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