Surfactant Proteins and NO in Inflammatory Disease

描述（由申请人提供）：本研究项目的主要目标是研究NO化学如何在肺部炎症疾病的启动和传播中发挥作用。 特别是，我们将研究改变NO化学在肺部炎症动物模型，消融SP-D基因的影响。 缺乏SP-D基因的小鼠在没有感染因子的情况下在肺内发展非特异性炎性疾病。 这种疾病的特征是实质浸润和支气管周围中性粒细胞脂蛋白沉积症，以及肺的NO化学变化（S-亚硝基硫醇（SNO）丢失，组织内硝基酪氨酸增加，细支气管肺泡灌洗（BAL）内硝酸盐相对较大增加）。 因此，该动物模型为研究NO在肺部炎症中的作用提供了理想的机会。 我们将使用药理学和遗传学干预来操纵NO的生产在这个模型中，并检查这些操作对疾病发展的影响。 此外，我们提出正常信号NO的丧失是这种病理的一部分，因此，我们将研究吸入NO或其氧化还原同类物亚硝酸乙酯在治疗肺部炎症中的可能用途，以进一步了解分子机制参与肺部炎症性疾病，以及NO如何改变这些机制，我们将检查组织和灌洗液中活性物质的潜在蛋白质靶，特别是，我们将评估硝化蛋白质、S-亚硝基化蛋白质和氧化蛋白质的产生。这样的实验可能会导致有价值的信息有关的反应性物种的生理信号通路，以及这些途径是如何在炎症过程中改变。 最后，我们将研究如何拯救的表型纯化SP-D可能会受到NO介导的SP-D的修改。 这些实验将为SP-D和NO如何参与生理肺功能的维持提供有价值的信息。

DESCRIPTION (provided by applicant): The major goal of this research project is to investigate how NO chemistry plays a role both in the initiation and in the propagation of inflammatory disease within the lung. In particular, we will investigate the effects of altered NO chemistry within an animal model of pulmonary inflammation, ablation of the SP-D gene. Mice lacking the SP-D gene develop a non-specific inflammatory disease within the lung in the absence of an infectious agent. This disease is characterized by parenchymal infiltrates and peribronchial neutrophilial lipoproteinosis, and alterations in the NO chemistry of the lung (loss of S-nitrosothiol, SNO, and gain of nitrotyrosine within tissue and a relative greater increase of nitrates within the bronchiolar alveolar lavage, BAL). Therefore, this animal model provides an ideal opportunity to investigate the role that NO plays in pulmonary inflammation. We will use both pharmacological and genetic interventions to manipulate NO production within this model and examine the effects of these manipulations upon the development of disease. Furthermore, we propose that the loss of normal signaling NO is part of this pathology, therefore, we will investigate the possible use of inhaled NO or its redox congener, ethyl nitrite, in treatment of pulmonary inflammation, in order to further our understanding of the molecular mechanisms involved in pulmonary inflammatory disease, and how NO modifies these mechanisms, we will examine the potential protein targets of reactive species both within the tissue and the lavage, in particular, we will assess the production of nitrated proteins, S-nitrosylated proteins, and oxidized proteins. Such experiments may lead to valuable information concerning the physiological signaling pathways of reactive species and how these pathways are altered during inflammation. Finally, we will examine how rescue of the phenotype by purified SP-D may be affected by NO-mediated modifications of SP-D. These experiments wilt provide valuable information as to how SP-D and NO are involved in the maintenance of physiological pulmonary function.