Lyso-PS and resolution of acute lung inflammation

Lyso-PS 和急性肺部炎症的解决

• 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
• 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

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.

而中性粒细胞（PMN）的募集和激活对于肺宿主防御微生物（如真菌）至关重要。项目1)它们也会造成潜在的伤害（例如臭氧，项目3）。一旦感染被控制或消毒，抑制PMN募集和增强清除的信号对于炎症的适当解决和组织功能的恢复是必不可少的。失去这种控制可能导致慢性肺部炎症、永久性损伤（如肺气肿）和/或异常组织修复（如纤维化）。有证据表明，募集的pmn通常死于细胞凋亡，并被巨噬细胞（MO）原位清除。中性粒细胞