Lyso-PS and resolution of acute 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（例如真菌）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适当解决炎症和恢复组织功能至关重要。这种控制的丧失可能导致慢性肺部炎症、永久性损伤（例如肺气肿）和/或异常组织修复（例如纤维化）。有证据表明，募集的中性粒细胞通常通过凋亡而死亡，并被原位巨噬细胞（MO）清除。PMN 在崩解之前除去，防止炎性细胞内成分的释放。通常，很少凋亡的PMN是明显的，这表明去除是高效的，然而，在慢性肺病（例如COPD、CF和严重哮喘）中描述了PMN清除的缺陷。中性粒细胞募集的“关闭”和中性粒细胞清除的“开启”通常以高度协调的方式发生，尽管这些信号还没有很好地理解。据推测，新的磷脂溶血磷脂酰丝氨酸（溶血PS）信号增强PMN的清除和抑制生产的中介PMN招聘。从机制上讲，假设在募集的PMN中NADPH氧化酶的激活导致通过创新的质谱技术检测到的溶血PS的稳健产生。在活化的PMN表面展示的Lyso-PS通过G蛋白偶联受体G2 A向MO发出信号，以激活cPL{A}2和前列腺素类物质的产生。反过来，腺苷酸环化酶、PKA和Raci被激活，导致激活和垂死的PMN的高容量吞噬和促炎介质产生的抑制。此外，MO通过自分泌/旁分泌方式放大信号的替代机制产生溶血PS。具体目的是1）确定急性炎症期间人和鼠PMN和MO中溶血PS的产生途径，2）定义溶血PS信号传导在嗜中性粒细胞消退中的机制和后果，以及3）通过在急性肺部炎症的鼠模型中故意供应溶血PS来增强炎症消退。溶血PS生产，信号和生物学后果的调查在体外和体内正常条件下，在中断或缺陷的信号将定义这种新的脂质的作用，在根本控制嗜中性粒细胞。因此，这些研究将显著有助于定义适用于疾病状态的策略，其中PMNs和凋亡细胞的受损去除与失调的肺部炎症有关。

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.