Spred-2 deficiency exacerbates lipopolysaccharide-induced acute lung inflammation in mice.
Spred-2 deficiency exacerbates lipopolysaccharide-induced acute lung inflammation in mice.
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DOI：
10.1371/journal.pone.0108914
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Matsukawa A
中科院分区：
文献类型：
--
作者：
Xu Y;Ito T;Fushimi S;Takahashi S;Itakura J;Kimura R;Sato M;Mino M;Yoshimura A;Matsukawa A
急性呼吸窘迫综合征(ARDS)是一种由有害刺激和病原体引起的严重且危及生命的急性肺损伤(ALI)。ALI的特点是明显的急性炎症和肺泡细胞因子水平升高。丝裂原活化蛋白激酶(MAPK)途径参与细胞因子的产生，但调节这些途径的机制尚不清楚。在这里，我们集中讨论了Sprouty相关的EVH1结构域蛋白(Spred)-2，它是Ras-Raf-细胞外信号调节蛋白(ERK)-MAPK通路的负调节因子，在脂多糖(LPS)诱导的急性肺炎症中起到了作用。野生型(WT)小鼠和SPRED-2−/−小鼠气管内注射脂多糖(50微克/50微克L PBS)诱导肺部炎症。注射脂多糖后，取肺组织进行白细胞浸润、细胞因子和趋化因子产生、ERK-MAPK活化及免疫病理检查。在体外实验中，从未经处理的WT和Spred-2−/−小鼠的肺泡巨噬细胞中提取细胞，并用内毒素刺激。在体外实验中，将siRNA特异性下调Spred-2或将编码Spred-2正义序列的质粒导入小鼠RAW264.7巨噬细胞或MLE-12肺上皮细胞中，使Spred-2过表达。Spred-2−/−小鼠与WT小鼠相比，脂多糖诱导的急性肺炎症明显加重，表现为白细胞数、后期肺泡肿瘤坏死因子-α、CxCL_2和CCL_2水平以及肺组织病理改变。选择性蛋白酪氨酸激酶/ERK抑制剂U0126可减轻Spred-2−/−小鼠炎症反应。在RAW264.7细胞和MLE-12细胞中，Spred-2的特异性敲除增强了内毒素诱导的细胞因子和趋化因子的反应，而在RAW264.7细胞中过表达Spred-2则降低了这种反应。ERK-MAPK通路参与了内毒素诱导的急性肺炎症。SPRED-2通过负向调节ERK-MAPK通路，控制内毒素诱导的肺部炎症的发展。因此，Spred-2可能是治疗ALI的靶点。
Acute respiratory distress syndrome (ARDS) is a severe and life-threatening acute lung injury (ALI) that is caused by noxious stimuli and pathogens. ALI is characterized by marked acute inflammation with elevated alveolar cytokine levels. Mitogen-activated protein kinase (MAPK) pathways are involved in cytokine production, but the mechanisms that regulate these pathways remain poorly characterized. Here, we focused on the role of Sprouty-related EVH1-domain-containing protein (Spred)-2, a negative regulator of the Ras-Raf-extracellular signal-regulated kinase (ERK)-MAPK pathway, in lipopolysaccharide (LPS)-induced acute lung inflammation. Wild-type (WT) mice and Spred-2−/− mice were exposed to intratracheal LPS (50 µg in 50 µL PBS) to induce pulmonary inflammation. After LPS-injection, the lungs were harvested to assess leukocyte infiltration, cytokine and chemokine production, ERK-MAPK activation and immunopathology. For ex vivo experiments, alveolar macrophages were harvested from untreated WT and Spred-2−/− mice and stimulated with LPS. In in vitro experiments, specific knock down of Spred-2 by siRNA or overexpression of Spred-2 by transfection with a plasmid encoding the Spred-2 sense sequence was introduced into murine RAW264.7 macrophage cells or MLE-12 lung epithelial cells. LPS-induced acute lung inflammation was significantly exacerbated in Spred-2−/− mice compared with WT mice, as indicated by the numbers of infiltrating leukocytes, levels of alveolar TNF-α, CXCL2 and CCL2 in a later phase, and lung pathology. U0126, a selective MEK/ERK inhibitor, reduced the augmented LPS-induced inflammation in Spred-2−/− mice. Specific knock down of Spred-2 augmented LPS-induced cytokine and chemokine responses in RAW264.7 cells and MLE-12 cells, whereas Spred-2 overexpression decreased this response in RAW264.7 cells. The ERK-MAPK pathway is involved in LPS-induced acute lung inflammation. Spred-2 controls the development of LPS-induced lung inflammation by negatively regulating the ERK-MAPK pathway. Thus, Spred-2 may represent a therapeutic target for the treatment of ALI.
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影响因子：
3.8
作者：
Li, Xinyan;Jiang, Song;Tapping, Richard I.
通讯作者：
Tapping, Richard I.
影响因子：
4.8
作者：
Favata, MF;Horiuchi, KY;Trzaskos, JM
通讯作者：
Trzaskos, JM
影响因子：
3.2
作者：
Asti, C;Ruggieri, V;Caselli, GF
通讯作者：
Caselli, GF
DOI：
10.1152/ajplung.00453.2001
发表时间：
2002-06-01
影响因子：
4.9
作者：
Maus, UA;Koay, MA;Lohmeyer, J
通讯作者：
Lohmeyer, J
影响因子：
5.5
作者：
Aga, M;Watters, JJ;Bertics, PJ
通讯作者：
Bertics, PJ