This application is submitted in response to the broad challenge area of Translational Science (15-ES-101*) and the specific challenge topic of """"""""Effects of environmental exposures on phenotypic outcomes using non- human models."""""""" Chronic inflammatory diseases of the airways such as asthma or chronic obstructive pulmonary disease (COPD) arise from a complex interaction between genetic factors and environmental exposures. Our laboratory has established murine models that mimic the pathology of ozone (O3)-induced exacerbation of airway inflammation. The current application will utilize this model together with gene knockout and conditional over expressor mice to investigate the importance in changes in gene expression and post translational modifications of surfactant protein D, an immunoprotective component of the proximal and distal airway lining. Our studies showed that inhalation of O3, a common air pollutant, induced a significant exacerbation of the asthmatic changes in allergen sensitized mice together with the appearance of abnormal, trimeric SP-D and activated, myeloid dendritic cells. We hypothesize that SP-D acts as a """"""""master switch"""""""" between the onset and resolution of airway inflammation: Native SP-D is a suppressor of activation of the proinflammatory dendritic cells and acts through the C-terminal by binding to the negative signal receptor SIRP. In contrast, a de-oligomerized (trimeric) SP-D that has undergone oxidative damage by O3, activates dendritic cells through the exposed N-terminal by ligating the collagen receptor, calreticulin/CD91. The asthmatic airways are particularly susceptible to O3-induced changes in the SP-D molecule because of the presence of mature myeloid dendritic cells carrying the calreticulin/CD91.
Aim 1 is to investigate the hypothesis that O3-induced exacerbation of allergic airway inflammation is associated with the appearance of SP-D trimers with an active N-terminal domain.
Aim 2 is to study the hypothesis that native SP-D binds to SIRP? and delivers inhibitory signals while trimeric SP-D binds to calreticulin/CD91 and induces proinflammatory activation of NF-kB, TNF and TARC (Ccl17) release by dendritic cells.
Aim 3 is to investigate whether the C- terminal suppresses and the trimeric SP-D activates epithelial migration of bone marrow derived, proinflammatory dendritic cells. In vitro bone-marrow derived dendritic cell cultures and in vivo conditional SP-D expressing mice and adeno-associated virus gene replacement of wild-type and mutant SP-D (mimicking either the C-terminal of the molecule or the SP-D trimer) will be studied for maturation and migration of dendritic cells. Results of this project will yield clinically and scientifically significant information on the role of SP-D in regulation of the innate immune system during O3-induced airway changes and on potential therapeutic utilization of this naturally occurring immuno-protective agent in the lung.
Air pollution, particularly O3, induces exacerbations of asthma that substantially worsen morbidity and mortality. In healthy individuals inhalation of O3 elicits mechanisms such as homeostatic increase in SP-D synthesis that protect the lung from development of chronic damage. Currently neither the mechanism of O3-induced SP-D production nor the consequent alterations of the pulmonary immune system is understood. Results from this application will define the implications of SP-D in O3-induced exacerbation of asthma and will provide novel approaches to manipulate the pulmonary immune system.
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