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

基本信息

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
项目类别：
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

项目摘要

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，并且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入院患者的 23%，创伤是该人群的第五大死因。老年创伤患者的器官损伤明显更严重，住院时间更长，需要更多的使用。出院后的资源，并死于是年轻人的 3 倍，我们的长期目标是确定 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目标。我们最近在小鼠 HS 模型中证明了 HS。通过上调 NOD2 信号传导，上调肺泡巨噬细胞 (AM) 中 NOD2（NOD 家族成员和 CARD15 的产物）的表达。随后，AM 敏感地响应 NOD2 配体胞壁酰二肽（MDP），这是一种源自细菌壁成分肽聚糖（PGN）的分子，这会导致肺部炎症加剧。更重要的是，我们进一步发现 NOD2 信号传导还会诱导自噬。值得注意的是，这种 NOD2 诱导的 AM 自噬在老年小鼠（20 个月大）中受到损害，并且自噬是几乎所有人类细胞类型中持续存在的基本细胞过程，并且会被各种应激条件上调，包括导致炎症的应激条件。 T/HS后的中性粒细胞（PMN）在抑制肺部炎症方面发挥着重要的调节作用；然而，在老年创伤人群中，AM和PMN中的自噬诱导受损导致促炎因子和抗炎因子之间的不平衡，并导致 T/HS 后肺部炎症加剧和延长。为了检验这一假设，我们提出以下具体目标：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。确定 NOD2 诱导的自噬在 HS 引发的肺部炎症调节中的作用以及衰老受损的自噬对 ALI 发展的影响。具体目标 2. 确定衰老受损的自噬的机制。我们将讨论受损的自噬如何增强老年小鼠 HS 后的肺部炎症，以及自噬是否通过调节炎性体和/或焦亡来改变 HS 引发的肺部炎症。