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Lung defects in neonatal and adult stromal-derived factor–1 conditional knockout mice

机译:新生和成年基质衍生因子-1条件性基因敲除小鼠的肺部缺陷

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Stromal-derived factor (SDF)-1/CXCL12 is a cytokine that is involved in organogenesis, hematopoiesis, chemoattraction, and wound healing. An SDF-1 knockout mouse (SDF-1-/-) has provided important insights into the role of SDF-1 in fetal development. Because the SDF-1 knockout is lethal in the perinatal period, we have created a conditional SDF-1 knockout mouse. In the present study, we induced conditionally knocked out SDF-1 in neonatal mice and found that lung development was compromised; neonatal lungs showed increased alveolar airspace and abnormal ultrastructure. Conditional knockout of SDF-1 in adult mice resulted in an emphysemic morphology, with increased alveolar airspace and thickened alveolar septa. Fluorescence angiography showed pulmonary vessel hyperdilation. To determine whether the hyperdilation involved nitric oxide, we inhibited endothelial nitric oxide synthase (eNOS) with N (G)-nitro-L- arginine methyl ester. This resulted in the inhibition of pulmonary vessel hyperdilation. Western blot results showed increased phosphorylation of eNOS in our induced SDF-1 knockout mice, indicating that eNOS is normally repressed in the presence of SDF-1, and that activation of eNOS contributes to pulmonary pathology. Thus, a conditional knockout mouse has been successsfully created for SDF-1; initial characterization indicates that SDF-1 is intimately involved in lung development and physiology.
机译:基质基质衍生因子(SDF)-1 / CXCL12是一种细胞因子,参与器官发生,造血,趋化和伤口愈合。 SDF-1基因敲除小鼠(SDF-1 -/-)为SDF-1在胎儿发育中的作用提供了重要见识。由于SDF-1基因敲除在围产期具有致死性,因此我们创建了条件性SDF-1基因敲除小鼠。在本研究中,我们有条件地诱导了新生小鼠的SDF-1基因敲除,并发现其肺发育受到损害。新生儿肺显示肺泡空域增加和超微结构异常。成年小鼠有条件地敲除SDF-1导致肺气肿的形态,肺泡空域增加,肺泡间隔增厚。荧光血管造影显示肺血管过度扩张。为了确定过度扩张是否涉及一氧化氮,我们用N(G)-硝基-L-精氨酸甲酯抑制了内皮型一氧化氮合酶(eNOS)。这导致了肺血管过度扩张的抑制。蛋白质印迹结果显示,在我们诱导的SDF-1基因敲除小鼠中eNOS的磷酸化增加,表明eNOS在SDF-1存在下通常被抑制,而eNOS的激活有助于肺部病理。因此,已经成功地为SDF-1创建了条件敲除鼠标;初始特征表明SDF-1与肺发育和生理密切相关。

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