The role of neutrophil elastase in the development of obesity related tissue damage
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Obesity is increasing worldwide, and the associated health-risks are also on the rise. Eventually, obesity related tissue damage leads to complications such as chronic inflammation, diabetes, cardiovascular disease, and non-alcoholic fatty liver disease. Adipose tissue expansion in obesity triggers specific mechanisms that cause tissue damage. The immune system is especially agitated with excessive fat accumulation, which triggers inflammation and subsequent immune cell infiltration of tissue. Neutrophils are a major immune cell that cause damage in obesity, and the protease neutrophil elastase (NE) is a major neutrophil released factor of tissue damage. The goal of this study is to use tissue extracted from neutrophil elastase knockout (NEKO) mice that have been fed a high-fat high-fructose diet (HFHFD), and compare them to wild-type (WT) mice fed a normal chow diet (NCD), high-fat diet (HFD), and HFHFD to understand the effect of neutrophil elastase damage in obesity. Tissue from aged (NEKO) mice will also be examined to evaluate the role of neutrophils and NE in tissue damage in aging and obesity. Mice in these experimental groups were sacrificed and had their tissue extracted for various staining protocols to discover the extent of tissue damage and immune cell infiltration between mice with and mice without NE. One experiment had 4 different diets fed to mice. The other experiment had mice aged for 2 years, and mice aged for 3 months and 4 months. Mice from the first experiment were fed for 4 months and separated into 4 groups based on diet, WT-NCD, WT-HFD, WT-HFHFD, and NEKO-HFHFD. Our data indicates that, in comparison with WT-HFHF mice, NEKO-HFHFD mice had less steatosis, fibrosis, immune cell infiltration, and apoptosis within the liver. Neutrophil infiltration into the liver is increased by the HFHFD diet. HFHFD diet also stimulates fibrosis, as indicated by collagen deposition in the liver. Neutrophil accumulation is also associated with the increase of macrophages and CD4 Th Cells in the liver, particularly in WT mice fed the HFHFD. Interestingly, the liver from NEKO-HFHFD mice had dramatically reduced infiltration of neutrophils, macrophages, and CD4+ Th cells. Our data suggests that NE is required for HFHFD induced inflammation and fibrosis in the liver. Mice from the second experiment were split into 3 groups based on age, WT-Young (3 months and 4 months), WT-Old, and NEKO-Old. All groups were fed the same normal chow diet, but WT Old and NE KO Old were both aged to 2 years old. Our data revealed that NE deletion in aged mice reduced fibrosis, elastin fragmentation, calcification, and presence of NE within the aorta. While part of the mechanism for neutrophil elastase related tissue damage has been explored through this one-year master degree research project, more work is needed to fully understand how NE is stimulated and causes tissue damage. Future work should examine the potential interaction between neutrophils and other immune cells in obesity and aging.
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