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

项目摘要 囊性纤维化(CF)患者的中位生存年龄仍在40岁左右，肺恶化 是CF患者死亡的主要原因。因为呼吸恶化会恶化他们的病程 以不可逆转的方式呼吸状态，减少任何并发症是提高其质量的关键 寿命和寿命。Cf患者在其生命的不同阶段接受手术和其他程序， 经常出现呼吸道并发症。中性粒细胞介导的肺部炎症与 细菌定植和机械通气性损伤被认为是导致损伤的重要因素。 到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因子 铜绿假单胞菌是CF呼吸道的主要定植菌株。鞭毛蛋白刺激诱导激活的 中性粒细胞和导致肺损伤。中性粒细胞活化也参与了机械性肺损伤 通风。我们的初步研究表明，挥发性麻醉药减弱了Toll样受体(TLR)5和 鞭毛蛋白介导的小鼠肺损伤模型。这一结果表明，挥发性麻醉剂可能 减轻CF患者细菌定植所致的肺损伤。经常需要全身麻醉 手术和其他程序，并提供由挥发性和静脉麻醉剂。我们和其他人有 研究表明，挥发性麻醉剂具有免疫调节作用。我们的初步数据表明，挥发性 麻醉剂可抑制免疫活性受试者TLR5的激活。我们之前展示了易失性 麻醉药还可减弱黏附分子β-2整合素。我们的初步数据表明，β2整合素 参与了呼吸机所致的肺损伤。这项研究旨在检验我们的假设，即在CF挥发物中 麻醉药将减轻1)铜绿假单胞菌介导的肺损伤和2)机械通气- 用CF转基因小鼠和患者肺诱导肺损伤。我们会在两个目标下进行研究： (目的1)在活体慢性肺纤维化临床前模型中确定麻醉药物对肺功能的影响 (目的2)探讨麻醉药物对CF型肺组织体外培养的影响。 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 CF患者的养生方案。因为所有测试的药物都在临床上使用，我们希望临床翻译 是非常可行的。此外，我们计划开发减轻肺损伤的新药，但缺乏 以挥发性麻醉药为原型用于慢性阻塞性肺疾病患者的麻醉效果。此外，这一点 这项研究是至关重要的，因为我们将评估麻醉剂在免疫受损环境中的效果，这是 从临床角度来看是重要的信息，但尚未经过测试。

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.