Anionic Surfactant Lipid Regulation of Inflammation and Infection in the Lung

描述（由申请人提供）：肺表面活性物质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免疫中起核心作用。表面活性剂双棕榈酰磷脂酰胆碱的主要脂质成分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）目前被认为是识别病原体、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剂的两种次要成分，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（TLRs）激活的有效抑制剂，TLRs作为微生物入侵的传感器并引发炎症反应。表面活性剂中的PtdGro和PtdIns的作用似乎通过抑制非感染性刺激（如每天吸入肺部的超细颗粒上存在的细菌脂多糖）产生的不必要的组织炎症，在肺部发挥保护作用。我们假设PtdGro和PtdIns的作用是为炎症的发生设定一个高阈值，从而防止肺部因偶然暴露于空气中的微生物产物而慢性炎症。除了抑制炎症外，PtdGro和PtdIns还能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。呼吸道合胞病毒是两岁以下儿童住院治疗的主要原因。RSV和IFA也是哮喘和慢性阻塞性肺疾病的严重加重剂。本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。我们计划通过以下途径阐明脂质作用的分子基础：1)通过炎症和感染的细胞培养模型，确定TLRs抑制和病毒感染的结构基础；2)确定阴离子脂质在微生物配体挑战小鼠肺部环境下的体内作用效果；3)定量脂质拮抗剂对RSV和IFA的体内外作用；4)明确阴离子脂质抑制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的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。

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.