A Role for Low Density Lipoprotein Receptor-Related Protein 1 in the Cellular Uptake of Tissue Plasminogen Activator in the Lungs.
A Role for Low Density Lipoprotein Receptor-Related Protein 1 in the Cellular Uptake of Tissue Plasminogen Activator in the Lungs.
复制标题
DOI：
10.1007/s11095-015-1763-6
复制
发表时间：
2016-01
影响因子：
3.7
通讯作者：
Stringer KA
中科院分区：
文献类型：
--
作者：
Lin S;Racz J;Tai MF;Brooks KM;Rzeczycki P;Heath LJ;Newstead MW;Standiford TJ;Rosania GR;Stringer KA
了解吸入型组织型纤溶酶原激活剂（tPA）的肺清除机制。使用体内小鼠模型和离体小鼠全器官细胞悬液，我们研究了肺利用LRP 1受体介导的内吞作用（RME）摄取外源性tPA（有或无LRP 1抑制剂、受体相关蛋白（RAP））的能力，并将其与肝脏进行了定量比较。我们还使用了一种新的成像技术来评估LRP 1在小鼠肝脏和肺切片中的含量。经气管内给药后，BALF中tPA浓度随时间下降，遵循提示RME清除机制的双室药代动力学。离体研究表明，肺和肝细胞通过LRP 1 RME摄取tPA的能力相似，RAP使其减少约50%。肺和肝对tPA的摄取相当可能是由于等量的LRP 1，其中肺泡上皮中存在丰富的LRP 1。我们的研究结果表明，LRP 1 RME是一个候选的清除机制吸入tPA的安全和有效的吸入tPA治疗可塑性支气管炎和其他纤维蛋白炎性气道疾病，其中吸入tPA可能有效用的给药方案的发展具有影响。
To gain knowledge of lung clearance mechanisms of inhaled tissue plasminogen activator (tPA). Using an in vivo mouse model and ex vivo murine whole organ cell suspensions, we examined the capability of the lungs to utilize LRP1 receptor-mediated endocytosis (RME) for the uptake of exogenous tPA with and without an LRP1 inhibitor, receptor associated protein (RAP), and quantitatively compared it to the liver. We also used a novel imaging technique to assess the amount LRP1 in sections of mouse liver and lung. Following intratracheal administration, tPA concentrations in the BALF declined over time following two-compartment pharmacokinetics suggestive of RME clearance mechanism. Ex vivo studies showed that lung and liver cells are similarly capable of tPA uptake via LRP1 RME which was reduced by ~50% by RAP. The comparable lung and liver uptake of tPA is likely due to equivalent amounts of LRP1 of which there was an abundance of LRP1 in alveolar epithelium. Our findings indicate that LRP1 RME is a candidate clearance mechanism for inhaled tPA which has implications for the development of safe and effective dosing regimens of inhaled tPA for the treatment of plastic bronchitis and other fibrin-inflammatory airway diseases in which inhaled tPA may have utility.