Extracellular Adenosine During Ventilator Induced Lung Injury

呼吸机引起的肺损伤期间的细胞外腺苷

• 批准号: 7778925
• 负责人: Holger K. Eltzschig
• 金额: $ 36.69万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7778925
• 关键词: ADORA3 gene; Acute; Acute Lung Injury; Adenine; Adenosine; Agonist; Alveolar; Amiloride; Area; Attenuated; Blood capillaries; Bone Marrow; Capillary Permeability; Critical Illness; Data; Edema; Endothelium; Epithelium; Equilibrium; Extravasation; Gene Deletion; Gene Targeting; Generations; Hypoxemia; Hypoxia; In Vitro; Individual; Inflammation; Inflammatory; Inflammatory Response; Injury; Investigation; Kinetics; Light; Link; Liquid substance; Lung; Mechanical ventilation; Mechanics; Metabolic Pathway; Molecular; Morbidity - disease rate; Mus; Myelogenous; Nosocomial Infections; Nucleotides; Outcome; Pathogenesis; Pathway interactions; Patients; Pneumonia; Prevention; Principal Investigator; Process; Production; Proteins; Pulmonary Edema; Purinergic P1 Receptors; Reaction; Regulation; Repression; Research; Respiratory Failure; Role; Severities; Signal Transduction; Site; Source; Stretching; Supportive care; Surface; Syndrome; Therapeutic; Tissues; Ventilator-induced lung injury; Work; attenuation; base; capillary; ecto-nucleotidase; expectation; extracellular; improved; in vitro Model; in vivo; inhibitor/antagonist; interstitial; mortality; novel; programs; public health relevance

DESCRIPTION (provided by applicant): Extracellular nucleotides liberated at inflammatory tissue sites are metabolized to adenosine by surface expressed ecto-nucleotidases (CD73 and CD39). Ongoing studies indicate that adenosine liberated by this process is available to activate surface adenosine receptors (A1AR, A2AAR, A2BAR, A3AR), and has been shown to attenuate acute lung injury. In the present study, we will use in vitro models of mechanical stretch and murine ventilator induced lung injury to study adenosine-tissue protection during ALI. Preliminary studies indicate a contribution of pulmonary CD39 and CD73 as control points for generation of extracellular adenosine during VILI. Moreover, studies in gene-targeted mice for individual ARs suggest a prominent role of A2BAR signaling for lung protection during VILI. Thus, we will pursue work toward: A) Defining details of extracellular adenosine generation during mechanical stretch or VILI; B) Define transcriptonal regulation and consequences of signaling through ARs during VILI; and C) Extend evidence for a role of adenosine generation and signaling as therapy of VILI. We expect that these studies will shed new light on molecular mechanisms through which cyclic stretch as occurs during mechanical ventilation elevates extracellular adenosine levels as a tissue protective mechanism. We will have developed strategies that utilize these mechanisms to attenuate inflammation and capillary-alveolar leakage during VILI. Taken together, these studies will lay the groundwork for novel and specific therapeutic approaches in the treatment of acute lung injury. PUBLIC HEALTH RELEVANCE: These studies will lay the groundwork for novel and specific therapeutic approaches in the treatment of acute lung injury.

描述（由申请人提供）：在炎症组织部位释放的细胞外核苷酸通过表面表达的核酸外切酶（CD73和CD39）代谢为腺苷。正在进行的研究表明，这一过程释放的腺苷可激活表面腺苷受体（A1AR、A2AAR、A2BAR、A3AR），并已被证明可以减轻急性肺损伤。在本研究中，我们将使用机械拉伸和小鼠呼吸机诱导的肺损伤的体外模型来研究 ALI 期间的腺苷组织保护。初步研究表明肺 CD39 和 CD73 作为 VILI 期间细胞外腺苷生成的控制点。此外，对基因靶向小鼠的个体 AR 的研究表明，A2BAR 信号在 VILI 期间的肺保护中发挥着重要作用。因此，我们将致力于：A) 定义机械拉伸或 VILI 过程中细胞外腺苷生成的细节； B) 定义 VILI 期间通过 AR 进行的转录调控和信号传导后果； C) 扩展腺苷生成和信号转导作为 VILI 治疗作用的证据。我们期望这些研究将为机械通气期间发生的循环拉伸提高细胞外腺苷水平作为组织保护机制的分子机制提供新的线索。我们将制定利用这些机制来减轻 VILI 期间炎症和毛细血管肺泡渗漏的策略。总而言之，这些研究将为治疗急性肺损伤的新颖且具体的治疗方法奠定基础。公众健康相关性：这些研究将为治疗急性肺损伤的新颖且具体的治疗方法奠定基础。