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（由申请人提供）：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来源。尽管已知循环白细胞在肺IR损伤中很重要，但常驻肺白细胞的作用仍然未知。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。该项目通过使用原位缓冲液灌注小鼠肺 IR 模型，重点研究常驻肺间质白细胞和细胞因子介质在肺 IR 损伤早期的作用。该项目将测试总体假设，即主要是常驻肺巨噬细胞被 IR 激活，产生 TNF-α，并为全面的肺 IR 损伤的启动做好准备。此外，通过腺苷A2A受体的ATL-303激活来抑制巨噬细胞激活应该可以改善大多数急性肺IR损伤。 具体目标 1 将识别对诱导肺 IR 损伤早期急性期至关重要的常驻肺白细胞（巨噬细胞、中性粒细胞、淋巴细胞）。我们假设急性肺IR损伤主要是由肺巨噬细胞引发的。 具体目标 2 将确定导致急性肺 IR 损伤的关键早期转录事件（NF-κB 激活）和细胞因子/趋化因子激活（TNF-α、IFN-γ、IL-1、MIP-1α、MCP-1 和 RANTES） ，并确定负责的白细胞。我们假设损伤主要（但不仅仅是）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发。 具体目标 3 将确定驻留白细胞上腺苷 A2A 受体的激活是否可以独立于循环白细胞改善急性肺 IR 损伤。我们假设主要在肺巨噬细胞上激活 A2A 受体将改善肺 IR 损伤，而与循环白细胞无关。 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。拟议的研究将直接解决 IR 损伤的原因，希望启动进一步的研究，重点关注旨在预防或改善急性肺 IR 损伤的治疗策略。