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性疾病的发生和传播中发挥作用。特别是，我们将在肺部炎症的动物模型中研究改变NO化学的影响，SP-D基因的消融。缺乏SP-D基因的小鼠在没有感染因子的情况下会在肺部发生非特异性炎症性疾病。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，以及肺NO化学改变（组织内s -亚硝基硫醇（SNO）的损失和硝基酪氨酸的增加，细支气管肺泡灌洗液（BAL）中硝酸盐的相对较大增加）。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。我们将在该模型中使用药理学和遗传干预来操纵NO的产生，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的丢失是这种病理的一部分，因此，我们将研究吸入NO或其氧化还原同属物亚硝酸盐乙酯在治疗肺部炎症中的可能使用，以进一步了解涉及肺部炎症疾病的分子机制，以及NO如何改变这些机制，我们将检查组织内和洗胃内活性物质的潜在蛋白质靶点，特别是。我们将评估硝化蛋白、s -亚硝基化蛋白和氧化蛋白的生产。这些实验可能会导致有关反应性物种的生理信号通路以及这些通路在炎症期间如何改变的有价值的信息。最后，我们将研究纯化SP-D对表型的拯救如何受到no介导的SP-D修饰的影响。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.