Biliverdin administration protects against endotoxin-induced acute lung injury in rats

• Published in: American journal of physiology. Lung cellular and molecular physiology Vol. 289; no. 6; pp. L1131 - L1137
• Main Authors: Sarady-Andrews, Judit K, Liu, Fang, Gallo, David, Nakao, Atsunori, Overhaus, Marcus, Ollinger, Robert, Choi, Augustine M, Otterbein, Leo E
• Format: Journal Article
• Language: English
• Published: United States 01.12.2005
• Subjects: Animals; Biliverdine - administration & dosage; Capillary Permeability - drug effects; Endothelial Cells - metabolism; Endothelial Cells - pathology; Heme Oxygenase-1 - metabolism; Interleukin-10 - metabolism; Interleukin-6 - metabolism; Lipopolysaccharides - toxicity; Lung - metabolism; Lung - pathology; Lung Injury; Macrophages - metabolism; Macrophages - pathology; Male; Pneumonia - chemically induced; Pneumonia - drug therapy; Pneumonia - metabolism; Pneumonia - pathology; Rats; Rats, Sprague-Dawley; Shock, Septic - chemically induced; Shock, Septic - drug therapy; Shock, Septic - metabolism; Shock, Septic - pathology; Time
• ISSN: 1040-0605; 1522-1504
• DOI: 10.1152/ajplung.00458.2004

1 Department of Surgery, Beth Israel Deaconess Medical Center, Boston, Massachusetts; 2 Division of Pulmonary Allergy and Critical Care Medicine, 3 Department of Surgery, and 4 Division of Gastroenterology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; and 5 Department of Surgery, Innsbruck Medical University, Innsbruck, Austria Submitted 9 December 2004 ; accepted in final form 1 July 2005 Given the high morbidity and mortality rates associated with pulmonary inflammation in sepsis, there is a pressing need for new therapeutic modalities to prevent acute respiratory distress. The enzyme heme oxygenase-1 (HO-1) provides potent cytoprotection against lung injury; however, the mechanism by which it does so is unclear. HO-1 catabolizes heme into biliverdin (BV), which is rapidly converted to bilirubin by BV reductase. We tested the hypothesis that BV administration could substitute for the effects observed with HO-1. Using the well-described rat model of LPS-induced shock, we demonstrate that exposure to BV imparts a potent defense against lethal endotoxemia systemically, as well as in the lungs, and effectively abrogates the inflammatory response. BV administration before a lethal dose of LPS leads to a significant improvement in long-term survival: 87% vs. 20% in sham-treated controls. BV treatment suppressed LPS-induced increases in lung permeability and lung alveolitis and significantly reduced serum levels of the LPS-induced proinflammatory cytokine IL-6. Moreover, bilirubin administered just after LPS also abrogated lung inflammation. BV treatment also augmented expression of the anti-inflammatory cytokine IL-10. Similar effects on production were observed with BV treatment in vitro in mouse lung endothelial cells and RAW 264.7 macrophages treated with LPS. In conclusion, these data demonstrate that BV can modulate the inflammatory response and suppress pathophysiological changes in the lung and may therefore have therapeutic application in inflammatory disease states of the lung. biliverdin reductase; oxidative stress; inflammation; heme oxygenase-1 Address for reprint requests and other correspondence: L. E. Otterbein, Harvard Medical School, Beth Israel Deaconess Medical Center, 99 Brookline Ave., Ste. 370G, Boston, MA 02215 (e-mail: lotterbe{at}bidmc.harvard.edu )