Lyso-PS and resolution of acute lung inflammation

Lyso-PS 和急性肺部炎症的解决

基本信息

批准号：
8053030
负责人：
DONNA L BRATTON
金额：
$ 29.36万
依托单位：
NATIONAL JEWISH HEALTH
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-02-01 至 2016-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8053030
关键词：
Acute Adenylate Cyclase Air Apoptosis Apoptotic Asthma Biological Cartoons Cells Chronic Chronic Obstructive Airway Disease Chronic lung disease Cyclic AMP Cyclic AMP-Dependent Protein Kinases Defect Disease Eicosanoids Ethers Excision Fibrosis Functional disorder G-Protein-Coupled Receptors Guanosine Triphosphate Phosphohydrolases Host Defense Human Impaired wound healing In Situ In Vitro Infection Inflammation Inflammation Mediators Ingestion Injury Investigation Lipids Lung Lung Inflammation Mass Spectrum Analysis Mediator of activation protein Microbe Modeling Mus NADPH Oxidase Neutrophil Activation Neutrophilia Oxidants Ozone Pathway interactions Phospholipase Phospholipids Production Prostaglandins Pulmonary Emphysema Recruitment Activity Resolution Role Signal Pathway Signal Transduction Structure of parenchyma of lung Surface Techniques Tissues autocrine chemokine cytokine fungus in vivo innovation lysophosphatidylserine macrophage neutrophil novel paracrine prevent restoration

项目摘要

While neutrophil (PMN) recruitment and activation are crucial for lung host defense against microbes (e.g. fungi. Project 1) they also contribute to potential injury (e.g. ozone, Project 3). Once infection is contained or sterilized, signals to both suppress PMN recruitment and enhance removal are essential for proper resolution of inflammation and restoration of tissue function. Loss of such controls likely contributes to chronic lung inflammation, permanent damage (e.g. emphysema) and/or abnormal tissue repair (e.g. fibrosis). Evidence suggests that recruited PMNs usually die by apoptosis, and are removed by macrophage (MO) in situ. PMN removal, before disintegration, prevents release of phlogistic intracellular constituents. Ordinarily, few apoptotic PMNs are evident suggesting that removal is highly efficient, however, defects in PMN clearance are described in chronic lung disease (e.g. COPD, CF and severe asthma). The "turn off' of PMN recruitment and the "turn on" of PMN removal normally occur in a highly orchestrated manner though the signals are not well understood. It is hypothesized that the novel phospholipid lysophosphatidylserine (lyso-PS) signals for both enhanced PMN removal and suppression of production of mediators for PMN recruitment. Mechanistically, it is hypothesized that activation of the NADPH oxidase in recruited PMNs results in robust production of lyso-PS detected by innovative mass spectrometry techniques. Lyso-PS displayed on the activated PMN surface signals to MO via the G-protein coupled receptor G2A for the activation of cPL{A}2 and prostanoid production. In turn, adenyl cyclase, PKA and Raci are activated resulting in high capacity engulfment of activated and dying PMNs and suppression of pro-inflammatory mediator production. Additionally, MO produce lyso-PS by alternative mechanisms amplifying the signal in an autocrine/paracrine manner. The specific aims are to 1) determine the pathways of production of lyso-PS in human and murine PMNs and MO during acute inflammation, 2) define the mechanisms and consequences of lyso-PS signaling in the resolution of neutrophilia, and 3) to enhance resolution of inflammation by deliberately supplying lyso-PS in a murine model of acute lung inflammation. Investigation of lyso-PS production, signaling and biological consequences in vitro and in vivo under normal conditions and during disrupted or deficient signaling will define the role of this novel lipid in the fundamental control of neutrophilia. As such, these studies will contribute significantly to the definition of strategies applicable to disease states where PMNs and impaired removal of apoptotic cells are implicated in dysregulated lung inflammation.

虽然中性粒细胞 (PMN) 的募集和激活对于肺宿主防御微生物（例如真菌。项目 1）至关重要，但它们也会造成潜在的损伤（例如臭氧，项目 3）。一旦感染被遏制或消灭，抑制中性粒细胞募集和增强去除的信号对于正确解决炎症和恢复组织功能至关重要。失去这种控制可能会导致慢性肺部炎症、永久性损伤（例如肺气肿）和/或异常组织修复（例如纤维化）。有证据表明，招募的 PMN 通常会因细胞凋亡而死亡，并被巨噬细胞 (MO) 原位清除。中性粒细胞网络在崩解之前去除，可以防止炎性细胞内成分的释放。通常，很少有明显的凋亡中性粒细胞，这表明清除中性粒细胞的效率很高，然而，慢性肺病（例如慢性阻塞性肺病、慢性阻塞性肺病和严重哮喘）中存在中性粒细胞清除的缺陷。尽管信号尚不清楚，但 PMN 募集的“关闭”和 PMN 去除的“开启”通常以高度协调的方式发生。据推测，新型磷脂溶血磷脂酰丝氨酸 (lyso-PS) 信号可增强 PMN去除和抑制 PMN 募集介质的产生从机制上来说，假设募集的 PMN 中 NADPH 氧化酶的激活会导致 PMN 的大量产生。通过创新质谱技术检测到的 Lyso-PS 通过 G 蛋白偶联受体 G2A 向 MO 发出信号，从而激活 cPL{A}2 和前列腺素生成。和 Raci 被激活，导致高容量吞噬活化和垂死的 PMN，并抑制促炎介质的产生。此外，MO 通过放大信号的替代机制产生 lyso-PS。自分泌/旁分泌方式的具体目标是 1) 确定急性炎症期间人类和小鼠 PMN 和 MO 中溶血 PS 的产生途径，2) 确定溶血 PS 信号在中性粒细胞消退中的机制和后果， 3) 通过在急性肺部炎症小鼠模型中故意提供溶血PS来增强炎症的消退。在正常条件下以及信号传导中断或缺陷期间，对溶血-PS 产生、信号传导和体外和体内生物学后果的研究将确定这种新型脂质在中性粒细胞的基本控制中的作用。因此，这些研究将极大地有助于定义适用于中性粒细胞和凋亡细胞清除受损与肺部炎症失调有关的疾病状态的策略。