臺灣博碩士論文加值系統

Sepsis is a state of hyperinflammation characterized by impaired host immune responses which can induce multiple organ failure including acute liver dysfunction. Moreover, obesity, a chronic inflammatory condition can aggravate prognosis on sepsis. In this study, we investigated the effects of calcitriol in obese and weight reduction mice with sepsis-induced acute liver dysfunction. C57BL/6 male mice (n = 100) were fed with a high fat diet for 10 weeks to induce obesity. Half of the obese mice were subjected to weight reduction via caloric restriction and changes in dietary fat distribution. This was done by gradually transitioning from 60% kcal fat to 30% kcal fat, and 10% kcal fat distribution, respectively. Cecal ligation and puncture was done to induce sepsis and either saline or calcitriol was intravenously administered post-surgery. Mice were sacrificed at either 12 hours or 24 hours after treatment. The results showed a significant difference between the weight of the obese mice compared with the normal control. Weight reduction group has similar body weight as compared to the normal control. Furthermore, liver weight of the obese group is higher than that of the normal control and weight reduction groups which indicates hepatomegaly. The ALT activity was downregulated in weight reduction groups in comparison to the obese groups. The levels of IL-6 and IL-1ß significantly decreased in the calcitriol-treated and weight reduction groups. Synergistic effects of calcitriol administration and weight reduction resulted on the downregulation of pro-inflammatory cytokines in the plasma such as IL-6, TNF- α, and IL-17A simultaneously increasing the concentrations of IFN- γ, IL-4 and IL-10. We thereby conclude that calcitriol can reduce both systemic and localized hepatic inflammation in septic obese and weight reduction mice. Interestingly, synergistic effects of calcitriol and weight reduction was observed to be more beneficial in our septic obese mouse models.

Sepsis is a state of hyperinflammation characterized by impaired host immune responses which can induce multiple organ failure including acute liver dysfunction. Moreover, obesity, a chronic inflammatory condition can aggravate prognosis on sepsis. In this study, we investigated the effects of calcitriol in obese and weight reduction mice with sepsis-induced acute liver dysfunction. C57BL/6 male mice (n = 100) were fed with a high fat diet for 10 weeks to induce obesity. Half of the obese mice were subjected to weight reduction via caloric restriction and changes in dietary fat distribution. This was done by gradually transitioning from 60% kcal fat to 30% kcal fat, and 10% kcal fat distribution, respectively. Cecal ligation and puncture was done to induce sepsis and either saline or calcitriol was intravenously administered post-surgery. Mice were sacrificed at either 12 hours or 24 hours after treatment. The results showed a significant difference between the weight of the obese mice compared with the normal control. Weight reduction group has similar body weight as compared to the normal control. Furthermore, liver weight of the obese group is higher than that of the normal control and weight reduction groups which indicates hepatomegaly. The ALT activity was downregulated in weight reduction groups in comparison to the obese groups. The levels of IL-6 and IL-1ß significantly decreased in the calcitriol-treated and weight reduction groups. Synergistic effects of calcitriol administration and weight reduction resulted on the downregulation of pro-inflammatory cytokines in the plasma such as IL-6, TNF- α, and IL-17A simultaneously increasing the concentrations of IFN- γ, IL-4 and IL-10. We thereby conclude that calcitriol can reduce both systemic and localized hepatic inflammation in septic obese and weight reduction mice. Interestingly, synergistic effects of calcitriol and weight reduction was observed to be more beneficial in our septic obese mouse models.

Table of Contents
Abstract I
Chapter 1. Introduction 1
1.1 Obesity 1
1.1.1 Definition 1
1.1.2 Pathophysiology 2
1.1.3 Treatment 3
1.2 Weight Reduction 4
1.2.1 Definition 4
1.2.2 Weight reduction in obesity and inflammation 5
1.3 Sepsis 6
1.3.1 Definition 6
1.3.2 Sepsis-induced acute liver dysfunction 9
1.3.3 Immune responses in acute liver injury 10
1.4 Vitamin D 11
1.4.1 Function 11
1.4.2 Synthesis and metabolism 11
1.4.3 Vitamin D status in sepsis 14
1.4.4 Vitamin D function in immune response 14
1.4.5 Vitamin D in sepsis-induced acute liver dysfunction 15
Chapter2. Aims and Hypothesis 16
Chapter 3. Materials and Methods 17
3.1 Animals 17
3.2 Experimental design 17
3.3 Cecal ligation and puncture 21
3.3 Measurement of plasma vitamin D levels 21
3.4 Measurement of plasma ALT activity 21
3.5 Measurement of plasma AST activity 22
3.6 Extraction of hepatic lipids and measurement of liver triglycerides and total cholesterol 22
3.7 Measurement of plasma concentrations of TG 23
3.8 Measurement of plasma TC 23
3.9 Measurement of hepatic non-esterified free fatty acids 23
3.10 Quantification of TBARS in the liver 24
3.11 Quantification of plasma leptin 24
3.12 Plasma concentrations of adiponectin 24
3.13 Measurement of plasma cytokines 25
3.14 Measurement of pro-inflammatory cytokines in the liver 25
3.15 Measurement of inflammatory cytokines and chemokines in the peritoneal lavage fluid 25
3.16 Statistical analysis 26
Chapter 4. Results 27
4.1 Body weight of mice 27
4.2 Organ weight of mice 27
4.3 Relative organ weight of mice 27
4.4 Concentrations of liver enzymes in the plasma 27
4.5 Concentrations of hepatic lipids 28
4.6 Concentrations of plasma lipids 28
4.7 Concentrations of plasma vitamin D 28
4.8 Concentrations of TBARS in the liver 28
4.9 Concentrations of plasma adiponectin and leptin 28
4.10 Concentrations of cytokines in the plasma 29
4.11 Concentrations of of cytokines in the liver 29
4.12 Concentrations of cytokines and chemokines in the PLF 29
Chapter 5. Discussion 43
5.1 Effects of HFD in the weight of the mice 43
5.2 Cecal ligation and puncture as a gold standard technique in sepsis induction 44
5.3 Effects of calcitriol and weight reduction on liver enzymes 44
5.4 Effects of calcitriol and weight reduction on lipid metabolism in sepsis and obesity 45
5.5 Effects of intravenous calcitriol administration on plasma vitamin D levels 46
5.5 Effects of calcitriol and weight reduction on hepatic lipid peroxidation 46
5.6 Effects of calcitriol and weight reduction on plasma leptin and adiponectin 47
5.8 Effects of calcitriol and weight reduction on systemic inflammatory mediators 48
5.9 Effects of calcitriol and weight reduction on hepatic inflammatory markers 49
5.10 Effects of calcitriol and weight reduction on cytokines in the peritoneal lavage fluid 49
Chapter 6. Conclusion 51
References 52

List of Tables
Table 1. Sequential organ failure assessment score (SOFA) [32] 8
Table 2. Compositions of the diets 18
Table 3. Organ weights of mice after 16 weeks of feeding 32
Table 4. Relative organ weights of mice 33

List of Figures
Figure 1. Synthesis and metabolism of vitamin D [45] 13
Figure 2. Diagram of experimental design 20
Figure 3. Body weight of mice after 16 weeks of feeding, 31
Figure 4. Activity of liver enzymes in the plasma. 34
Figure 5. Concentrations of hepatic lipids 35
Figure 6. Concentrations of plasma lipids. 36
Figure 7. Concentration of 25(OH)D in the plasma. 37
Figure 8. Concentrations of TBARS in the liver. 38
Figure 9. Concentrations of adiponectin and leptin in the plasma. 39
Figure 10. Concentrations of pro- and anti-inflammatory cytokines in the plasma. 40
Figure 11. Concentrations of pro-inflammatory cytokines in the liver. 41
Figure 12. Concentrations of cytokines and chemokines in PLF. 42

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