Hyperbilirubinemia exaggerates endotoxin-induced hypothermia

Abstract

Systemic inflammation is accompanied by an increased production of reactive oxygen species (ROS) and by either fever or hypothermia (or both). To study aseptic systemic inflammation, it is often induced in rats by the intravenous administration of bacterial lipopolysaccharide (LPS). Knowing that bilirubin is a potent ROS scavenger, we compared responses to LPS between normobilirubinemic Gunn rats (heterozygous, asymptomatic; J/C) and hyperbilirubinemic Gunn rats (homozygous, jaundiced; J/J) to establish whether ROS mediate fever and hypothermia in aseptic systemic inflammation. These two genotypes correspond to undisturbed versus drastically suppressed (by bilirubin) tissue accumulation of ROS, respectively. A low dose of LPS (10 mg/kg) caused a typical triphasic fever in both genotypes, without any intergenotype differences. A high dose of LPS (1,000 mg/kg) caused a complex response consisting of early hypothermia followed by late fever. The hypothermic response was markedly exaggerated, whereas the subsequent fever response was strongly attenuated in J/J rats, as compared to J/C rats. J/J rats also tended to respond to 1,000 mg/ kg with blunted surges in plasma levels of all hepatic enzymes studied (alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase), thus suggesting an attenuation of hepatic damage. We propose that the reported exaggeration of LPS-induced hypothermia in J/J rats occurs via direct inhibition of nonshivering thermogenesis by bilirubin and possibly via a direct vasodilatatory action of bilirubin in the skin. This hypothermiaexaggerating effect might be responsible, at least in part, for the observed tendency of J/J rats to be protected from LPS-induced hepatic damage. The attenuation of the fever response to 1,000 mg/kg could be due to either direct actions of bilirubin on thermoeffectors or the ROS-scavenging action of bilirubin. However, the experiments with 10 mg/kg strongly suggest that ROS signaling is not involved in the fever response to low doses of LPS.

Elucidating the role of leptin in systemic inflammation: a study targeting physiological leptin levels in rats and their macrophages

“…*Statistically significant difference between the leptininfused rats and their saline-infused counterparts; †statistical difference from the group not injected with LPS. systemic inflammation is more severe (4,7,23,34,53,63). This phenomenon has been well characterized in rats, and there is now reason to believe that an analogous response exists in human sepsis (12).…”

Fever Is Associated with Reduced, Hypothermia with Increased Mortality in Septic Patients: A Meta-Analysis of Clinical Trials

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