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Resident Leukocytes in Lung Ischemia-Reperfusion Injury

肺缺血再灌注损伤中的驻留白细胞

基本信息

批准号：
7227088
负责人：
Victor E Laubach
金额：
$ 36.15万
依托单位：
UNIVERSITY OF VIRGINIA
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：
2005-05-01 至 2009-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7227088
关键词：
3-nitrotyrosine Acute Address Adenosine Adenosine A2A Receptor Adoptive Transfer Affect Agonist Airway Resistance Alveolar Macrophages Antioxidants Biology Blood Vessels Bone Marrow Buffers CCL2 gene Cells Cytokine Activation Data Event Exhibits Extravasation Genetic Glycine Goals Hepatic Histology Hospitals IL8 gene In Situ Inflammatory Injury Interferon Type II Interleukin-1 Interleukin-1 Receptors Interleukin-6 Intervention Ischemia Kidney Knock-out Knockout Mice Leukocytes Lipid Peroxidation Liquid substance Lung Lung Compliance Lung Transplantation Lymphocyte Macrophage Activation Measurement Measures Mediating Mediator of activation protein Modeling Morbidity - disease rate Mus NF-kappa B Oxidative Stress Pattern Phase Physiological reperfusion Population Production Pulmonary artery structure RANTES Receptor Activation Reperfusion Injury Reperfusion Therapy Research Personnel Resistance Respiratory Burst Respiratory physiology Role Signal Transduction Small Inducible Cytokine A3 Source Staging Sulfhydryl Compounds T-Lymphocyte Testing Therapeutic Tissues Transcription Factor AP-1 Transplantation Tumor Necrosis Factor-alpha Wild Type Mouse activating transcription factor cell type chemokine cytokine experience granulocyte human TNF protein improved interstitial knockout gene lung injury lung ischemia macrophage monocyte mortality mouse model neutrophil novel pressure prevent programs receptor reconstitution transcription factor

项目摘要

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。尽管已知循环白细胞在肺IR损伤中很重要，但驻留的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。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，ATL- 303激活腺苷A2 A受体对巨噬细胞激活的抑制应该可以改善大部分急性肺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。