Aging-Related Mechanism of Post-Hemorrhagic Shock Acute Lung Injury

失血性休克后急性肺损伤的衰老相关机制

• 批准号: 9130376
• 负责人: Jie Fan
• 金额: $ 38.5万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9130376
• 关键词: Accounting; Acetylmuramyl-Alanyl-Isoglutamine; Acute Lung Injury; Address; Admission activity; Adult Respiratory Distress Syndrome; Aging; Alveolar Macrophages; Autophagocytosis; Autophagosome; Bacteria; Cause of Death; Cell physiology; Cessation of life; Development; Elderly; Event; Exhibits; Family; Funding Opportunities; Goals; HMGB1 Protein; Health; Hemorrhagic Shock; Hospitals; Human; Inflammation; Inflammatory; Injury; Intervention; Lead; Ligands; Lung; Lung Inflammation; Modeling; Multiple Organ Failure; Mus; Natural Immunity; Nature; Organ; Pathway interactions; Patients; Peptidoglycan; Play; Population; Process; Proteins; Pulmonary Inflammation; Regulation; Research Proposals; Resolution; Resources; Role; Sepsis Syndrome; Signal Transduction; Stress; System; TLR4 gene; Testing; Time; Trauma; Trauma patient; United States National Institutes of Health; adaptive immunity; age related; aged; base; cell type; human old age (65+); killings; member; neutrophil; novel; older patient; pathogen; prophylactic; response

 DESCRIPTION (provided by applicant): Acute lung injury (ALI) is a major component of multiple organ dysfunction syndrome (MODS) following hemorrhagic shock (HS)/trauma (T), and often serves as a direct cause of patient death. Studies have shown that patients older than 65 years account for 23% of all trauma admissions, and trauma represents the fifth leading cause of death in this population. Elderly trauma patients present with significantly worse organ injury, remain in the hospital longer, require greater use of resources after discharge, and die at 3 times the rate of the younger population. Our long-term goal is to determine the aging-related mechanism that promotes ALI following HS/T, thereby potentially identifying novel targets for prophylactic intervention. We have recently demonstrated in a mouse HS model that HS upregulates expression of NOD2, a member of NOD family and the product of CARD15, in alveolar macrophages (AM) through high mobility group box 1 (HMGB1)/TLR4 signaling. Upregulated NOD2 subsequently sensitizes the AM to respond to NOD2 ligand muramyl dipeptide (MDP), a molecule derived from the bacteria wall component peptidoglycan (PGN), and this leads to augmented inflammation in the lung. More importantly, we further found that NOD2 signaling also induces autophagy in the AM, which in turn demonstrates a potent negative regulatory role in lung inflammation. Notably, this NOD2-induced AM autophagy was impaired in aged mice (20-month old), and was associated with exacerbated lung inflammation. Autophagy is an ongoing basic cell process in almost all human cell types and is upregulated by various stress conditions, including those leading to inflammation. We hypothesize that the HMGB1-TLR4-NOD2 signaling-induced autophagy in AM and neutrophils (PMN) following T/HS plays an important regulatory role in dampening lung inflammation; however, in the elderly trauma population, impaired autophagy induction in AM and PMN leads to an imbalance between pro- and counter-inflammatory factors, and thereby results in exacerbated and prolonged lung inflammation after T/HS. To test this hypothesis, we propose the following specific aims: Specific Aim 1. To determine the influence of aging-impaired autophagy on the development of post-HS lung inflammation. We will determine the role of NOD2-induced autophagy in the regulation of HS-primed lung inflammation and the influence of aging- impaired autophagy on the development of ALI. Specific Aim 2. To determine the mechanism by which aging- impaired autophagy exaggerates post-HS ALI. We will address how impaired autophagy augments lung inflammation following HS in aged mice, and whether autophagy through regulating inflammasome and/or pyroptosis alters HS-primed lung inflammation.

 描述(申请人提供)：急性肺损伤(ALI)是失血性休克(HS)/创伤(T)后多器官功能障碍综合征(MODS)的主要组成部分，通常是患者死亡的直接原因。研究表明，65岁以上的患者占所有创伤住院患者的23%，创伤是这一人群的第五大死因。老年创伤患者的器官损伤明显严重，住院时间更长，出院后需要更多的资源利用，并在 这一比例是年轻人口的3倍。我们的长期目标是确定在HS/T后促进ALI的衰老相关机制，从而潜在地确定预防性干预的新靶点。我们最近在小鼠HS模型中证实，HS通过高迁移率族蛋白1(HMGB1)/TLR4信号上调NOD家族成员和CARD15产物NOD2在肺泡巨噬细胞(AM)中的表达。上调的NOD2随后使AM对NOD2配体胞浆二肽(MDP)敏感，MDP是一种源自细菌壁组分肽聚糖(PGN)的分子，这导致肺部炎症加剧。更重要的是，我们进一步发现，NOD2信号还诱导AM中的自噬，这反过来在肺部炎症中显示出强大的负向调节作用。值得注意的是，这种由NOD2诱导的AM自噬在老年小鼠(20个月大)中受到损害，并与加重的肺部炎症有关。自噬是几乎所有人类细胞类型中正在进行的基本细胞过程，并在各种应激条件下上调，包括那些导致炎症的应激条件。我们推测HMGB1-TLR4-NOD2信号在T/HS后AM和中性粒细胞(PMN)中诱导的自噬在抑制肺部炎症中起着重要的调节作用；然而，在老年创伤人群中，AM和PMN自噬诱导的受损导致促炎因子和抗炎因子之间的失衡，从而导致T/HS后肺部炎症的加重和延长。为了验证这一假说，我们提出了以下具体目标：具体目标1.确定衰老受损的自噬对HS后肺部炎症发展的影响。我们将确定NOD2诱导的自噬在HS诱导的肺炎症中的调节作用，以及衰老受损的自噬对ALI发生发展的影响。具体目的2.确定衰老受损的自噬夸大HS后ALI的机制。我们将讨论自噬受损如何增加老年小鼠HS后的肺部炎症，以及是否通过调节炎症和/或下垂改变HS启动的肺部炎症。