Role of hypercapnia on the lung airways

高碳酸血症对肺气道的作用

• 批准号: 9903435
• 负责人: Jacob I Sznajder
• 金额: $ 46.72万
• 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/9903435
• 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 氧和一氧化氮激活细胞信号通路，这对肺健康很重要 和疾病。然而，人们对肺细胞(其他 而不是颈动脉体部)感知二氧化碳(CO2)浓度的变化并对其做出反应。一个 二氧化碳水平的增加(高碳酸血症)通常是体内气体交换受损的结果 肺部疾病，如慢性阻塞性肺疾病(COPD)和其他。 在美国，大约有1700万人患有慢性阻塞性肺病，现在是第三位。 世界范围内总死亡率的主要原因。多项研究报告称，患有 慢性阻塞性肺病和高碳酸血症的预后更差。然而，肺部患者的高碳酸血症 疾病在很大程度上是可以容忍的，因为仍然有这样的观念，即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，已经证明了 二氧化碳激活特定的细胞内信号通路，对肺和 生物体功能。我们已经进行了实验，使用的是公正的、产生假设的、 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 肺部和呼吸道的高碳酸血症。我们为这笔赠款做准备的初步结果 应用表明，高二氧化碳水平激活了导致变化的特定信号通路 在呼吸道的收缩能力上。因此，我们建议阐明信号通路和 高碳酸血症增加气道收缩功能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。在关于特定目标1的实验中，我们将 确定高碳酸血症是否通过以下途径增加气道平滑肌收缩 Caspase-7的激活和miR-133a-MEF2D的下调。在有关的研究中 具体目标2，我们将确定高碳酸血症是否会增加肌动蛋白聚合 因此，通过RhoA和钙调神经磷酸酶实现的气道平滑肌收缩能力和研究 关于特定目标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α-SRF和/或WnT-CTGF途径增加RhoA-SRF和/或WnT-CTGF细胞外基质。 拟议实验的完成将提供有关信号通路的新信息 以及高二氧化碳水平导致肺气道高反应性的机制，这是 对于患有慢性阻塞性肺病和高碳酸血症等慢性肺部疾病的患者来说很重要。