The Anti-Inflammatory Role of Bilirubin on "Two-Hit" Sepsis Animal Model.

INTRODUCTION: Bilirubin is a product of the heme catabolism pathway, and it is excreted in bile and removed from the body through the urine. Bilirubin has potent antioxidant properties but also plays a role in anti-inflammation by protecting the body against endotoxin-induced lung inflammation, down-regulating the expression of adhesion molecules, and inhibiting the infiltration of inflammatory cells. Thus, bilirubin is a promising agent that could use in inflammation disease treatment. The application of bilirubin on the "two-hit" sepsis animal model has been, to date, unknown. METHODS: we used lipopolysaccharide to induce initial insults in C57BL/6 mice. After 24 h, mice underwent cecal ligation and puncture to induce the "two-hit" sepsis model. Next, mice were administered 30 mg/kg bilirubin and we observed an improvement. RESULTS: We observed that bilirubin inhibited the expression of pro-inflammatory cytokines, while the levels of anti-inflammatory cytokines were significantly augmented in the lung. Bilirubin improved the survival rate in the sepsis model. Furthermore, we suggest that bilirubin can modulate the accumulation of T-regulatory cells and myeloid-derived suppressor cells. Notably, bilirubin suppressed the activation and functions of T-cells. CONCLUSIONS: These results clarified that bilirubin might improve tissue injury in sepsis through anti-inflammatory mechanisms.

Comparison of oncological benefits of deep neuromuscular block in obese patients with gastric cancer (DEBLOQS_GC study): A study protocol for a double-blind, randomized controlled trial.

PURPOSE: Many studies have demonstrated the advantage of maintaining intraoperative deep neuromuscular block (NMB) with sugammadex. This trial is designed to evaluate the impact of muscle relaxation during laparoscopic subtotal gastrectomy on the oncological benefits, particularly in obese patients with gastric cancer. MATERIALS AND METHODS: This is a double-blind, randomized controlled multicenter prospective trial. Patients with clinical stage I-II gastric cancer with a body mass index of 25 and over, who undergo laparoscopic subtotal gastrectomy will be eligible for trial inclusion. The patients will be randomized into a deep NMB group or a moderate NMB group with a 1:1 ratio. A total of 196 patients (98 per group) are required. The primary endpoint is the number of harvested lymph nodes, which is a critical index of the quality of surgery in gastric cancer treatment. The secondary endpoints are surgeon's surgical condition score, patient's sedation score, and surgical outcomes including peak inspiratory pressure, operation time, postoperative pain, and morbidity. DISCUSSION: This is the first study that compares deep NMB with moderate NMB during laparoscopic gastrectomy in obese patients with gastric cancer. We hope to show the oncologic benefits of deep NMB compared with moderate NMB during subtotal gastrectomy. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov (NCT03196791), date of registration: October 10, 2017.

The Effects of Flecainide Acetate on Inflammatory-Immune Response in Lipopolysaccharide-Stimulated Neutrophils and on Mortality in Septic Rats.

BACKGROUND: Flecainide acetate is a drug used primarily for cardiac arrhythmia. Some studies also imply that flecainide acetate has the potential to regulate inflammatory-immune responses; however, its mechanism of action is contended. We determined the effects of flecainide acetate on lipopolysaccharide (LPS)-stimulated human neutrophils in vitro and on mortality in a septic rat model. METHODS: Neutrophils from human blood were cultured with varying concentrations of flecainide acetate (1 µM, 10 µM, or 100 µM) with or without LPS (100 ng/ml). To assess neutrophil activation, the protein levels of tumor necrosis factor-alpha (TNF-α) and interleukin (IL)-6 and IL-8 were measured after a 4-hour culture period. To assess the intracellular signaling pathways, the levels of phosphorylation of p38 mitogen-activated protein kinase (p38), extracellular signal-regulated kinase (ERK) 1/2, and c-Jun N-terminal kinase (JNK) were measured after a 30-minute culture period, and the nuclear translocation of nuclear factor (NF)-κB was measured after a 1-hour culture period. Additionally, the survival rate was investigated in a rat sepsis model. RESULTS: Flecainide acetate down-regulated the activation of proinflammatory cytokines, including TNF-α and IL-6 and IL-8, and intracellular signaling pathways including ERK 1/2 and NF-κB. Flecainide acetate also improved the survival rate in the rat sepsis model. CONCLUSIONS: Collectively, these findings indicate that flecainide acetate can improve survival in a rat sepsis model by attenuating LPS-induced neutrophil responses. We therefore suggest that flecainide acetate plays an important role in modulating inflammatory-immune responses.