Alternate day calorie restriction improves systemic inflammation in a mouse model of sepsis induced by cecal ligation and puncture.

BACKGROUND: Calorie restriction (CR) exerts cytoprotective effects by up-regulating survival factors, such as mammalian target of rapamycin (mTOR), sirtuin, and peroxisome proliferator-activated receptor-γ co-activator 1α (PGC-1α). These survival factors have well-established roles in attenuating the inflammatory response. However, it is unclear whether CR affects sepsis-related inflammation. The purpose of this study was to determine whether CR affects sepsis-induced inflammation in a cecal ligation and puncture (CLP)-induced mouse model of sepsis. METHODS: Male C57BL/6N mice underwent alternate day calorie restriction or normal feeding for 8 d before CLP-induced sepsis. After induction of sepsis, liver and lung histopathology and serum levels of cytokines and survival factors were assessed. RESULTS: Serum cytokine and high mobility group box protein 1 (HMGB1) levels were lower in animals that underwent alternate day calorie restriction compared with normally-fed mice after CLP. Alternate day calorie restriction also increased levels of sirtuin, PGC-1α, and mTOR. While 80% of mice in the CLP group died within 48 h after undergoing CLP, 50% of mice died in the ACR + CLP group (P < 0.05). CONCLUSION: Alternate day calorie restriction decreased mortality in a mouse model of sepsis. In addition to attenuated organ injury, a significant reduction in cytokine and HMGB1 levels was observed. These findings suggest that alternative day calorie restriction may reduce excessive inflammation.

Vitamin E derivative ETS-GS reduces liver ischemia-reperfusion injury in rats.

BACKGROUND: Ischemic liver injury is often the result of surgical procedures such as liver transplantation and hepatic resection. Liver damage occurs after reperfusion, leading to increased systemic inflammation. Recent studies have reported that vitamin E and glutathione can ameliorate ischemia-reperfusion (I/R) injury. In the present study, we evaluated the ability of a new vitamin E derivative, ETS-GS, to improve liver I/R injury. MATERIALS AND METHODS: Male Wistar received a subcutaneous injection of ETS-GS (10 mg/kg) or saline before experimentally-induced liver I/R injury or sham treatment. The rats were sacrificed after the 60-min ischemia and 24-h reperfusion. Histology and serum levels of cytokines [tumor necrosis factor (TNF)-α, interleukin (IL)-6, and high-mobility group box 1 (HMGB1) protein] and liver enzymes were determined to evaluate the protective effects of ETS-GS. RESULTS: We found that ETS-GS treatment attenuated I/R-induced histologic alterations, reduced levels of liver enzymes aspartate aminotransferase (AST), alanine aminotransferase (ALT), and lactate dehydrogenase (LDH). In addition, ETS-GS treatment decreased serum cytokine levels. CONCLUSIONS: Taken together, our results demonstrate that ETS-GS attenuates I/R injury in a rat model and suggests that ETS-GS may exert anti-inflammatory effects. Accordingly, ETS-GS may have therapeutic potential to treat various clinical conditions involving I/R injury.

Remifentanil and glucose suppress inflammation in a rat model of surgical stress.

PURPOSE: Postoperative stress produces an inflammatory response. Recent studies have shown that narcotic analgesics suppress the immune system. Nutritional management during perioperative care has also been reported to affect inflammation. We therefore examined whether remifentanil or glucose administration could ameliorate postsurgical inflammatory responses using a rat model of surgical stress. METHODS: We divided male Wistar rats randomly into five groups: (1) control, (2) sevoflurane+lactated Ringer's solution, (3) sevoflurane+lactated Ringer's solution with 1% glucose, (4) sevoflurane+remifentanil+lactated Ringer's solution, and (5) sevoflurane+remifentanil+ lactated Ringer's solution with 1% glucose. In all groups, serum samples were obtained at various time points after surgery, and secreted cytokine concentrations were determined. In addition, we assessed the activation of protein kinase B (Akt) and forkhead/winged helix box class O (FOXO3), which play a role in gluconeogenesis/stress responses. RESULTS: Surgical stress increased the serum concentrations of tumor necrosis factor-α and interleukin-6. Groups receiving remifentanil with anesthesia showed an attenuated inflammatory response. The inflammatory response was also reduced by administering 1% glucose. Furthermore, 1% glucose induced Akt and FOXO3 phosphorylation in the quadriceps femoris muscle 12 h after surgery. CONCLUSIONS: Anesthesia based on remifentanil and perioperative administration of lactated Ringer's solution containing 1% glucose may be able to control inflammatory responses caused by surgical stress.

Total parenteral-nutrition-mediated dendritic-cell activation and infiltration into the small intestine in a rat model.

PURPOSE: Total parenteral nutrition (TPN) is commonly carried out in the clinical setting. However, effects of TPN on the immune system, including dendritic cells (DC), are not well understood. The purpose of this study was to determine whether TPN affects DC activation and infiltration into the intestinal barrier. METHODS: Male Wistar rats were given conventional nutrition (CN) or TPN for 7 days. DCs were visualized by immunohistochemistry. Levels of nucleotide-binding oligomerization domain protein 2 (NOD2) and high-mobility group box 1 (HMGB1) protein were assessed by Western blot. RESULTS: The number of DCs at the small intestinal barrier was significantly increased in the TPN group (9.2 ± 3.1 cells/microscopic field) compared with the CN group (0.5 ± 0.6 cells/microscopic field; p < 0.05), as were protein expression levels of NOD2 and HMGB1. CONCLUSION: These results suggest that TPN increases activation and infiltration of DCs into the small intestine, potentially involving an increase in NOD2 and HMGB1 levels in the small intestine.

Dendritic cell activation in response to ischemia-reperfusion injury of the small intestine.

PURPOSE: Recent studies have increased our understanding of the important role that the immune system plays in ischemia-reperfusion (I/R) injury. Although dendritic cells (DCs) are important regulators of intestinal immunity, their role in the response to intestinal I/R injury is not well understood. The aim of this study was to determine whether I/R injury affects DC infiltration into the intestinal barrier. METHODS: Wistar rats were subjected to I/R injury or a sham operation. Dendritic cells were visualized by immunohistochemistry, and after 12 h of reperfusion protein levels for nucleotide-binding oligomerization domain protein 2 (NOD2), high-mobility group box 1 (HMGB1), and Toll-like receptor 4 (TLR4) were assayed by Western blotting. RESULTS: The number of DCs increased at the small intestine barrier in response to intestinal I/R. A Western blot analysis of small intestinal tissue revealed that levels of NOD2, HMGB1, and TLR4 protein increased in rats subjected to I/R injury in comparison to control rats. CONCLUSIONS: These results suggest that intestinal I/R increases the infiltration of DCs into the small intestine, thus potentially involving the upregulation of NOD2, HMGB1, and TLR4. Therefore, intestinal I/R might activate DCs through NOD2 and HMGB1.

Heat shock protein 72 protects insulin-secreting beta cells from lipopolysaccharide-induced endoplasmic reticulum stress.

PURPOSE: Hyperthermia-induced activation of stress response proteins allows cells to withstand metabolic insults. In this study we set out to determine whether insulin secretion by pancreatic beta cells was affected by the acute inflammatory response, systemic inflammation-induced hyperglycaemia, and whole-body hyperthermia. Given that systemic-inflammation induces ER stress, we further examined whether hyperthermia can attenuate the extent of LPS-induced ER stress. MATERIALS AND METHODS: Rats were randomised and divided into three treatment groups. Control rats received a 0.9% NaCl solution. Rats in the lipopolysaccharide (LPS) group received 7.5 mg of LPS/kg. Rats in the whole-body hyperthermia (WBH) + LPS group were exposed to 42 degrees C for 15 min, followed by injection with 7.5 mg of LPS/kg after 48 h. Glucose-potentiated insulin release and extent of ER stress were measured in beta cells. RESULTS: LPS inhibited glucose-induced insulin release from islet cells and induced the expression of Bip/GRP78, XBP-1, and CHOP transcripts. The inhibition of glucose-induced insulin release and induction of ER stress proteins by LPS was attenuated by WBH. CONCLUSIONS: Our findings suggest that LPS-induced systemic inflammation decreased insulin release due to the effects of ER stress proteins on insulin secretion. Furthermore, the induction of ER stress proteins was prevented by pretreating rats with WBH. This may suggest that inhibiting the induction of ER stress proteins through WBH can restore insulin release in various disease states.

Hyperglycemia contributes to cardiac dysfunction in a lipopolysaccharide-induced systemic inflammation model.

OBJECTIVES: Hyperglycemia is frequently observed in nondiabetic patients during acute illness. Furthermore, intensive insulin therapy significantly reduces mortality and morbidity due to several critical illnesses, including cardiac or infectious diseases. The purpose of this study was to determine whether cardiac function is affected by hyperglycemia and its treatment with insulin. DESIGN: Lipopolysaccharide (LPS) was administered intravenously to rats, with or without the administration of insulin with glucose. SETTING: University Medical Center research laboratory. SUBJECTS: Male Wistar rats. INTERVENTIONS: In this study, we determined the effect of hyperglycemia and insulin therapy on cardiac function in an LPS-induced systemic inflammation model. MEASUREMENTS AND MAIN RESULTS: Levels of serum cytokines, nitrate/nitrite, and high-mobility group box 1 protein after LPS treatment were measured in hyperglycemic rats and those treated with insulin. The following parameters were examined to assess cardiac function in Langendorff-perfused hearts: left ventricular developed pressure, left ventricular end-diastolic pressure, and left ventricular pressure development during isovolumetric contraction (+dP/dtmax) and relaxation (-dP/dtmin). We observed that levels of cytokines, nitrate/nitrite, and high-mobility group box 1 significantly increased. However, treatment of hyperglycemic rats with insulin was associated with significantly less severe disease as assessed by cytokine levels. Furthermore, hyperglycemia was associated with decreased +dP/dtmax and -dP/dtmin in Langendorff-perfused hearts of hyperglycemic rats, whereas insulin treatment improved these parameters. CONCLUSIONS: Hyperglycemia was associated with the induction of various inflammatory mediators and an inhibition of cardiac function. Treatment of hyperglycemia with insulin protected against inflammation and cardiac dysfunction in a rat model of LPS-induced systemic inflammation. This improvement is likely because of the neutralization of deleterious effects associated with hyperglycemia and the specific actions of insulin on the inflammatory response.

Danaparoid sodium prevents cerulein-induced acute pancreatitis in rats.

Systemic inflammatory mediators, including the protein high-mobility group box 1 (HMGB1), play an important role in the development of acute pancreatitis. Anticoagulants such as danaparoid sodium (DA) may be able to inhibit sepsis-induced inflammation, but the mechanism of action is not well understood. We hypothesized that DA would act as an inhibitor of inflammation and prevent cerulein-induced acute pancreatitis. Male Wistar rats were used as subjects in this study. Each received a bolus of 50 U/kg of DA or saline-injected into the tail vein, followed by 4 injections of 50 mg/kg cerulean (i.p.) at 1-h intervals. Cytokine (IL-6), NO, and HMGB1 levels in serum and pancreatic tissue were measured after the cerulein injection. Pancreas histopathology and wet-dry ratio significantly improved in the DA-injected (50 U/kg) animals compared with saline-injected rats. Serum and pancreatic HMGB1 levels decreased over time in DA-treated animals. Danaparoid sodium also decreased cytokine, NO, and HMGB1 levels during cerulein-induced inflammation. As a result, DA ameliorated pancreas pathology in the rat model of cerulein-induced acute pancreatitis. This study demonstrates that DA treatment prevents cerulein-induced acute pancreatitis in a rat model. This effect may be mediated through inhibition of cytokines, NO, and HMGB1.

High-dose intravenous immunoglobulin G improves systemic inflammation in a rat model of CLP-induced sepsis.

OBJECTIVE: Intravenous immunoglobulin therapy has been proposed as an advanced treatment for sepsis. Yet, its benefit remains unclear and the mechanism of action is poorly understood. One key mediator in the development of sepsis is high mobility group box 1 (HMGB1). Therefore, we examined the serum and lung tissue levels of HMGB1 in a rat model of sepsis. DESIGN AND SETTING: Prospective controlled animal study in a university laboratory. MATERIALS: Rats received either cecal ligation and puncture-induced sepsis or had additional intravenous immunoglobulin treatment in boluses of 100, 300, or 1,000 mg/kg. MEASUREMENTS AND RESULTS: After induction of sepsis and respective treatment conditions, histopathology, wet/dry weight ratios, and signaling molecules were examined in pulmonary tissue. Serum and pulmonary levels of cytokine and HMGB1 were measured. High dose intravenous immunoglobulin (1,000 mg/kg)-treated animals demonstrated significantly improved survival and pulmonary histopathology compared to the control rats. Serum and pulmonary HMGB1 levels were lower over time among intravenous immunoglobulin-treated animals. Furthermore, administration of intravenous immunoglobulin resulted in inhibition of NF-kappaB activity. CONCLUSIONS: High-dose intravenous immunoglobulin decreased the mortality and pulmonary pathology in a rat model of sepsis. A significant reduction in HMGB1 levels was also observed, which may be mediated by inhibition of inflammation and NF-kappaB. DESCRIPTOR: 23. Acute respiratory distress syndrome (ARDS) and acute lung injury (ALI): experimental models.