Resident Leukocytes in Lung Ischemia-Reperfusion Injury

肺缺血再灌注损伤中的驻留白细胞

• 批准号: 6919071
• 负责人: Victor E Laubach
• 金额: $ 37.34万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-05-01 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6919071
• 关键词: alveolar macrophages; chemokine; cytokine; genetic transcription; laboratory mouse; leukocyte activation /transformation; leukocytes; lung injury; lung ischemia /hypoxia; lung transplantation; macrophage; nuclear factor kappa beta; pathologic process; purinergic receptor; receptor expression

DESCRIPTION (PROVIDED BY APPLICANT): Although there has been considerable progress in lung transplant biology, post-transplant ischemia-reperfusion (IR) injury remains the major source of early mortality. Although circulating leukocytes are known to be important in lung IR injury, the role of resident lung leukocytes remains unknown. Thus our long-term goal is to understand the mechanisms of cytokine- and leukocyte-mediated acute lung IR injury. This Project focuses on the role of resident, interstitial lung leukocytes and cytokine mediators in the early phase of lung IR injury by using an in situ, buffer-perfused mouse lung IR model. This project will test the overall hypothesis that it is primarily the resident pulmonary macrophages which are activated by IR, produce TNF-alpha, and set the stage for initiation of full-blown lung IR injury. In addition, inhibition of macrophage activation by ATL- 303 activation of adenosine A2A receptors should ameliorate the majority of acute lung IR injury. Specific Aim 1 will identify the resident lung leukocytes (macrophages, neutrophils, lymphocytes) that are critical for induction of the early, acute phase of lung IR injury. We hypothesize that acute lung IR injury is primarily initiated by the pulmonary macrophages. Specific Aim 2 will determine key early transcriptional events (NF-kappaB activation) and cytokine/ chemokine activation (TNF-alpha, IFN-gamma, IL-1, MIP-1alpha, MCP-1, and RANTES) leading to acute lung IR injury, and identify the responsible leukocytes. We hypothesize that injury is largely, but not solely, initiated by macrophage-produced TNF-alpha and TNF-alpha-mediated signaling via cytokines, chemokines, and transcription factors. Specific Aim 3 will determine if activation of adenosine A2A receptors on resident leukocytes ameliorates acute lung IR injury independent of circulating leukocytes. We hypothesize that A2A receptor activation primarily on pulmonary macrophages will ameliorate lung IR injury independent of circulating leukocytes. Even in the most experienced hospitals, IR injury continues to be a major cause of morbidity and mortality early after lung transplantation. The proposed studies will directly address the causes IR injury with the hopes of initiating further studies focusing on therapeutic strategies aimed at preventing or ameliorating acute lung IR injury.

描述（申请人提供）：尽管肺移植生物学已经取得了相当大的进展，但移植后缺血再灌注（IR）损伤仍然是早期死亡的主要原因。虽然循环中的白细胞在肺IR损伤中是重要的，但肺内白细胞的作用仍不清楚。因此，我们的长期目标是了解细胞因子和白细胞介导的急性肺IR损伤的机制。本研究利用原位缓冲液灌注的小鼠肺IR模型，探讨肺间质白细胞和细胞因子在肺IR早期损伤中的作用。本项目将检验总体假设，即主要是驻留的肺巨噬细胞被IR激活，产生TNF-α，并为全面的肺IR损伤的启动奠定基础。此外，通过腺苷A2 A受体的ATL- 303活化抑制巨噬细胞活化应改善大部分急性肺IR损伤。 具体目标1将确定对诱导肺IR损伤的早期急性期至关重要的驻留肺白细胞（巨噬细胞、中性粒细胞、淋巴细胞）。我们推测急性肺IR损伤主要由肺巨噬细胞启动。 特异性目标2将确定导致急性肺IR损伤的关键早期转录事件（NF-κ B活化）和细胞因子/趋化因子活化（TNF-α、IFN-γ、IL-1、MIP-1 α、MCP-1和RANTES），并鉴定负责的白细胞。我们推测损伤主要是由巨噬细胞产生的TNF-α和TNF-α通过细胞因子、趋化因子和转录因子介导的信号传导引起的。 特异性目的3将确定驻留白细胞上的腺苷A2 A受体的活化是否独立于循环白细胞而改善急性肺IR损伤。我们假设，A2 A受体活化主要对肺巨噬细胞将改善肺IR损伤独立于循环白细胞。 即使在最有经验的医院，IR损伤仍然是肺移植后早期发病和死亡的主要原因。这些研究将直接探讨肺缺血再灌注损伤的原因，并希望能进一步研究预防或改善急性肺缺血再灌注损伤的治疗策略。