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（由适用提供）：急性肺损伤（ALI）是出血性休克（HS）/创伤（T）后多个器官功能障碍综合征（MOD）的主要组成部分，并且通常是导致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的23％，创伤代表了该人群中第五大死亡原因。老年创伤患者的器官损伤明显较差，在医院保留更长的时间，需要更多的资源使用，并在出院后死亡 年轻人口的比率是3倍。我们的长期目标是确定与HS/T之后促进ALI的衰老相关机制，从而有可能识别预防性干预的新目标。我们最近在鼠标HS模型中证明了HS在肺泡巨噬细胞（AM）中更新NOD2（NOD2）的表达，该模型是通过高移动性组Box 1（HMGB1）/TLR4信号传导。上调的NOD2随后感觉到AM对NOD2配体穆拉米尔二肽（MDP）响应，这是一种源自细菌壁成分peptedoglycan（PGN）的分子，这会导致肺部的增强感染。更重要的是，我们进一步发现，NOD2信号传导也诱导了AM的自噬，这反过来又显示出潜在的负调节作用在肺部感染中。值得注意的是，这种NOD2诱导的AM自噬在老年小鼠（20个月大）中受损，并与加剧的肺部感染有关。自噬是几乎所有人类细胞类型的持续基本细胞过程，并且通过各种压力条件（包括导致炎症的压力条件）进行更新。我们假设HMGB1-TLR4-NOD2信号传导诱导的AM和中性粒细胞（PMN）T/HS之后在损害肺部感染中起重要的调节作用；然而，在最古老的创伤人群中，AM和PMN的自噬诱导受损会导致促和反炎性因素之间的失衡，从而导致T/HS后加剧和延长肺部注射。为了检验这一假设，我们提出了以下特定目的：具体目的1。确定衰老损伤自噬对HS肺部注射后开发的影响。我们将确定NOD2诱导的自噬在调节HS促进的肺部炎症中的作用，以及衰老破裂自噬对ALI发展的影响。具体目的2。确定衰老受损自噬夸大后HS ALI的机制。我们将解决老年小鼠HS后自噬增强肺注射的受损，以及通过调节炎症体和/或投掷的自噬是否会改变HS培养的肺注射。