Cross-talk between lung natural killer cells and dendritic cells in COPD

COPD 中肺自然杀伤细胞和树突状细胞之间的串扰

• 批准号: 9412091
• 负责人: Christine M. Basmajian
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9412091
• 关键词: Activated Natural Killer Cell; Adhesions; Air; Apoptosis; Autologous; Binding; Binding Proteins; Biological Availability; Cause of Death; Cell Adhesion; Cells; Chronic Obstructive Airway Disease; Cytoplasmic Granules; Data; Dendritic Cells; Diagnosis; Disease Progression; Emotional; Epithelial; Epithelial Cells; Excision; Exposure to; Family; Female; Goals; Granzyme; Healthcare; Hospitals; Human; In Vitro; Inflammation; Inflammatory; Innate Immune System; Lead; Lung; Lung Inflammation; Lymphocyte; Lytic; Mediating; Mediator of activation protein; Medical; Modeling; Morbidity - disease rate; Mus; NCAM1 gene; NK Cell Activation; Natural Killer Cells; Pathogenesis; Pathology; Pathway interactions; Patients; Phase; Process; Production; Proteins; Publishing; Pulmonary Emphysema; Receptor Cell; Receptor Signaling; Signal Transduction; Smoker; Stress; Structure of parenchyma of lung; Testing; Therapeutic; Time; Translating; United States; Veterans; airway inflammation; cell injury; cell killing; cell type; cigarette smoke; clinically relevant; cytokine; cytotoxic; cytotoxicity; exposure to cigarette smoke; human tissue; immunological synapse; immunological synapse formation; inflammatory milieu; interleukin-22; male; mortality; mouse model; novel; novel therapeutic intervention; perforin; peripheral blood; receptor; targeted treatment; therapeutic target

Chronic obstructive pulmonary disease (COPD) is the 3rd leading cause of death in the United States, yet there are no current therapeutic treatments to halt disease progression. Airway inflammation and parenchymal destruction are central to the pathogenesis of COPD. Numerous inflammatory cell types have been implicated in COPD but an understanding of how these cell types contribute to lung destruction is lacking. Natural killer cells (NKs), an important component of the innate immune system, are known for their ability to detect and kill stressed, infected, or damaged cells. Our data demonstrate that NKs from the lungs of COPD patients are able to kill more autologous lung epithelial cells than NKs from the lungs of smokers without COPD. Similarly, in a murine cigarette smoke (CS) exposure model, lung NKs from CS-exposed mice are more cytotoxic towards autologous epithelial cells than air-exposed NKs. Therefore understanding the processes that control NK activation could identify therapeutic targets. In order to become activated, NKs undergo a priming phase, typically mediated by dendritic cells (DCs). We propose to use both human tissues and our murine CS- exposure model to demonstrate that mature DCs are necessary for NK priming. We will also investigate the mechanism of killing by focusing on the steps leading to cytotoxicity: adhesion to target cell, polarization of lytic granules, and degranulation. Finally, we will determine whether lung NK production of IL-22, a cytokine capable of inducing epithelial cells to make pro-inflammatory molecules, is also contributing to COPD pathology. To demonstrate the relevance of our findings to COPD, we also propose to study NKs and DCs from human lung tissue. Our goal is to translate results from these murine and human studies into clinically relevant discoveries regarding NK cytotoxicity in COPD pathogenesis.

慢性阻塞性肺疾病（COPD）是美国第三大死亡原因， 但是目前还没有治疗方法来阻止疾病的发展。气道炎症和 实质破坏是COPD发病机制的核心。大量炎性细胞 这些细胞类型与COPD有关，但了解这些细胞类型如何促进肺功能， 毁灭是缺乏的。自然杀伤细胞（NK），先天免疫的重要组成部分， 系统以其检测和杀死应激、感染或受损细胞的能力而闻名。我们的数据 证明来自COPD患者肺的NK能够杀死更多的自体肺上皮细胞， 与来自非COPD吸烟者肺的NK细胞相比。同样，在小鼠香烟烟雾（CS）中， 暴露模型，来自CS暴露小鼠的肺NK对自体上皮细胞更具细胞毒性， 比暴露在空气中的NK细胞。因此，了解控制NK激活的过程可以 确定治疗靶点。为了被激活，NK通常经历引发阶段， 由树突状细胞（DC）介导。我们建议使用人类组织和我们的小鼠CS- 暴露模型来证明成熟DC对于NK引发是必需的。我们还将 通过关注导致细胞毒性的步骤来研究杀伤机制：粘附于 靶细胞、溶解颗粒极化和脱粒。最后，我们将确定是否肺 NK产生IL-22，一种能够诱导上皮细胞产生促炎性细胞因子 分子，也有助于COPD病理学。为了证明我们的发现与 COPD，我们还建议研究来自人肺组织的NK和DC。我们的目标是翻译 从这些小鼠和人类研究中获得的关于NK的临床相关发现 COPD发病机制中的细胞毒性。