Adenosine Regulation of Alveolar Fluid Homeostasis

腺苷对肺泡液稳态的调节

基本信息

批准号：
7333233
负责人：
Phillip H Factor
金额：
$ 37.88万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-01-01 至 2009-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7333233
关键词：
Acceleration Active Biological Transport Acute Acute Lung Injury Acute respiratory failure Address Adenine Nucleotides Adenosine Adenoviruses Adenylate Cyclase Adrenergic Agonists Adrenergic Receptor Affect Affinity Agonist Alveolar Alveolus Attenuated Binding Biological Biological Assay Biosensor Brain Bronchoalveolar Lavage Fluid Caffeine Cardiogenic Shock Carrier Proteins Catecholamine Receptors Catecholamines Cell physiology Cells Clinical Complement Consumption Critical Illness Culture Media Cyclic AMP Cystic Fibrosis Transmembrane Conductance Regulator Data Databases Development Distal Down-Regulation Edema Energy Supply Ensure Environment Epithelial Epithelial Cells Exposure to Extracellular Space Family Feedback Figs - dietary Gases Gene Transfer Genetically Engineered Mouse Guanosine Triphosphate Heart Homeostasis Human Hyperoxia Ice Immune system Impairment In Vitro Injury Investigation Kidney Knowledge Lead Link Liquid substance Location Lung Measurement Measures Mediating Membrane Metabolic Metabolism Methods Modeling Molecular Mus Na(+)-K(+)-Exchanging ATPase Ouabain Oxygen Pathway interactions Patients Physiological Physiological Processes Plasma Polymerase Chain Reaction Preparation Principal Investigator Procaterol Process Production Protein Biosynthesis Protein Overexpression Proteins Pulmonary Edema Purine Nucleosides Purinergic P1 Receptors Purpose Range Rattus Receptor Activation Receptor Signaling Recombinants Regulation Resolution Respiratory Failure Respiratory physiology Role Sepsis Signal Transduction Signal Transduction Pathway Signaling Molecule Source Structure Structure of parenchyma of lung System Testing Time Trauma Triiodothyronine Receptors Up-Regulation Water adenosine deaminase adenoviral-mediated alveolar epithelium analog autocrine base beta-2 Adrenergic Receptors body system experience extracellular improved in vivo in vivo Model indexing inhibitor/antagonist injured lung injury mouse model novel paracrine physiologic model programs protein function receptor receptor binding receptor function repaired research study response tool uptake vpr Genes

项目摘要

DESCRIPTION (provided by applicant): Pulmonary edema is removed from the alveolar airspace by active Na+ transport by alveolar epithelial cells. It is intuitive that active transport increases epithelial cell energy consumption at times when cellular energy stores could be compromised. Data from a variety of experimental systems indicate that cells match energy consumption with energy supply by reducing active Na+ transport when energy stores are reduced. To date no such counter-regulatory mechanisms have been described in alveolar epithelial cells. Adenosine is produced from metabolism of AMP when intracellular ATP consumption and/or cAMP production are high. We speculate that increased levels of cAMP (from b-receptor signaling) and AMP/ADP (from Na,K-ATPase activity) in the setting of lung injury provide substrate for adenosine production in the alveolus. We recently noted that adenosine has concentration dependent, bidirectional effects on alveolar active Na+ transport in isolated rat lungs. Specifically, low concentrations of adenosine (=10-8M) increase alveolar active Na+ transport by ~100% via type 2a adenosine receptors (A2aR) whereas high concentrations (=10-6M) reduce it via type 1 adenosine receptors (A1R). We have also identified these receptors in distal rat and mouse lung tissue and isolated rat and mouse alveolar type 2 epithelial cells. These new observations are the first descriptions of a role for adenosine and its receptors in the alveolar epithelium and the first autocrine/paracrine mechanism that conditionally up- and down-regulates alveolar epithelial active Na+ transport. Based on this preliminary data, we hypothesize that: Alveolar epithelial adenosine receptors participate in the regulation of active Na+ transport in normal and injured lungs. The known inter-relationship of adenosine with cAMP production and ATP consumption and our preliminary data cause us to propose a new paradigm of regulation of alveolar active Na+ transport. Specifically, we believe that in normal lung alveolar adenosine concentrations in the extracellular space are low and serve as a positive modulator of alveolar active Na+ transport, probably via an A2aR dependent pathway. Conversely, during lung injury high ATP utilization and cAMP production lead to extracellular adenosine concentrations sufficient to inhibit adenylyl cyclase and reduce active transport via an A1R dependent pathway. This model suggests that adenosine and its receptors participate in a feedback loop that allows alveolar epithelial cells to fine tune cAMP sensitive active Na+ transport in response to changes in ATP utilization and/or cAMP production. To test our hypothesis we are proposing the following 3 scientific aims: Aim 1: Characterize adenosine receptors in the alveolar epithelium and determine if, and how, they regulate alveolar active Na+ transport in normal lungs. Aim 2: Determine the mechanism(s) by which adenosine receptors modulate alveolar active Na+ transport. Aim 3: Determine if alveolar epithelial adenosine receptor signaling is protective or maladaptive during acute lung injury. The focused studies we are proposing integrate pharmacologic manipulations, genetically engineered mice, and gene transfer with physiologic models to generate models of gain and loss of epithelial adenosine receptor function that will allow us to test our hypothesis and to determine if adenosine receptors serve protective or maladaptive roles in the alveolar epithelium.

描述（由申请人提供）：通过肺泡上皮细胞的主动 Na+ 转运，从肺泡空腔中消除肺水肿。直观的是，当细胞能量储存可能受到损害时，主动运输会增加上皮细胞的能量消耗。来自各种实验系统的数据表明，当能量储存减少时，细胞通过减少活性Na+运输来使能量消耗与能量供应相匹配。迄今为止，肺泡上皮细胞中尚未描述过此类反调节机制。当细胞内 ATP 消耗和/或 cAMP 产生较高时，腺苷由 AMP 代谢产生。我们推测，肺损伤时 cAMP（来自 b 受体信号传导）和 AMP/ADP（来自 Na,K-ATP 酶活性）水平升高为肺泡中腺苷的产生提供了底物。我们最近注意到，腺苷对离体大鼠肺中的肺泡活性 Na+ 转运具有浓度依赖性、双向作用。具体来说，低浓度的腺苷 (=10-8M) 通过 2a 型腺苷受体 (A2aR) 将肺泡活性 Na+ 转运增加约 100%，而高浓度 (=10-6M) 通过 1 型腺苷受体 (A1R) 减少肺泡活性 Na+ 转运。我们还在大鼠和小鼠远端肺组织以及分离的大鼠和小鼠肺泡 2 型上皮细胞中鉴定了这些受体。这些新观察结果首次描述了腺苷及其受体在肺泡上皮中的作用，以及第一个有条件上调和下调肺泡上皮活性Na+转运的自分泌/旁分泌机制。基于这些初步数据，我们假设：肺泡上皮腺苷受体参与正常和受损肺中活性 Na+ 转运的调节。已知的腺苷与 cAMP 产生和 ATP 消耗的相互关系以及我们的初步数据使我们提出了一种调节肺泡活性 Na+ 转运的新范式。具体来说，我们认为，在正常肺泡中，细胞外空间的腺苷浓度较低，并且可能通过 A2aR 依赖性途径，作为肺泡活性 Na+ 转运的正调节剂。相反，在肺损伤期间，高 ATP 利用率和 cAMP 产生导致细胞外腺苷浓度足以抑制腺苷酸环化酶并减少通过 A1R 依赖性途径的主动转运。该模型表明，腺苷及其受体参与反馈环路，使肺泡上皮细胞能够微调 cAMP 敏感的活性 Na+ 转运，以响应 ATP 利用和/或 cAMP 产生的变化。为了检验我们的假设，我们提出以下 3 个科学目标：目标 1：表征肺泡上皮中的腺苷受体，并确定它们是否以及如何调节正常肺中的肺泡活性 Na+ 转运。目标 2：确定腺苷受体调节肺泡活性 Na+ 转运的机制。目标 3：确定肺泡上皮腺苷受体信号传导在急性肺损伤期间是保护性的还是适应不良的。我们提出的重点研究将药理学操作、基因工程小鼠和基因转移与生理模型结合起来，以生成上皮腺苷受体功能获得和丧失的模型，这将使我们能够检验我们的假设并确定腺苷受体是否起到保护作用或适应不良作用在肺泡上皮细胞中的作用。