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Respiratory Health In The FY17 PRMRP Case Study

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In this application, we propose to address Respiratory Health in the FY17 PRMRP topic area. Inhalation of harmful chemicals and particles, which include potentially toxic metals such as cadmium, titanium and aluminum, silica, heavy metals, numerous organic compounds, and airborne contaminants associated with degraded soil during military deployment and service may induce respiratory problems. Moreover, cigarette smoking is very popular among military personnel and is main risk factors of pulmonary emphysema development, which is characterized by alveolar wall destruction. Alveolar type II (ATII) cells have a highly oxidative phenotype and numerous mitochondria. They are heavily dependent on mitochondrial function for energy generation …show more content…

(8). Our preliminary data indicate that alveolar type (ATII) cells isolated from individuals with emphysema have higher nuclear DSBs than control smokers or nonsmokers. Moreover, we observed an increase in mtDNA damage in ATII cells in this disease in comparison with controls. We also found lower XRCC4-like factor (XLF) expression, which is involved in NHEJ pathway (9, 10), in ATII cells in emphysema in comparison with controls. Furthermore, we detected that high oxidative stress induced by exposure to cigarette smoke induces XLF oxidation and localization in mitochondria. DJ-1 is a cytoprotective protein localized in mitochondria. However, we observed that it interacts with XLF in ATII cells in emphysema, which indicates the critical role of XLF/DJ-1 complex in mitochondrial function. In addition, our results suggest that the number of mitochondria is decreased in these cells isolated from emphysema patients in comparison with control smokers and nonsmokers. Our hypothesis is that high levels of ROS in emphysema induce XLF oxidation and mtDNA damage leading to mitophagy and cell death (Fig. 1). Elucidating the molecular mechanisms contributing to mitophagy in primary ATII cells will advance our understanding of the contribution of mitochondria physiology to emphysema development. ATII cells will be isolated from excess tissue obtained from lung transplants of patients with emphysema, Veterans with respiratory problems and from control organ donors

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