Macrophage endocytosis in resolving lung inflammation

巨噬细胞内吞作用解决肺部炎症

• 批准号: 8454234
• 负责人: PETER M HENSON
• 金额: $ 63.71万
• 依托单位: NATIONAL JEWISH HEALTH
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8454234
• 关键词: Acute; Address; Adult Respiratory Distress Syndrome; Anti-Inflammatory Agents; Anti-inflammatory; Apoptotic; Autoimmunity; Automobile Driving; Cells; Chronic; Chronic Obstructive Airway Disease; Clinical; Defect; Development; Disease; Endocytosis; Environment; Excision; Fibrosis; Homeostasis; Indium; Infection; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Ingestion; Injury; Interleukin-4; Interstitial Lung Diseases; Leukocytes; Lung; Lung Inflammation; Lung diseases; Maintenance; Mediating; Organ; PPAR gamma; Particulate; Pathogenesis; Pathway interactions; Phase; Phenotype; Phosphatidylserines; Pneumonia; Process; Production; Property; Reaction; Recruitment Activity; Resolution; Role; Signal Pathway; Signal Transduction; Site; Source; Staging; Stimulus; Structure; Testing; Therapeutic; Tissues; Variant; Wound Healing; human disease; immunogenic; improved; in vivo; macrophage; monocyte; neutrophil; novel; parasitism; programs; repaired; response; trafficking; uptake

DESCRIPTION (provided by applicant): Inflammation is an essential effector process for responses to parasitism, infection and tissue injury. On the other hand, it also contributes to the pathogenesis of most human diseases. This paradox results in part from the fact that inflammation itself can, and often does; itself induce injury to the tissues in the process of resolving the infection or healing the wound. Optimally, therefore, an acute inflammatory response completes its protective (and pro-immunogenic) functions and then rapidly resolves, allowing the tissue to return to normal structure and function. A key element in this resolution is removal of the inflammatory cells themselves as well as the cell and tissue debris that is produced as an inevitable accompaniment to the process. This clearance function is primarily carried out by uptake of debris and cells into macrophages that accumulate at the site as part of the inflammatory process. Studies of macrophages in inflammation have tended in the past to focus on their contribution to recognizing the injurious stimulus in the first place, and in controlling the inflammation by virtue of their sequential production of pro- and then anti- inflammatory mediators. More recently, however, their participation in the resolution phase is becoming better understood, and, we hypothesize, results from a change in macrophage function that we identify as a change in "programing state". In particular, the reparative macrophages are hypothesized to gain a substantial capacity for macropinocytosis, the ingestion process suggested to remove both dying inflammatory cells and the particulate, and even soluble, debris that accompanies inflammation. Questions that are to be addressed in the proposal include: 1) demonstrating that macrophages with specifically high capability for macropinocytosis develop in the resolving inflamed lung and are effective scavengers of both debris and dying inflammatory cells, 2) distinguishing between incoming monocytes or previously macropinocytosis-poor macrophages as the source for such scavenger cells, 3) exploring the mechanism driving the macrophage programing by testing a proposed phosphatidylserine/IL- 4/PPARgamma signaling pathway (i.e. suggesting that it develops as a response to the presence of the activated and dying inflammatory cells themselves), 4) demonstrating that the pro-macropinocytic programing state and thus, clearance of inflammatory debris, can be enhanced in vivo by stimulating these pathways to improve the resolution.

描述(由申请人提供)：炎症是对寄生虫、感染和组织损伤做出反应的基本效应过程。另一方面，它也有助于 大多数人类疾病的发病机制。这种悖论的部分原因是，炎症本身可以，而且通常确实会；在解决感染或愈合伤口的过程中，它本身会对组织造成伤害。因此，最好的情况是，急性炎症反应完成其保护性(和促免疫原性)功能，然后迅速消退，使组织恢复正常结构和功能。这项决议的一个关键要素是清除炎症细胞本身以及不可避免地伴随这一过程而产生的细胞和组织碎片。这种清除功能主要是通过将碎片和细胞摄取到巨噬细胞中来实现的，巨噬细胞在炎症过程中聚集在部位。巨噬细胞在炎症中的研究过去往往集中在它们在识别最初的伤害性刺激方面的贡献，以及通过它们顺序地产生促炎和抗炎介质来控制炎症。然而，最近，人们对它们参与分解阶段的理解变得更好了，我们推测，这是由于巨噬细胞功能的变化，我们认为这是“编程状态”的变化。特别是，修复性巨噬细胞被假设为获得大量的巨噬细胞吞噬能力，摄取过程表明既可以清除垂死的炎症细胞，也可以清除伴随炎症而来的颗粒，甚至是可溶的碎片。建议中要解决的问题包括：1)证明具有特别高巨噬细胞吞噬能力的巨噬细胞在消退炎症的肺中发展，并且是碎片和死亡炎症细胞的有效清除者；2)区分进入的单核细胞或先前缺乏巨噬细胞吞噬能力的巨噬细胞作为这种清道夫细胞的来源；3)通过测试所提出的磷脂酰丝氨酸/IL-4/PPAR-γ信号通路来探索驱动巨噬细胞编程的机制(即，表明它是对激活的和正在死亡的炎症细胞本身的存在的反应)；4)证明支持巨噬细胞的编程状态，从而清除炎症碎片，通过刺激这些途径来提高分辨率，可以在体内增强。