Anionic Surfactant Lipid Regulation of Inflammation and Infection in the Lung

描述（由申请人提供）：肺的肺表面活性剂系统是一种脂质和蛋白质复合物，在调节肺泡室表面张力和控制先天性免疫中发挥核心作用。表面活性剂的主要脂质成分二棕榈酰磷脂酰胆碱是负责降低肺泡表面张力的分子。表面活性剂蛋白A和D（SP-A和SP-D）现在被理解为参与识别病原体、促进其吞噬和调节炎症的重要调节分子。我们最近发现，肺表面活性物质的两种次要组分，阴离子磷脂磷脂酰甘油（PtdGro）和磷脂酰肌醇（PtdIns），也是肺内炎症和感染的有效调节剂。这些脂质是多种Toll样受体（TLR）激活的有效抑制剂，TLR作为微生物入侵的传感器并引发炎症反应。表面活性剂中PtdGro和PtdIns的作用似乎通过抑制不必要的组织炎症而在肺中发挥保护作用，否则这些炎症将响应于非感染性刺激而发生，例如每天吸入肺中的超细颗粒上存在的细菌脂多糖。我们假设PtdGro和PtdIns的作用是为炎症的参与设定高阈值，从而防止肺部因偶然暴露于空气中的微生物产物而慢性发炎。除了抑制炎症外，PtdGro和PtdIns还有效抑制呼吸道合胞病毒（RSV）和甲型流感病毒（IFA）对肺细胞的感染。RSV是生命头两年住院的主要原因。RSV和IFA也是哮喘和慢性阻塞性肺病的严重加重剂。该建议的重点是了解阴离子表面活性剂脂质如何发挥其作用。我们计划通过以下方式阐明脂质作用的分子基础：1）通过使用炎症和感染的细胞培养模型确定抑制TLR和病毒感染的结构基础; 2）在微生物配体挑战小鼠肺的背景下确定阴离子脂质在体内的作用功效; 3）在体外和体内定量脂质拮抗剂对RSV和IFA的作用; 4）确定阴离子脂质抑制RSV和IFA感染的分子机制。本提案中描述的工作与儿童和成人细菌和呼吸道病毒感染的治疗直接相关，对哮喘和慢性阻塞性肺病患者的治疗具有重要意义。 公共卫生相关性：这项工作的重点是肺的气体交换区域内发现的脂质的新发现的功能。这些脂质是肺部炎症的有效抑制剂，并保护器官免受炎症过程的无意激活。这些脂质还具有意想不到的抗呼吸道合胞病毒的抗病毒活性，呼吸道合胞病毒可导致新生儿和患有哮喘和慢性阻塞性肺病的个体的严重疾病。

DESCRIPTION (provided by applicant): The pulmonary surfactant system of the lung is a lipid and protein complex that plays a central role in regulating the surface tension of the alveolar compartment and controlling innate immunity. The major lipid component of surfactant, dipalmitoyl-phosphatidylcholine, is the molecule responsible for the reduction of alveolar surface tension. Surfactant proteins A and D (SP-A and SP-D) are now understood to be important regulatory molecules involved in recognizing pathogens, facilitating their phagocytosis and regulating inflammation. We have recently discovered that two of the minor components of pulmonary surfactant, the anionic phospholipids phosphatidylglycerol (PtdGro) and phosphatidylinositol (PtdIns), are also potent regulators of inflammation and infection within the lung. These lipids are effective inhibitors of the activation of multiple Toll-like receptors (TLRs), which serve as sensors for microbial invasion and elicit inflammatory responses. The actions of PtdGro and PtdIns within surfactant appear to play a protective role in the lung by suppressing unnecessary tissue inflammation that would otherwise occur in response to non-infectious stimuli such as bacterial lipopolysaccharide present on ultrafine particles inhaled into the lung on a daily basis. We hypothesize that the role of PtdGro and PtdIns is to set a high threshold for the engagement of inflammation thereby preventing the lung from being chronically inflamed by casual exposure to airborne microbial products. In addition to suppressing inflammation, PtdGro and PtdIns also potently suppress infection of lung cells by respiratory syncytial virus (RSV) and influenza A virus (IFA). RSV is a major cause of hospitalization in the first two years of life. RSV and IFA also act as serious exacerbants of asthma and chronic obstructive pulmonary disease. The focus of this proposal is to understand how the anionic surfactant lipids exert their action. We plan to elucidate the molecular basis of the actions of the lipids by: 1) determining the structural basis of suppression of TLRs and viral infection, by using cell culture models of inflammation and infection; 2) determining the efficacy of action of the anionic lipid in vivo in the context microbial ligand challenges to the lungs of mice; 3) quantifying the action of the lipid antagonists against RSV and IFA in vitro and in vivo; 4) defining the molecular mechanisms by which the anionic lipids suppress RSV and IFA infection. The work described in this proposal has direct relevance to treatment of bacterial and respiratory viral infections in children and adults, and important implications for treatment of individuals with asthma and chronic obstructive pulmonary disease. PUBLIC HEALTH RELEVANCE: This work focuses on the newly discovered function of lipids found within the gas exchange regions of the lung. These lipids are potent suppressors of inflammation in the lung, and protect the organ from inadvertent activation of inflammatory processes. These lipids also have unexpected anti-viral activity against respiratory syncytial virus, which causes serious disease in newborns and individuals with asthma and chronic obstructive pulmonary disease.