Bile pigments in emergency and critical care medicine

Abstract

Bile pigments, such as bilirubin and biliverdin, are end products of the heme degradation pathway in mammals and are widely known for their cytotoxic effects. However, recent studies have revealed that they exert cytoprotective effects through antioxidative, anti-inflammatory, and immunosuppressive properties. All these mechanisms are indispensable in the treatment of diseases in the field of emergency and critical care medicine, such as coronary ischemia, stroke, encephalomyelitis, acute lung injury/acute respiratory distress syndrome, mesenteric ischemia, and sepsis. While further research is required before the safe application of bile pigments in the clinical setting, their underlying mechanisms shed light on their utilization as therapeutic agents in the field of emergency and critical care medicine. This article aims to summarize the current understanding of bile pigments and re-evaluate their therapeutic potential in the diseases listed above.

Keywords: Antioxidant therapy; Bile pigments; Emergency and critical care medicine.

Fig. 1

Bilirubin-biliverdin redox cycle. In the BR-BV redox cycle, BR reductase reduces BV by using NADPH and H + as an electron donor. This forms the products BR and NADP + . When BR is oxidized by ROS, BR reverts to become BV once again. This BV-BR redox cycle demonstrates the potential antioxidative properties of bile pigments in multiple disease models. (BR: bilirubin, BV: biliverdin, ROS: reactive oxygen species)

Fig. 2

Bile pigments and cardiovascular diseases. CL is bound to cytc in the inner mitochondrial membrane and is released during the early stages of apoptosis in cardiomyocytes. Once oxidized by ROS, cytc leaves the mitochondria through the outer mitochondrial membrane and takes part in apoptosis. It is thought that the antioxidative properties of BR inhibit the release of cytc and in turn, prevent apoptosis in cardiomyocytes. Furthermore, BR administration is known to inhibit inflammation through downregulation of TNF-α, NOX-2, and MCP-1 during cardiac ischemia/reperfusion injury. (CL: cardiolipin, cytc: cytochrome c, ROS: reactive oxygen species, BR: bilirubin, TNF: tumor necrosis factor, NOX: nicotinamide adenine dinucleotide phosphate oxidase, MCP: monocyte chemoattractant protein)

Fig. 3

Bile pigments and encephalomyelitis. In encephalomyelitis, BR acts an important immunomodulator through multiple mechanisms, especially in T cell reactivity. BR inhibits STAT-1 and IκB phosphorylation, which are essential for CIITA and NF-κB activation in T cell activation. BR also achieves this via suppressing the upregulation of CD28, B7-1, and B7-2, and scavenging of ROS. Furthermore, BR treatment notably decreases the production of Th-1, Th-2, and Th-17 cytokines. Through these mechanisms, BR is thought to suppress T cell reactivity and act as a therapeutic agent in encephalomyelitis. (BR: bilirubin, NF-κB: nuclear factor kappa B, ROS: reactive oxygen species, Th: T helper cell)

Fig. 4

Summary of the mechanics of bile pigments in emergency and critical care medicine. The studies mentioned in this review demonstrate that the cytoprotective effects of bile pigments are achieved through its antioxidative, anti-inflammatory, and immunosuppressive properties, which are exhibited in multiple diseases of different etiologies. They are also known to inhibit fibrosis in chronic disease models and take part in miRNA expression and maintain cell integrity. Although many of these mechanisms are not clearly determined, cumulative and multifunctional therapeutic effects of bile pigments shed light on their utilization in the field of emergency and critical care medicine