Phospholipidomics and inflammation in sepsis

项目摘要/摘要 脓毒症仍然是发病率和死亡率的主要原因。通常情况下，50%的脓毒症病例始于 肺部感染。脓毒症伴有多器官功能障碍、细胞因子风暴和播散性 凝血综合征。这些过程直接涉及血管内皮细胞。虽然发炎， 凝血功能紊乱和内皮通透性改变是脓毒症急性发作的公认因素 肺损伤(ALI)--内皮细胞过程中的内源性介质和细胞机制 脓毒症条件下的炎症激活和凝血仍然知之甚少。在试点研究中，我们 基于质谱法的炎症肺组织中截短氧化磷脂的鉴定 磷脂组学方法。我们令人兴奋的初步数据显示，tr-oxpls明显加重了肺 感染性ALI细胞和动物模型的功能障碍和血管内皮屏障受损。vbl.使用 金黄色葡萄球菌(S.Au，USA300 CA-MRSA临床试验)诱导的肺炎相关ALI模型 菌株923)或热灭活金黄色葡萄球菌(HKSA)本研究将首次采用定量 磷脂组学方法鉴定ALI过程中升高的特异型tr-oxpls并阐明其在 加重炎症的因素和凝血级联失调。我们假设增加了 脓毒症时产生的tr-oxpls通过诱导NLRP3炎症小体的表达而加重肺损伤 激活剂硫氧还蛋白相互作用蛋白(TXNIP)；并通过抑制血管抗凝剂的表达， 组织因子途径抑制物(TFPI)。总之，这些事件导致炎症信号的激活， 凝血功能紊乱，肺内炎性细胞浸润，器官损伤。AIM-1将决定 金黄色葡萄球菌感染动物肺中产生的tr-oxpl谱。AIM-2将研究TR-2的影响。 金黄色葡萄球菌所致脓毒症条件下产生的OxPL对肺损伤的严重程度。AIM-3将研究分子 Tr-OxPL诱导脓毒症炎症和凝血反应加重的机制。AIM-4将测试新的 基于机制的策略，以减轻tr-oxpls的产生及其在金黄色葡萄球菌中的病理后果。 诱导感染性ALI。

Project Summary/Abstract Sepsis remains a major cause of morbidity and mortality. Typically, 50% of all sepsis cases start as an infection in the lungs. Sepsis is accompanied by multiple organ dysfunction, cytokine storm, and disseminated coagulation syndrome. These processes directly involve vascular endothelial cells. Although inflammation, dysregulated coagulation, and alterations in endothelial permeability are recognized factors of septic acute lung injury (ALI), the endogenous mediators and cellular mechanisms orchestrating processes of endothelial inflammatory activation and coagulation in septic conditions remain poorly understood. In pilot studies we identified truncated oxidized phospholipids (TR-OxPLs) in the inflamed lungs using Mass Spectrometry-based phospholipidomics approach. Our exciting preliminary data show that TR-OxPLs markedly exacerbated lung dysfunction and impaired vascular endothelial barrier in cell and animal models of septic ALI. Using pneumonia-related models of ALI induced by live Staphylococcus aureus (S. au, USA300 CA-MRSA clinical strain 923) or heat-killed S. au (HKSA) this translational study will employ for the first time the quantitative phospholipidomics approach to identify specific TR-OxPLs elevated during ALI and elucidate their role as factors exacerbating inflammation and dysregulating coagulation cascade. We hypothesize that increased generation of TR-OxPLs during sepsis augments lung injury by inducing expression of NLRP3 inflammasome activator, thioredoxin interacting protein (TXNIP); and by suppressing the expression of vascular anticoagulant, Tissue Factor Pathway Inhibitor (TFPI). Altogether, these events lead to activation of inflammatory signaling, dysregulated coagulation, inflammatory cell infiltration in the lung, and organ damage. Aim-1 will determine the spectrum of TR-OxPL generated in the lungs of S. au-challenged animals. Aim-2 will study the impact of TR- OxPL generated in S. au-induced septic conditions on the severity of lung injury. Aim-3 will study molecular mechanisms of TR-OxPL-induced exacerbation of septic inflammation and coagulation. Aim-4 will test new mechanism-based strategies to alleviate TR-OxPLs generation and their pathologic consequences in S. au- induced septic ALI.