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.

项目概要/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) 其特征为非心脏来源的双侧肺部浸润和严重动脉低氧血症。 在美国，此类疾病每年导致近 20 万人住院，7.5 万人死亡。 尽管最近取得了进展，死亡率仍然很高，并且大多数幸存者患有持续性肺病 动物模型对引发机制产生了重要的见解。 肺损伤，然而很少有研究关注其解决的过程。在这方面，我们。 相信巨噬细胞起着关键作用，肺部有大量的巨噬细胞聚集。 在早期 ALI 期间，在未缓解的 ALI 患者中，巨噬细胞持续存在，并作为亲-的丰富来源。 纤维化分子，包括转化生长因子-¿ (TGF-¿)。在自限性 ALI 小鼠模型中， 在以持续性为特征的 ALI 模型中，巨噬细胞经历由 Fas 驱动的细胞凋亡。 炎症和纤维化、巨噬细胞凋亡是难以检测的，这些观察结果构成了基础。 我们的中心假设是巨噬细胞凋亡是解决 ALI 所必需的，并且巨噬细胞 细胞凋亡抵抗导致纤维化，目标 1 将在自限性和纤维化的小鼠模型中检验这一假设。 通过以下方法治疗非缓解性 ALI：a) 全身施用 caspase 抑制剂以抑制巨噬细胞凋亡，b) 使用小鼠，有条件地消融巨噬细胞上的 Fas 死亡受体，c) 选择性诱导 转基因小鼠中的巨噬细胞凋亡将检验抗凋亡分子 c- 的假设。 使用非缓解性 ALI 小鼠模型，FLIP 在抵抗细胞凋亡的巨噬细胞中上调。 目标 2 中的实验还将测试噻唑烷二酮、吡格列酮使巨噬细胞敏感的能力 Fas 通过下调 c-FLIP 诱导细胞凋亡，并将探讨吡格列酮治疗对 目标 3 将检验来自非受试者的肺泡巨噬细胞的假设。 NIH 资助的一项正在进行的试验将作为解决 ALI 对细胞凋亡具有抵抗力的来源。 为此目的，将分析巨噬细胞和 BAL 液中是否存在细胞凋亡。 BAL 液中前胶原肽 III 的水平将与巨噬细胞凋亡之间的相关性进行定量。 前胶原肽 III 水平将使用单变量和多变量分析进行评估。 巨噬细胞在解决肺损伤中的作用是一个新的、尚未开发的领域，之前尚未得到解决。 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 肺部，将为针对无法解决的急性肺损伤的新治疗策略铺平道路。