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

囊性纤维化患者肺部病理生理学麻醉/镇静方案的优化

基本信息

批准号：
10341229
负责人：
Koichi Yuki
金额：
$ 22.13万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-02-04 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10341229
关键词：
Affect Age Anesthesia procedures Anesthetics Antibiotics Attenuated Bacteria Bacterial Infections Binding Bronchiectasis Bronchodilator Agents Cell Adhesion Molecules Cell Death Clinical Clinical Research Cystic Fibrosis Cystic Fibrosis Transmembrane Conductance Regulator Data Deoxyribonucleases Deterioration Development Europe Exposure to Flagellin Functional disorder General Anesthesia Hemoptysis Hospitalization Immunocompetent Immunocompromised Host Individual Inflammation Inflammatory Response Injury Integrins Intensive Care Units Intravenous Intravenous Anesthetics Investigation Lead Life Ligands Lipopolysaccharides Lipoproteins Live Birth Longevity Lung Lung Compliance Lung Transplantation Mechanical ventilation Mechanics Mediating Methods Microbe Modeling Molecular Molecular Structure Morbidity - disease rate Mus Mutation Neutrophil Activation Neutrophil Infiltration Neutrophilic Infiltrate Operative Surgical Procedures Patients Pattern Peptide Hydrolases Periodicity Perioperative Persons Pneumothorax Postoperative Period Pre-Clinical Model Procedures Property Prospective Studies Pseudomonas aeruginosa Publishing Pulmonary Cystic Fibrosis Pulmonary Inflammation Quality of life Recurrence Regimen Regulator Genes Respiratory Failure Role Saline Sedation procedure Signal Transduction Slice Staphylococcus aureus Stimulant Stretching Structure of parenchyma of lung TLR2 gene TLR4 gene TLR5 gene Testing Time Toll-like receptors Transgenic Mice Transgenic Organisms Ventilator-induced lung injury Wild Type Mouse airway inflammation base body system clinical translation clinically significant comorbidity cystic fibrosis airway cystic fibrosis mouse cystic fibrosis patients cytokine drug testing experience experimental study functional disability high risk immunoregulation improved in vivo in vivo Model lung injury mortality mouse model neutrophil novel therapeutics pathogen preclinical study prototype pulmonary function receptor recruit respiratory response sedative

项目摘要

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.

项目概要囊性纤维化 (CF) 患者的中位生存年龄仍为 40 多岁，肺部恶化情况也很严重。这是 CF 患者死亡的主要原因，因为呼吸系统恶化会加重其病程。呼吸状态以不可逆转的方式发生，减轻任何并发症对于提高呼吸质量至关重要 CF 患者在生命的不同阶段接受手术和其他手术。经常经历与中性粒细胞介导的肺部炎症相关的呼吸道并发症。定植细菌和机械通气引起的损伤被认为是导致损伤的重要因素。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，刺激鞭毛蛋白可诱导激活的招募。中性粒细胞并导致肺损伤中性粒细胞活化也参与机械性肺损伤。我们的初步研究表明，挥发性麻醉剂会减弱 Toll 样受体 (TLR)5 和小鼠模型中鞭毛蛋白介导的肺损伤结果表明挥发性麻醉剂可能。减轻 CF 患者定植细菌引起的肺损伤通常需要全身麻醉。我们和其他人都使用挥发性麻醉剂和静脉麻醉剂来进行手术和其他手术。研究表明，挥发性麻醉剂具有免疫调节作用。我们之前的研究表明，麻醉剂可能会阻碍免疫功能正常的受试者中 TLR5 的激活。麻醉剂还会减弱粘附分子 β2 整合素。我们的初步数据表明 β2 整合素。参与通气引起的肺损伤本研究旨在检验我们的假设，即 CF 挥发性。麻醉剂会减弱 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这将在两个目标下进行研究：（目标 1）在体内 CF 临床前模型中确定麻醉药物对肺功能的作用（目标 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。成功完成提案后，我们将进行临床研究以确定最佳麻醉剂由于所有测试的药物均已投入临床使用，因此我们期望临床转化。此外，我们计划开发减轻肺损伤但缺乏的新药物。使用挥发性麻醉剂作为 CF 患者一般使用的原型的麻醉效果。研究至关重要，因为我们将评估麻醉剂在免疫功能低下的情况下的效果，即从临床角度来看，这是重要的信息，但尚未经过测试。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The Role of Pulmonary Function Test in Perioperative Management of Patients with Cystic Fibrosis.

肺功能测试在囊性纤维化患者围手术期管理中的作用。

DOI：
发表时间：
2022
期刊：
Translational perioperative and pain medicine
影响因子：
0
作者：
Manzor,Mariel;Asztalos,Gabor;Yuki,Koichi
通讯作者：
Yuki,Koichi

Anesthetics isoflurane and sevoflurane attenuate flagellin-mediated inflammation in the lung.

DOI：
10.1016/j.bbrc.2021.04.045
发表时间：
2021-06-11
期刊：
Biochemical and biophysical research communications
影响因子：
3.1
作者：
Yuki K;Mitsui Y;Shibamura-Fujiogi M;Hou L;Odegard KC;Soriano SG;Priebe GP;Koutsogiannaki S
通讯作者：
Koutsogiannaki S