Contribution of Small Airways to Mucociliary Transport Dysfunction

项目总结 呼吸道系统由内衬有呼吸道上皮的不对称二分支管组成。 这在与环境的界面上形成了一道屏障。呼吸道具有一种简单的传导功能 富氧空气进入肺泡腔，在那里气体与血液交换。通过这样做，病原体和 微粒进入肺部。粘液纤毛运输是一种宿主防御机制，它保护肺部免受 入侵的生物。粘液纤毛运输的缺陷导致许多呼吸道疾病，如哮喘， 慢性阻塞性肺疾病、特发性肺纤维化、囊性纤维化和原发纤毛 运动障碍。通过调查，我们对MCT在大气道中的作用机制有了一定的了解。 粘膜下腺分泌物的作用。我们发现，由粘膜下腺分泌的粘液链 对于启动大颗粒在大通道中的运动至关重要。我们还发现，在CF航空公司，由于损失了 CFTR介导的阴离子分泌，粘液链异常弹性。它们不能从粘膜下分离 腺管开口，在呼吸道表面运输时经常向后退缩。小型航空公司 构成了肺表面气道的大部分，提示这可能有助于某些 在几种呼吸道疾病中出现的异常。小气道粘液纤毛缺陷的假说 在慢性阻塞性肺疾病中的作用机制在很大程度上仍未得到证实。此外，其特点是 MCT在小气道中的特点仍然知之甚少。为了了解粘液纤毛的运输 ，我们开发了一种基于正电子发射的粘液纤毛传输分析方法，具有高空间和 以前没有达到过的时间分辨率。我们使用CF呼吸道疾病作为受损患者的疾病模型 粘液纤毛运输。为了实现我们了解粘液纤毛机制的首要目标 在小型和大型航空公司的运输中，我们将在以下具体目标中检验假设：目标1.什么 超时运动的机制是不是在体内？粘液粘弹性的破坏会改变吗？ 超时运动？粘膜下腺粘液分泌丧失会影响异时运动吗？是 慢性阻塞性肺疾病患者的亚时运动受损？目的2.细小的CF是否存在粘液纤毛清除缺陷 航空公司？CFTR的丢失是否会导致MCC缺陷？HEMT会纠正它吗？吸入性粘液溶解剂(TCEP) 改正吗？目的3.早期干预(出生时)是否足以预防/延缓CF呼吸道疾病？会吗？ HEMT能使仔猪CF呼吸道疾病恢复正常吗？粘液溶解剂作为桥梁疗法有效吗？ 直到HEMT开始？这一结果对于理解MCT的作用机制和机制具有重要意义 MCT得到了控制，并最终确定了肺部疾病的新靶点。研究结果也将指导 开发新的疗法或疗法的组合。

PROJECT SUMMARY The airway system is composed of asymmetric dichotomously branching tubes lined with respiratory epithelium that form a barrier at the interface with the environment. The airways carry a simple function of conducting oxygen rich air to the alveolar space where gas exchange with the blood occur. By doing that, pathogens and particles enter the lungs. Mucociliary transport is a host defense mechanism that protect the lungs from invading organisms. Defects in mucociliary transport contributes to many airway diseases such as asthma, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, cystic fibrosis, and primary ciliary dyskinesia. We developed limited understanding of the mechanism of MCT in large airways by investigating the role of submucosal gland secretions. We found that mucus strands secreted by submucosal glands are critical to initiate movement of large particles in large airways. We also found that in CF airways, due to loss of CFTR-mediated anion secretion, mucus strands are abnormally elastic. They fail to detach from submucosal gland duct opening and often recoil backward while transporting on the airway surface. Small airways constitute the majority of the surface airway of the lungs and it is suggested that may contribute to some of the abnormalities seen in several airway diseases. The hypothesis that mucociliary defects in small airways contribute to CF airway disease pathogenesis has largely remained untested. In addition, the characteristic features of MCT in small airways has remained poorly understood. To understand mucociliary transport in the small airways, we developed a positron emission based mucociliary transport assay with high spatial and temporal resolution not achieved before. We used CF airway disease as a disease model of impaired mucociliary transport. To realize our overarching goal of understanding the mechanism of mucociliary transport in both small and large airways, we will test hypotheses in the following Specific Aims: Aim 1. What is the mechanism of metachronal motion in vivo? Does disruption of mucus viscoelastic properties alter metachronal motion? Does loss of submucosal gland mucus secretion affect metachronal motion? Is metachronal motion impaired in CF airways? Aim 2. Is mucociliary clearance defective in CF small airways? Does loss of CFTR cause an MCC defect? Will HEMT correct it? Will an inhaled mucolytic (TCEP) correct it? Aim 3. Is early intervention (at birth) sufficient to prevent/delay CF airway disease? Does HEMT revert CF airway disease back to normal in young piglets? Are mucolytics effective as a bridge therapy until HEMT are initiated? The results are very important in understanding the mechanism of MCT and how MCT is controlled, and ultimately identify desperately new targets for lung diseases. The results will also guide development of newer therapeutics or combination of therapeutics.