George and Cynthia Mitchell Center for Neurodegenerative Diseases, Department of Neurology, University of Texas Medical Branch, 301 University Boulevard, Medical Research Building, Room 10.138C, Galveston, Texas 77555-1045, USA.
Endocrinology. 2010 Oct;151(10):4717-24. doi: 10.1210/en.2010-0457. Epub 2010 Aug 4.
It is well known that interfaces, such as polar-nonpolar or liquid-air, play a key role in triggering protein aggregation in vitro, in particular the aggregation of peptides and proteins with the predisposition of misfolding and aggregation. Here we show that the interface present in the lungs predisposes the lungs to form aggregation of inhaled insulin. Insulin inhalers were introduced, and a large number of diabetic patients have used them. Although inhalers were safe and effective, decreases in pulmonary capacity have been reported in response to inhaled insulin. We hypothesize that the lung air-tissue interface provides a template for the aggregation of inhaled insulin. Our studies were designed to investigate the harmful potential that inhaled insulin has in pulmonary tissue in vivo, through an amyloid formation mechanism. Our data demonstrate that inhaled insulin rapidly forms amyloid in the lungs causing a significant reduction in pulmonary air flow. Our studies exemplify the importance that interfaces play in protein aggregation in vivo, illustrating the potential aggregation of inhaled proteins and the formation of amyloid deposits in the lungs. These insulin deposits resemble the amyloid structures implicated in protein misfolding disorders, such as Alzheimer's and Parkinson's diseases, and could as well be deleterious in nature.
众所周知，界面（如极性非极性或液-气）在体外触发蛋白质聚集方面起着关键作用，特别是在具有错误折叠和聚集倾向的肽和蛋白质聚集方面。在这里，我们表明肺部存在的界面使肺部易于形成吸入胰岛素的聚集。已经引入了胰岛素吸入器，并且大量糖尿病患者已经使用了它们。尽管吸入器是安全有效的，但据报道，吸入胰岛素会导致肺容量下降。我们假设肺的气-组织界面为吸入胰岛素的聚集提供了模板。我们的研究旨在通过淀粉样形成机制研究吸入胰岛素在体内对肺组织的潜在危害。我们的数据表明，吸入胰岛素在肺部迅速形成淀粉样蛋白，导致肺气流显著减少。我们的研究说明了界面在体内蛋白质聚集中的重要性，说明了吸入蛋白质的潜在聚集和肺部淀粉样蛋白沉积的形成。这些胰岛素沉积物类似于涉及蛋白质错误折叠疾病（如阿尔茨海默病和帕金森病）的淀粉样结构，并且在性质上可能是有害的。
