The deleterious effects of hypercapnia on the lungs

高碳酸血症对肺部的有害影响

基本信息

批准号：
8817060
负责人：
Jacob I Sznajder
金额：
$ 40.09万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-07-01 至 2018-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8817060
关键词：
Acidosis Acids Actins Acute Acute Lung Injury Adult Respiratory Distress Syndrome Alveolar Animal Model Applications Grants Blood Bronchopulmonary Dysplasia Carbon Dioxide Cell Migration Inhibition function Cell Proliferation Cell Respiration Cell model Chronic Chronic Obstructive Airway Disease Chronic lung disease Citric Acid Cycle Clinical Clinical Trials Cyclic AMP-Dependent Protein Kinases Cystic Fibrosis Data Data Reporting Dysplasia Environmental air flow Enzymes Epithelial Epithelial Cells Event Exposure to Fiber Fibroblasts Functional disorder Gases Grant Guanine Nucleotide Exchange Factors Hypercapnia Hypoxia Immunity Impairment In Vitro Intensive Care Units Intervention Isocitrate Dehydrogenase LIMK1 gene Lead Liquid substance Lung Lung diseases MAPK8 gene Mechanical ventilation Mediating MicroRNAs Modeling Molecular Morbidity - disease rate Mus Muscle Muscle Fibers Muscle satellite cell Natural regeneration Neuromuscular Diseases Outcome Partial Pressure Pathway interactions Patients Phosphorylation Preparation Publications Publishing Recovery Regulation Reporting Respiratory Diaphragm Respiratory physiology Rodent Role Signal Pathway System Testing Ubiquitin Ubiquitin-Proteasomal Pathway Validation Wound Healing alveolar epithelium cell motility clinically relevant clinically significant cofilin in vivo in vivo Model injured injury and repair insight knock-down lung injury migration mortality multicatalytic endopeptidase complex muscle regeneration novel planetary Atmosphere public health relevance repaired research study satellite cell

项目摘要

DESCRIPTION (provided by applicant): Hypercapnia (high pCO2) is observed in patients with lung diseases such as chronic obstructive pulmonary disease (COPD), cystic fibrosis, broncho-pulmonary dysplasia and advanced neuromuscular diseases. Also, a ventilation strategy that includes "permissive hypercapnia" is commonly used in mechanically ventilated patients with the acute respiratory distress syndrome (ARDS). Data from our group and others have challenged the existing paradigm suggesting that hypercapnia is beneficial for patients with ARDS. Instead, we have reported that elevated levels of CO2 have direct, deleterious effects on alveolar epithelial function and host immunity. Our published reports and data from preliminary studies in preparation for this proposal support our hypothesis that high levels of CO2 decrease alveolar epithelial cell migration and proliferation in the injured lung, thus, impairing lung injuy repair. Furthermore, we hypothesize that hypercapnia promotes the ubiquitin-proteasome mediated degradation of diaphragmatic myofibers and impairs the function of muscle satellite cells required for its regeneration. As such, in this application we propose to determine the mechanisms by which hypercapnia leads to impaired recovery from lung injury and the effect of high CO2 on diaphragm muscle degradation and impaired regeneration. We will test these hypotheses in three interrelated aims: in experiments pertaining to specific aim # 1, we will determine whether hypercapnia-mediated inhibition of GEFs-Rac1 leads to impaired cell migration; in experiments pertaining to specific aim #2, we will determine whether high CO2 via the miR-183/96/182 cluster impairs alveolar epithelial cell migration in vitro and lung injury repar in vivo; and in studies pertaining to specific aim # 3, we will determine whether hypercapnia leads to diaphragm dysfunction causing muscle degradation via the ubiquitin/proteasomal pathway and impaired muscle regeneration. We have conducted preliminary experiments for each of the specific aims which support the feasibility of this grant proposal. The proposed experiments will generate novel information on the mechanisms by which exposure to hypercapnia impairs alveolar epithelial and diaphragm function, which is of clinical significance for patients with ARDS who require mechanical ventilation and patients with chronic lung diseases and hypercapnia.

描述（由申请人提供）：高碳酸血症（高 pCO2）见于患有肺部疾病的患者，例如慢性阻塞性肺病（COPD）、囊性纤维化、支气管肺发育不良和晚期神经肌肉疾病。此外，包括“允许性高碳酸血症”在内的通气策略通常用于患有急性呼吸窘迫综合征（ARDS）的机械通气患者。我们小组和其他人的数据挑战了现有的范式，表明高碳酸血症对 ARDS 患者有益。相反，我们报告说，二氧化碳水平升高会对肺泡上皮功能和宿主免疫产生直接的有害影响。我们发表的报告和为该提案做准备的初步研究数据支持我们的假设，即高水平的二氧化碳会减少受损肺中的肺泡上皮细胞迁移和增殖，从而损害肺损伤修复。此外，我们假设高碳酸血症会促进泛素蛋白酶体介导的膈肌纤维降解，并损害其再生所需的肌肉卫星细胞的功能。因此，在本申请中，我们建议确定高碳酸血症导致肺损伤恢复受损的机制，以及高二氧化碳对膈肌退化和再生受损的影响。我们将在三个相互关联的目标中测试这些假设：在与特定目标 #1 相关的实验中，我们将确定高碳酸血症介导的 GEFs-Rac1 抑制是否会导致细胞迁移受损；在与特定目标#2相关的实验中，我们将确定通过miR-183/96/182簇的高CO2是否会损害体外肺泡上皮细胞迁移和体内肺损伤修复；在与具体目标#3相关的研究中，我们将确定高碳酸血症是否会导致膈肌功能障碍，从而通过泛素/蛋白酶体途径导致肌肉退化和肌肉再生受损。我们对每个具体目标进行了初步实验，以支持该拨款提案的可行性。拟议的实验将产生有关高碳酸血症损害肺泡上皮和膈肌功能的机制的新信息，这对于需要机械通气的 ARDS 患者以及患有慢性肺病和高碳酸血症的患者具有临床意义。