Adenosine Regulation of Alveolar Fluid Homeostasis

腺苷对肺泡液稳态的调节

• 批准号: 6998411
• 负责人: Phillip H Factor
• 金额: $ 39.01万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-01-01 至 2008-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6998411
• 关键词: active transport; adenosine; adenosine triphosphate; biological signal transduction; chemical structure function; cyclic AMP; disease /disorder model; fluid; homeostasis; intermolecular interaction; ion transport; laboratory mouse; laboratory rat; lung injury; metabolism; molecular pathology; protein localization; purinergic receptor; respiratory epithelium; sodium ion

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（由申请方提供）：肺水肿通过肺泡上皮细胞的主动Na+转运从肺泡气隙中清除。直观地，当细胞能量储存可能受损时，主动转运增加上皮细胞能量消耗。 来自各种实验系统的数据表明，当能量储存减少时，细胞通过减少主动Na+运输来使能量消耗与能量供应相匹配。到目前为止，还没有这样的反调节机制已被描述在肺泡上皮细胞。当细胞内ATP消耗和/或cAMP产生高时，腺苷由AMP代谢产生。我们推测，在肺损伤的情况下，cAMP（来自b-受体信号）和AMP/ADP（来自Na，K-ATP酶活性）水平的增加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肺泡主动Na+转运具有浓度依赖性的双向作用。 具体而言，低浓度腺苷（=10- 8 M）通过2a型腺苷受体（A2 aR）使肺泡主动Na+转运增加约100%，而高浓度腺苷（=10- 6 M）通过1型腺苷受体（A1 R）使其减少。 我们还确定了这些受体在远端大鼠和小鼠肺组织和分离的大鼠和小鼠肺泡2型上皮细胞。 这些新的观察结果是第一个描述的作用，腺苷及其受体在肺泡上皮细胞和第一个自分泌/旁分泌机制，有条件地上调和下调肺泡上皮细胞的主动Na+运输。 基于这些初步的数据，我们假设：肺泡上皮腺苷受体参与了正常和受损肺主动钠离子转运的调节。腺苷与cAMP产生和ATP消耗的已知相互关系以及我们的初步数据使我们提出了一种新的肺泡主动Na+转运调节范式。具体而言，我们认为，在正常肺肺泡腺苷浓度在细胞外空间是低的，并作为一个积极的调节器肺泡主动Na+运输，可能通过A2 aR依赖性途径。 相反，在肺损伤期间，高ATP利用和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A1 R依赖性途径的主动转运。该模型表明，腺苷及其受体参与了一个反馈回路，允许肺泡上皮细胞微调cAMP敏感的主动Na+转运，以响应ATP利用和/或cAMP产生的变化。为了验证我们的假设，我们提出了以下3个科学目标：目标1：表征肺泡上皮细胞中的腺苷受体，并确定它们是否以及如何调节正常肺中的肺泡主动Na+转运。 目的2：探讨腺苷受体调节肺泡主动钠转运的机制。目的3：确定肺泡上皮腺苷受体信号在急性肺损伤中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相结合，以产生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，并确定腺苷受体在肺泡上皮中是否起保护作用或适应不良作用。