Abstract

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.

Highlights

  • Bilirubin is a product of the heme catabolism pathway, and it is excreted in bile and removed from the body through the urine

  • About 70% of mice in the cecal ligation and puncture (CLP) group had survived at 2 days after CLP, Int

  • Bilirubin has been known as a toxic product of heme catabolism

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Summary

Introduction

Bilirubin is a product of the heme catabolism pathway, and it is excreted in bile and removed from the body through the urine. After 24 h, mice underwent cecal ligation and puncture to induce the “two-hit” sepsis model. Pathogen-associated molecular patterns (peptidoglycan, lipoproteins, lipopolysaccharides, CpG-containing DNA, and flagellin) and damage-associated molecular patterns (high-mobility group box 1 and histones) are recognized by pattern recognition receptors on the surface of macrophages, neutrophils, dendritic cells, and lymphocytes. The presence of these may trigger the activation of intracellular signal pathways leading to systemic inflammatory response syndrome (SIRS) [1,3]. SIRS reactions are stimulated by initial microorganism insults, creating a so-called cytokine storm, recognized by the secretion of inflammatory mediators such as tumor necrosis factor-alpha (TNF-α), interleukin (IL)-6, and interferon-gamma (IFN-γ) [6]. Uncontrolled overproduction of SIRS is aggravated in patients with sepsis, leading to early organ failures [1,5]

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