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.

尽管中性粒细胞（PMN）的募集和激活对于肺部宿主防御微生物至关重要（例如真菌。项目1）也会导致潜在的伤害（例如，臭氧，项目3）。一旦感染或消毒，既抑制PMN募集的信号，又可以增强去除，对于适当解决炎症和组织功能的恢复至关重要。这种对照的丧失可能导致慢性肺部炎症，永久性损伤（例如肺气肿）和/或组织不正常的组织修复（例如纤维化）。有证据表明，招募的PMN通常会因凋亡而死亡，并通过巨噬细胞（MO）原位去除。 PMN 在瓦解之前，去除可防止细胞内成分的释放。通常，很少有明显的凋亡PMN表明去除高效，但是，PMN清除的缺陷在慢性肺部疾病中（例如COPD，CF和严重哮喘）中描述了。尽管信号尚不清楚，但通常以高度精心策划的方式出现PMN募集的“关闭”和PMN删除的“打开”。假设新型磷脂溶脂磷脂酰丝氨酸（Lyso-PS）对于两种增强的PMN信号在机械上的去除和抑制PMN募集的生产。通过G蛋白耦合受体G2A的MO激活CPL {A} 2和前列腺素的生产，依次激活了腺基环酶，PKA和RACI另外，MO通过替代机制以自分泌/旁分泌方式放大信号。 2）在中性粒细胞分辨率中定义了Lyso-PS信号传导的机制和后果，3）通过故意在急性肺炎症的鼠模型中有意提供Lyso-PS来增强炎症的分辨率。在正常条件下以及在破坏或不足的信号传导下，对溶血-PS的产生，信号传导和生物学后果的研究将定义这种新型脂质在中性粒细胞的基本控制中的作用。因此，这些研究将对适用于疾病状态的策略的定义产生重大贡献，其中PMN和去除凋亡细胞的去除受损与失调的肺部炎症有关。