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首页> 外文期刊>EBioMedicine >Neutrophil Membrane Cholesterol Content is a Key Factor in Cystic Fibrosis Lung Disease
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Neutrophil Membrane Cholesterol Content is a Key Factor in Cystic Fibrosis Lung Disease

机译：中性粒细胞膜胆固醇含量是囊性纤维化肺病的关键因素

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Background: Identification of mechanisms promoting neutrophil trafficking to the lungs of patients with cystic fibrosis (CF) is a challenge for next generation therapeutics. Cholesterol, a structural component of neutrophil plasma membranes influences cell adhesion, a key step in transmigration. The effect of chronic inflammation on neutrophil membrane cholesterol content in patients with CF (PWCF) remains unclear. To address this we examined neutrophils of PWCF to evaluate the cause and consequence of altered membrane cholesterol and identified the effects of lung transplantation and ion channel potentiator therapy on the cellular mechanisms responsible for perturbed membrane cholesterol and increased cell adhesion. Methodology: PWCF homozygous for the @DF508 mutation or heterozygous for the G551D mutation were recruited (n=48). Membrane protein expression was investigated by mass spectrometry. The effect of lung transplantation or ivacaftor therapy was assessed by ELISAs, and calcium fluorometric and @m-calpain assays. Findings: Membranes of CF neutrophils contain less cholesterol, yet increased integrin CD11b expression, and respond to inflammatory induced endoplasmic reticulum (ER) stress by activating @m-calpain. In vivo and in vitro, increased @m-calpain activity resulted in proteolysis of the membrane cholesterol trafficking protein caveolin-1. The critical role of caveolin-1 for adequate membrane cholesterol content was confirmed in caveolin-1 knock-out mice. Lung transplant therapy or treatment of PWCF with ivacaftor, reduced levels of circulating inflammatory mediators and actuated increased caveolin-1 and membrane cholesterol, with concurrent normalized neutrophil adhesion. Interpretation: Results demonstrate an auxiliary benefit of lung transplant and potentiator therapy, evident by a reduction in circulating inflammation and controlled neutrophil adhesion.
机译：背景：确定促进中性粒细胞向囊性纤维化（CF）患者肺部转运的机制是下一代治疗方法的挑战。胆固醇是中性粒细胞质膜的一种结构成分，可影响细胞粘附，这是迁移的关键步骤。慢性炎症对CF（PWCF）患者中性粒细胞膜胆固醇含量的影响尚不清楚。为了解决这个问题，我们检查了PWCF的中性粒细胞，以评估膜胆固醇改变的原因和结果，并确定了肺移植和离子通道增强剂治疗对引起膜胆固醇紊乱和细胞粘附增加的细胞机制的影响。方法：招募了@ DF508突变的纯合子或G551D突变的纯合子（n = 48）。通过质谱研究膜蛋白的表达。肺移植或依伐卡托治疗的效果通过ELISA，荧光钙化和@ m-钙蛋白酶测定来评估。结果：CF中性粒细胞膜含有较少的胆固醇，但整合素CD11b表达增加，并通过激活@ m-钙蛋白酶对炎症诱导的内质网（ER）应激作出反应。在体内和体外，@ m-钙蛋白酶活性的增加导致膜胆固醇运输蛋白caveolin-1的蛋白水解。小窝蛋白-1基因敲除小鼠中证实了小窝蛋白1对适当的膜胆固醇含量的关键作用。用依伐卡托进行肺移植治疗或PWCF的治疗，降低循环炎症介质的水平并促成增加的Caveolin-1和膜胆固醇，同时使中性粒细胞粘附正常化。解释：结果证明了肺移植和增强剂治疗的辅助益处，这可通过减少循环炎症和控制中性粒细胞粘附来证明。

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