Single bolus injection of bilirubin improves the clinical outcome in a mouse model of endotoxemia.
Increasing serum levels of biliverdin and bilirubin was shown to be beneficial in settings of inflammation. Bilirubin was shown to be protective in LPS-induced lung injury in rats; however, the exact mechanism remains elusive. Here, we investigated whether a single bolus injection of bilirubin would exert anti-inflammatory effects in a mouse model of endotoxemia. Mice were challenged with sublethal doses (2 mg/kg body weight) of LPS, and the effects of intravenously administered bilirubin (40 mg/kg body weight) were assessed. In contrast to control animals, bilirubin-treated animals fully recovered from endotoxin shock within 24 h. Bilirubin treatment improved the clinical score significantly at all time points assessed, attenuated weight loss, and improved LPS-induced anorexia. Furthermore, bilirubin treatment inhibited LPS-induced leukocyte-endothelial interactions and leukocyte accumulation in various tissues. Expression of inflammatory genes, including endothelial adhesion molecules, but also IL-1beta and TNF-alpha, was significantly reduced in bilirubin-treated animals. Moreover, bilirubin inhibited LPS-induced expression of inflammatory genes in isolated cultured aortic endothelial cells and in bone marrow-derived macrophages. These data show that single-dose administration of bilirubin attenuates tissue injury induced by endotoxin, and that bilirubin, in addition to its antioxidant effects, also exerts potent anti-inflammatory activity.
Kadl
Alexandra
A
Cardiovascular Research Center and Department of Pharmacology, University of Virginia, Charlottesville, Virginia, USA.
Pontiller
Jens
J
Exner
Markus
M
Leitinger
Norbert
N
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology*; D001663:Bilirubin / Q000097:blood / Q000494:pharmacology*; D001664:Biliverdine / Q000097:blood; D015815:Cell Adhesion Molecules / Q000096:biosynthesis; D002450:Cell Communication / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D019446:Endotoxemia / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects; D018836:Inflammation Mediators / Q000378:metabolism; D053583:Interleukin-1beta / Q000096:biosynthesis; D007962:Leukocytes / Q000378:metabolism / Q000473:pathology; D008070:Lipopolysaccharides / Q000633:toxicity; D008168:Lung / Q000378:metabolism / Q000473:pathology; D055370:Lung Injury; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D051381:Rats; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D000893:Anti-Inflammatory Agents; D000975:Antioxidants; D015815:Cell Adhesion Molecules; D018836:Inflammation Mediators; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D001664:Biliverdine; D001663:Bilirubin