Surfactant Proteins and NO in Inflammatory Disease

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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.