Optimization of anesthetic/sedative regimen for pulmonary pathophysiology in cystic fibrosis patients

项目摘要 囊性纤维化（CF）患者的存活中位年龄仍在40多岁，并且肺恶化在40岁以下。 CF患者死亡的主要原因。因为呼吸恶化会恶化他们的病程， 呼吸状态以不可逆的方式，减轻任何并发症是至关重要的，以提高他们的质量， 寿命和寿命。CF患者在其生命的各个阶段进行手术和其他手术， 经常出现呼吸系统并发症。中性粒细胞介导的肺部炎症与 定植细菌和机械通气引起的损伤被认为是重要因素 围手术期肺部并发症鞭毛蛋白是假单胞菌对肺组织的主要刺激物 铜绿假单胞菌是CF气道中的主要定植菌株。鞭毛蛋白刺激诱导激活的 中性粒细胞并导致肺损伤。神经元活化也参与机械性肺损伤 通风.我们的初步研究表明，挥发性麻醉药减弱Toll样受体（TLR）5和TLR-1， 鞭毛蛋白介导的肺损伤的小鼠模型。结果提示，挥发性麻醉药可能 减轻CF患者中定植细菌引起的肺损伤。通常需要全身麻醉， 手术和其他程序，并通过挥发性和静脉麻醉剂提供。我们和其他人已经 表明挥发性麻醉剂具有免疫调节作用。我们的初步数据显示， 麻醉剂可阻碍免疫活性受试者中的TLR 5活化。我们之前的研究表明， 麻醉剂也减弱粘附分子β2整联蛋白。我们的初步数据表明，β2整合素 参与了通气诱导的肺损伤。本研究旨在验证我们的假设，在CF挥发性 麻醉剂将减弱1）铜绿假单胞菌介导的肺损伤和2）机械通气- 使用CF转基因小鼠和患者肺诱导肺损伤。将在两个目标下对此进行研究： (Aim 1）确定麻醉药物对CF临床前模型中体内肺功能的作用 (Aim 2）使用离体CF肺组织确定麻醉药物对肺切片培养物的作用。 在成功完成建议后，我们将进行临床研究，以确定最佳麻醉剂 治疗CF的方法因为所有测试的药物都在临床使用，我们希望临床翻译 是相当可行的。此外，我们计划开发新的药物，减轻肺损伤，但没有 使用挥发性麻醉剂作为CF患者中一般使用的原型的麻醉效果。另外这款 这项研究是至关重要的，因为我们将评估麻醉剂在免疫功能低下的情况下的作用， 从临床角度来看，这是重要的信息，但尚未得到验证。

Project Summary The median age for survival of cystic fibrosis (CF) patients is still in the mid 40s and pulmonary deterioration is the major cause of mortality for CF patients. Because respiratory exacerbation can worsen the course of their respiratory status in an irreversible manner, mitigating any complications is critical to improve their quality of life and life span. CF patients present to surgery and other procedures at various stages of their lives and frequently experience respiratory complications. Neutrophil-mediated lung inflammation associated with colonized bacteria and mechanical ventilation-induced injury are considered as important factors contributing to perioperative pulmonary complications. Flagellin is a primary stimulant of lung tissue by Pseudomonas aeruginosa, a major colonized strain in CF airway. Flagellin stimulation induces recruitment of activated neutrophils and causes lung injury. Neutrophil activation is also involved in the lung injury by mechanical ventilation. Our preliminary study showed that volatile anesthetics attenuated Toll like receptor (TLR)5 and flagellin-mediated lung injury in the mouse model. The result suggested that volatile anesthetics might attenuate lung injury caused by colonized bacteria in CF patients. General anesthesia is frequently required for surgery and other procedures and provided by volatile and intravenous anesthetics. We and others have shown that volatile anesthetics are immunomodulatory. Our preliminary data suggested that volatile anesthetics could hinder TLR5 activation in immunocompetent subjects. We previously showed that volatile anesthetics also attenuated adhesion molecule β2 integrins. Our preliminary data suggested that β2 integrins were involved in ventilation-induced lung injury. This study aims to test our hypothesis that in CF volatile anesthetics would attenuate 1) Pseudomonas aeruginosa-mediated lung injury and 2) mechanical ventilation- induced lung injury using CF transgenic mice and patients’ lung. This will be studied under two Aims: (Aim 1) Determine the role of anesthetic drugs on pulmonary function in a CF preclinical model in vivo (Aim 2) Determine the role of anesthetic drugs on lung slice cultures using CF lung tissue ex vivo. Upon the successful completion of the proposal, we will do clinical study to determine the optimal anesthetic regimen for people with CF. Because all the drugs tested are in clinical use, we expect that clinical translation is quite feasible. In addition, we plan to develop new drugs that attenuate lung injury but are devoid of anesthetic effects using volatile anesthetics as a prototype for general use in CF patients. In addition, this study is critical because we will assess the effect of anesthetics in immunocompromised setting, which is important information from clinical standpoint, but has not been tested yet.