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McMaster University

1. Khan, Momina. Investigating implications and mechanisms of diet induced obesity for multi organ function in a murine model of early sepsis.

Degree: PhD, 2017, McMaster University

Given the current obesity epidemic, the prevalence of overweight and obese patients with critical illness is increasing rapidly, however how obesity shapes critical illness and immune response to infection is not entirely understood. We developed a clinically relevant murine model of obesity in the context of sepsis, and examined organ specific inflammatory responses. Male C57BL/6 mice were fed either a high fat Western Diet (WD) (Modified Breslow, 21% Butterfat and 0.15% cholesterol) or normal chow diet (NCD) for 6, 15 or 27 weeks. Sepsis was induced by cecal ligation and perforation (CLP), and six hours post-surgery, plasma and tissue samples were harvested and flash frozen in liquid nitrogen. Septic obese mice at 15 and 27 weeks had significantly (p<0.0001) lower levels of lung myeloperoxidase (26.3±3.8 U/mg tissue) compared to age matched ad libitum (44.1±2.8 U/mg tissue) and diet restricted (63.2±5.60 U/mg tissue) controls, indicative of less lung inflammation. Obese mice (4.23±0.10g) had significantly enlarged livers compared to controls (1.55±0.80g and 1.22±0.031g), with pronounced steatosis, and hepatocyte ballooning, independent of sepsis. These findings are in congruence with clinical observations that obese individuals are protected from sepsis-induced lung injury, however the mechanisms involved are not entirely clear. We also examined effects of housing conditions on susceptibility to developing metabolic syndrome, and inflammatory response in our obesity and sepsis model. For this study, animals were fed either WD or NCD for 15 weeks and were housed in static or ventilated cages. Unlike static cages, ventilated cages have HEPA filtered air supply system and exhaust air ventilation, protecting the animals from air borne particles and preserving the microbiological barrier. Therefore, ventilated cages provide a more sterile environment compared to static cages. After 15 weeks, fecal matter was collected from the cages and mice were subjected to sepsis using the CLP technique. Six hours post surgery, animals were sacrificed and tissues were harvested, snap frozen and stored at -80°C. The animals from the more sterile environment (ventilated cages) had significantly (p<0.0001) less weight gain and did not show signs of overt hyperglycemia, compared to mice housed in a less sterile environment (static cages). In addition, obese mice housed in static cages had less lung injury compared to controls during early sepsis, however this difference was not evident in mice from ventilated cages. There were also significant differences in the fecal microbe composition, where ventilated groups had greater Firmicutes (69% ± 0.06% for WD and 76% ± 0.03%) and less Bacteroidetes population (15% ± 0.04% for WD and 12% ± 0.02% for NCD) compared to static groups (Firmicutes: 42% ± 0.08% for WD and 24% ± 0.02% for NCD, Bacteroidetes: 37% ± 12% for WD and 53% ± 29% for NCD). This study highlighted the impact of environment on the susceptibility to developing metabolic syndrome, and the potential impact on the associated… Advisors/Committee Members: Fox-Robichaud, Alison, Medical Sciences.

Subjects/Keywords: obesity; early sepsis; inflammation

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APA (6th Edition):

Khan, M. (2017). Investigating implications and mechanisms of diet induced obesity for multi organ function in a murine model of early sepsis. (Doctoral Dissertation). McMaster University. Retrieved from http://hdl.handle.net/11375/21972

Chicago Manual of Style (16th Edition):

Khan, Momina. “Investigating implications and mechanisms of diet induced obesity for multi organ function in a murine model of early sepsis.” 2017. Doctoral Dissertation, McMaster University. Accessed October 23, 2017. http://hdl.handle.net/11375/21972.

MLA Handbook (7th Edition):

Khan, Momina. “Investigating implications and mechanisms of diet induced obesity for multi organ function in a murine model of early sepsis.” 2017. Web. 23 Oct 2017.

Vancouver:

Khan M. Investigating implications and mechanisms of diet induced obesity for multi organ function in a murine model of early sepsis. [Internet] [Doctoral dissertation]. McMaster University; 2017. [cited 2017 Oct 23]. Available from: http://hdl.handle.net/11375/21972.

Council of Science Editors:

Khan M. Investigating implications and mechanisms of diet induced obesity for multi organ function in a murine model of early sepsis. [Doctoral Dissertation]. McMaster University; 2017. Available from: http://hdl.handle.net/11375/21972

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