和肺部炎症增加。外源性netrin-1通过腺苷2B受体显著减轻ALI的程度。
Rationale: Acute lung injury (ALI) is an inflammatory disorder characterized by hypoxemia and diffuse infiltration of neutrophils into the alveolar space. The migration and extravasation of neutrophils is guided through positive guidance cues, such as chemokines. Recent work has identified the neuronal guidance protein netrin-1 to be a negative guidance cue for leukocyte migration and to hold antiinflammatory potential.Objectives: To test the role of pulmonary netrin-1 during ALI. Methods: Pulmonary netrin-1 expression was evaluated during acute inflammation in vitro and in vivo; the netrin-1 promoter was studied using pGL4 luciferase reporter. ALI was induced through LPS inhalation and mechanical ventilation in wild-type, Ntn1(+/-), and A2BAR(-/-) animals. Exogenous netrin-1 was used to evaluate its impact on pulmonary inflammation.Measurements and Main Results: Wild-type animals demonstrated repression of pulmonary netrin-1 after LPS inhalation. In vitro studies confirmed the repression of netrin-1. Studies in the putative netrin-1 promoter identified a nuclear factor-kappa B-dependent mechanism to be involved in this repression. Ntn1(+/-) animals demonstrated increased inflammatory changes after LPS inhalation compared with Ntn1(+/+) animals. Reconstitution with netrin-1 dampened the infiltration of neutrophils and cytokine production in the alveolar space. This effect was dependent on the adenosine 2b receptor. The importance of netrin-1 for the control of pulmonary inflammation could be corroborated in a model of ventilator-induced lung injury.Conclusions: Pulmonary netrin-1 levels are repressed during ALI. This results in pronounced pulmonary damage, an increased infiltration of neutrophils, and increased pulmonary inflammation. Exogenous netrin-1 significantly dampens the extent of ALI through the adenosine 2B receptor.