Role of hypercapnia on the lung airways

高碳酸血症对肺气道的作用

• 批准号: 10115793
• 负责人: Jacob I Sznajder
• 金额: $ 46.01万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10115793
• 关键词: Acidosis; Actins; Acute; Affect; Applications Grants; Bacterial Infections; Blood; Bronchopulmonary Dysplasia; CASP7 gene; CSPG4 gene; Calcineurin; Calpain; Carbon Dioxide; Carotid Body; Cell physiology; Cells; Chronic; Chronic Obstructive Airway Disease; Chronic lung disease; Clinical; Cytoskeleton; Data; Deposition; Disease; Down-Regulation; DsRed; Exposure to; Extracellular Matrix; G Actin; Gases; Glomus Cell; Guidelines; Health; Human; Hypercapnia; Hypoxia; Immune response; Impairment; In Vitro; Individual; Intensive Care Units; Knockout Mice; Lead; Lung; Lung diseases; Morbidity - disease rate; Mus; Muscle; Muscle Contraction; Muscle function; Nitric Oxide; Outcome; Oxygen; PPP3CA gene; Partial Pressure; Pathway interactions; Patients; Preparation; Reporting; Research; Research Personnel; Role; Serum; Signal Pathway; Slice; Smooth Muscle Myocytes; Testing; Tissues; Transgenic Organisms; United States; Validation; Virus Diseases; adverse outcome; airway hyperresponsiveness; airway remodeling; alveolar epithelium; body sense; cofilin; connective tissue growth factor; design; experimental study; in vivo; insight; knock-down; mortality; novel; novel therapeutics; paxillin; polymerization; prevent; respiratory smooth muscle; transcriptome

Project Summary Oxygen and nitric oxide activate cellular signaling pathways, which are important in lung health and diseases. However, much less is known about the mechanisms by which lung cells (other than carotid bodies) sense and respond to changes in carbon dioxide (CO2) concentrations. An increase in the levels of CO2 (hypercapnia) is often a consequence of impaired gas exchange in lung diseases such as chronic obstructive pulmonary disease (COPD) and others. Approximately 17 million individuals in the US are afflicted by COPD, which now is the 3rd leading cause of overall mortality worldwide. Several studies have reported that patients with COPD and hypercapnia have worse outcomes. However, hypercapnia in patients with lung diseases is largely tolerated as there is still the notion that the effects of hypercapnia are not harmful to the lungs. Recent studies, including our own, have demonstrated that elevations in CO2 activate specific intracellular signaling pathways with adverse consequences for lung and organismal functions. We have conducted experiment using unbiased, hypotheses-generating, as well as hypotheses-driven approaches, which have generated preliminary data on the effects of hypercapnia on the lungs airways. Our preliminary results in preparation for this grant application suggest that high CO2 levels activate specific signaling pathways leading to changes in airway contractility. As such, we propose to elucidate the signaling pathways and mechanisms by which hypercapnia increases airway contractility and smooth muscle cell function via three interrelated specific aims. In experiments pertaining specific aim 1, we will determine whether hypercapnia increases airway smooth muscle contraction via activation of caspase-7 and downregulation of miR-133a-MEF2D. In studies pertaining specific aim 2, we will determine whether hypercapnia increases actin polymerization and thus airway smooth muscle contractility via RhoA and calcineurin and in studies pertaining specific aim 3, we will determine hypercapnia promotes airway remodeling by increasing αSMA and extracellular matrix via RhoA-SRF and/or Wnt-CTGF pathway. Completion of the proposed experiments will provide novel information on signaling pathways and mechanisms by which high CO2 levels lead to lung airways hyperreactivity, which is of importance for patients with chronic lung diseases such as COPD and hypercapnia.

项目摘要 氧气和一氧化氮激活细胞信号通路，这对肺部健康很重要 和疾病。然而，对肺细胞（其他细胞） 比颈动脉体）感知并响应二氧化碳（CO2）浓度的变化。一个 CO2（高碳酸血症）水平的增加通常是由于 肺部疾病，如慢性阻塞性肺病（COPD）等。 美国约有1700万人患有COPD，目前是第三大慢性阻塞性肺病。 是全球死亡率的主要原因。一些研究报告称， COPD和高碳酸血症的预后更差。然而，肺结核患者的高碳酸血症 疾病在很大程度上是可以耐受的，因为仍然存在高碳酸血症的影响不是 对肺部有害。最近的研究，包括我们自己的研究，已经表明， CO2激活特定的细胞内信号通路，对肺和 有机体功能我们已经进行了实验，使用无偏见的，假设生成， 以及假设驱动的方法，这些方法已经产生了关于影响的初步数据， 高碳酸血症的症状我们在准备这笔赠款的初步结果 应用表明，高CO2水平激活特定的信号通路，导致变化 呼吸道收缩性。因此，我们建议阐明信号通路， 高碳酸血症增加气道收缩性和平滑肌细胞的机制 通过三个相互关联的具体目标发挥作用。在关于具体目标1的实验中，我们将 确定高碳酸血症是否通过 caspase-7的激活和miR-133 a-MEF 2D的下调。在研究中， 具体目标2，我们将确定是否高碳酸血症增加肌动蛋白聚合 从而通过RhoA和钙调神经磷酸酶调节气道平滑肌收缩， 关于具体目标3，我们将确定高碳酸血症通过以下方式促进气道重塑： 通过RhoA-SRF和/或Wnt-CTGF途径增加αSMA和细胞外基质。 这些实验的完成将为信号通路提供新的信息 以及高CO2水平导致肺气道高反应性的机制， 这对慢性肺病患者如COPD和高碳酸血症的重要性。