首页> 外文期刊>International journal of molecular imaging >Understanding Lung Deposition of Alpha-1 Antitrypsin in Acute Experimental Mouse Lung Injury Model Using Fluorescence Microscopy
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Understanding Lung Deposition of Alpha-1 Antitrypsin in Acute Experimental Mouse Lung Injury Model Using Fluorescence Microscopy

机译:使用荧光显微镜了解急性实验性小鼠肺损伤模型中Alpha-1抗胰蛋白酶的肺沉积

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Human plasma-derived ?1-antitrypsin (AAT) delivered by intravenous infusion is used as augmentation therapy in patients with emphysema who have a genetic mutation resulting in deficiency of AAT. Inhalation is an alternative route of administration that can potentially increase the efficacy and convenience of treatment. This study was conducted to determine whether delivery to the lungs, initially via the intratracheal (IT) route of administration, would deliver efficacious levels of a recombinant AAT (rAAT) to the site of action in the lungs in mice. 125I-radiolabeled rAAT, fluorophore-conjugated rAAT (rAAT-Alexa488), and NE680 (neutrophil elastase 680, a silent fluorescent substrate of neutrophil elastase which fluoresces in the near-infrared range upon activation by neutrophil elastase) were used to characterize the pharmacokinetics and tissue distribution profile, distribution of rAAT within the lung, and efficacy of rAAT to inhibit neutrophil elastase at the site of action, respectively. The study has demonstrated that rAAT was able to gain access to locations where neutrophil elastase was localized. The histochemical quantification of rAAT activity relative to dose at the site of action provided here will improve confidence in predicting the human dose via the inhalation route.
机译:静脉输注的人血浆来源的β1-抗胰蛋白酶(AAT)被用作肺气肿患者的增强疗法,这些患者的遗传突变导致AAT缺乏。吸入是另一种给药途径,可以潜在地提高疗效和治疗便利性。进行这项研究是为了确定最初通过气管内(IT)给药途径向肺部的递送是否会将有效水平的重组AAT(rAAT)递送至小鼠肺部的作用部位。 125 I放射性标记的rAAT,荧光团偶联的rAAT(rAAT-Alexa488)和NE680(嗜中性粒细胞弹性蛋白酶680,嗜中性粒细胞弹性蛋白酶的沉默荧光底物,在被嗜中性粒细胞弹性蛋白酶激活后发出近红外范围的荧光)用于表征药代动力学和组织分布图,rAAT在肺内的分布以及rAAT在作用部位抑制中性粒细胞弹性蛋白酶的功效。该研究表明,rAAT能够进入嗜中性粒细胞弹性蛋白酶定位的位置。 rAAT活性相对于此处提供的作用部位剂量的组织化学定量将提高通过吸入途径预测人剂量的信心。

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