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Table 1 Summary of studies that investigate the therapeutic potential and detrimental effects of bilirubin (BR) and biliverdin (BV)

From: Bile pigments in emergency and critical care medicine

Summary

Species

Disease

References

Detrimental effects

 Elevated BV levels are associated with increased mortality in patients with paracetamol-induced hepatic necrosis

Human

Paracetamol-induced hepatic necrosis

[61]

 Neonatal exposure to high levels of BR causes severe motor symptoms and cerebral palsy

Human

Cerebral palsy

[62]

 Unbound BR is strongly associated with auditory toxicity in neonates greater than or equal to 34 weeks of gestational age

Human

Auditory toxicity

[63]

 Neonatal conditioning with concurrent hyperbilirubinemia and hypoxia-induced acidosis promoted long-term impairments in learning and memory complex sensorimotor functions. The toxicity is exacerbated through the activity of ASIC channels

Human, mouse

BR-induced neurotoxicity

[64]

Beneficial effects

 Intraperitoneal BR administration decreases infarct area in coronary I/R injury by preventing the oxidation of cardiolipin in the early cell death pathway

Rat

Cardiac I/R injury

[25]

 BR nanoparticle administration ameliorate mRNA expression of inflammatory markers and monocyte infiltration during cardiac I/R injury

Mouse

Cardiac I/R injury

[28]

 Intraperitoneal BV administration protected brain cells from oxidative injuries in MCA occlusion followed by reperfusion

Rat

Brain I/R injury

[32]

 BR suppressed polyclonal and antigen-specific T cell responses in experimental autoimmune encephalomyelitis in mice

Mouse

Autoimmune Encephalomyelitis

[35]

 BR nanoparticles delayed onset and progression of autoimmune encephalomyelitis and reduced the severity of the disease by acting on dendritic cells

Mouse

Autoimmune Encephalomyelitis

[36]

 BV administration prevented gene expression of inflammatory mediators and gene fragmentation due to oxidative stress in acute lung injury/acute respiratory distress syndrome

Rat

Acute lung injury/acute respiratory distress syndrome

[38]

 Hyperbilirubinemia ameliorated bleomycin-induced pulmonary fibrosis in rats

Rat

Bleomycin-induced pulmonary fibrosis

[41]

 Bile pigment administration improved mesenteric I/R injury through its antioxidative properties

Rat

Mesenteric I/R injury

[43, 44]

 BV administration achieves cytoprotective effects in mesenteric I/R injury through the suppression of NK-κB activation

Human

Mesenteric I/R injury

[46]

 Intraperitoneal administration of BV improved host survival via the inhibition of inflammatory and oxidative markers, reduced neutrophil migration, and suppression of mucosal degradation

Rat

Intestinal transplantation

[49, 50]

 BV maintained lung function post-transplantation and mitigated damage through the inhibition of inflammatory markers and MDA levels

Rat

Lung transplantation

[51]

 BV administration ameliorated vascular endothelial injury caused by I/R and mechanical trauma

Rat

Vein graft and balloon injury

[52]

 Hyperbilirubinemia prolonged graft survival and reduced acute rejection in heart transplantation

Rat

Cardiac transplantation

[53]

 BV modulates inflammatory mediators and improves gastrointestinal function in polymicrobial sepsis

Rat

Sepsis

[54]

 BV administration reduced endotoxemia-induced cellular damage in lungs and improved survival rates

Rat

Sepsis

[56]