Macrophage Apoptosis in Resolution of Acute Lung Injury

巨噬细胞凋亡在缓解急性肺损伤中的作用

• 批准号: 8528053
• 负责人: William Janssen
• 金额: $ 10.04万
• 依托单位: NATIONAL JEWISH HEALTH
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8528053
• 关键词: 2,4-thiazolidinedione; Ablation; Accounting; Acute Lung Injury; Address; Adult Respiratory Distress Syndrome; Affect; Alveolar Macrophages; Animal Model; Apoptosis; Apoptotic; Area; Bilateral; CASP8 and FADD-like apoptosis regulating protein; Caspase Inhibitor; Cell Death; Cells; Cessation of life; Cicatrix; Development; Disease; Down-Regulation; Exhibits; Fibrosis; Functional disorder; Hamman-Rich syndrome; Health Care Costs; Hospitalization; Hour; Hypoxemia; Individual; Inflammation; Injury; Insulin-Like Growth Factor I; Lead; Length of Stay; Liquid substance; Lung; Mediating; Modeling; Multivariate Analysis; Mus; Normal tissue morphology; Patients; Peptides; Pioglitazone; Play; Process; Procollagen; Recovery; Recruitment Activity; Resistance; Resolution; Role; Signal Transduction; Source; Structure; Survivors; Testing; Thiazolidinediones; Time; Transforming Growth Factors; Transgenic Mice; United States; United States National Institutes of Health; base; functional restoration; inhibitor/antagonist; insight; lung injury; macrophage; monocyte; mortality; mouse model; novel; novel therapeutics; peripheral blood; prevent; receptor; research study; response

PROJECT SUMMARY / ABSTRACT Acute lung injury (ALI) and its more severe form, the acute respiratory distress syndrome (ARDS), are characterized by bilateral pulmonary infiltrates of non-cardiac origin and severe arterial hypoxemia. These diseases account for nearly 200,000 hospitalizations and 75,000 deaths in the United States each year. Despite recent advances, mortality remains high and the majority of survivors suffer from persistent pulmonary dysfunction and lung fibrosis. Animal models have yielded important insights into the mechanisms that initiate lung injury, however few studies have focused on the processes that drive its resolution. In this regard, we believe that macrophages play a pivotal role. There is abundant accumulation of macrophages in the lungs during early ALI. In patients with non-resolving ALI, macrophages persist and serve as a rich source of pro- fibrotic molecules including transforming growth factor-¿ (TGF-¿). In mouse models of self-limited ALI, macrophages undergo apoptosis that is driven by Fas. Conversely in ALI models characterized by persistent inflammation and fibrosis, macrophage apoptosis is difficult to detect. These observations form the basis for our central hypothesis that macrophage apoptosis is required for the resolution of ALI and that macrophage resistance to apoptosis results in fibrosis. Aim 1 will test this hypothesis in mouse models of self-limited and non-resolving ALI by: a) systemically administering caspase inhibitors to inhibit macrophage apoptosis, b) using mice with conditional ablation of the Fas death receptor on macrophages, c) selectively inducing macrophage apoptosis in transgenic mice. Aim 2 will test the hypothesis that the anti-apoptotic molecule, c- FLIP, is upregulated in macrophages that are resistant to apoptosis using mouse models of non-resolving ALI. Experiments in Aim 2 will also test the ability of the thiazolidinedione, pioglitazone, to sensitize macrophages to Fas-induced apoptosis by downregulating c-FLIP and will explore the effects of pioglitazone treatment on inflammation and fibrosis. Aim 3 will test the hypothesis that alveolar macrophages from subjects with non- resolving ALI are resistant to apoptosis. An ongoing NIH-sponsored trial will serve as the source of macrophages and BAL fluid for this aim. Macrophages will be analyzed for the presence of apoptosis and levels of procollagen peptide III will be quantified in BAL fluid. The correlation between macrophage apoptosis and procollagen peptide III levels will be assessed using univariate and multivariate analysis. The focus on the macrophage in resolving lung injury is a new and untapped area that has not been previously addressed. Results of our study will provide essential insight into the processes that regulate the resolution of inflammation in the lungs and will pave the way for novel therapeutic strategies to target non-resolving acute lung injury.

项目摘要/摘要 急性肺损伤(ALI)及其更严重的形式--急性呼吸窘迫综合征(ARDS) 以非心脏来源的双侧肺浸润性病变和严重的动脉低氧血症为特征。这些 在美国，每年有近20万人因疾病住院，7.5万人死亡。 尽管最近取得了进展，但死亡率仍然很高，大多数幸存者患有持续性肺病。 功能障碍和肺纤维化。动物模型已经对启动的机制产生了重要的见解 然而，很少有研究集中于推动肺损伤解决的过程。在这方面，我们 认为巨噬细胞起着关键作用。肺内有大量的巨噬细胞聚集。 在阿里早期。在非分离性ALI患者中，巨噬细胞持续存在，并作为PRO-2的丰富来源。 纤维化分子包括转化生长因子-β(TGF-β)。在自限性ALI的小鼠模型中， 巨噬细胞经历了由Fas驱动的凋亡。相反，在以持久性为特征的ALI模型中 炎症和纤维化，巨噬细胞凋亡难以检测。这些观察结果构成了 我们的中心假设是，巨噬细胞凋亡是ALI消退所必需的，而且巨噬细胞 对细胞凋亡的抵抗会导致纤维化。目标1将在自限和自闭症小鼠模型中检验这一假说 非溶血性ALI：a)全身应用caspase抑制剂抑制巨噬细胞凋亡，b) 使用条件消融小鼠巨噬细胞上Fas死亡受体，c)选择性地诱导 转基因小鼠巨噬细胞的凋亡。目标2将检验这样一个假设，即抗凋亡分子c- 翻转，在抗凋亡的巨噬细胞中上调，使用非分辨率ALI的小鼠模型。 目标2的实验还将测试噻唑烷二酮，吡格列酮，使巨噬细胞对 Fas通过下调c-flip诱导细胞凋亡，并将探讨吡格列酮对细胞凋亡的影响 炎症和纤维化。目的3将检验来自非慢性阻塞性肺疾病患者的肺泡巨噬细胞的假设 解决ALI对细胞凋亡具有抵抗力。一项由NIH赞助的正在进行的试验将作为 巨噬细胞和BAL液为此目的。巨噬细胞将被分析是否存在凋亡和 BAL液中前胶原多肽III的水平将被量化。巨噬细胞凋亡的相关性研究 前胶原肽III水平将使用单变量和多变量分析进行评估。重点放在 巨噬细胞在解决肺损伤中的作用是一个新的未被开发的领域，以前还没有解决过。 我们的研究结果将为调节炎症消退的过程提供重要的见解 并将为针对未消退的急性肺损伤的新治疗策略铺平道路。