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

Judit K. Sarady-Andrews, Fang Liu, David Gallo, Atsunori Nakao, Marcus Overhaus, Robert Öllinger, Augustine M. Choi, Leo E. Otterbein

Research output: Contribution to journalArticle

146 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)L1131-L1137
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume289
Issue number6 33-6
DOIs
Publication statusPublished - Dec 1 2005
Externally publishedYes

    Fingerprint

Keywords

  • Biliverdin reductase
  • Heme oxygenase-1
  • Inflammation
  • Oxidative stress

ASJC Scopus subject areas

  • Physiology
  • Pulmonary and Respiratory Medicine
  • Physiology (medical)
  • Cell Biology

Cite this

Sarady-Andrews, J. K., Liu, F., Gallo, D., Nakao, A., Overhaus, M., Öllinger, R., Choi, A. M., & Otterbein, L. E. (2005). Biliverdin administration protects against endotoxin-induced acute lung injury in rats. American Journal of Physiology - Lung Cellular and Molecular Physiology, 289(6 33-6), L1131-L1137. https://doi.org/10.1152/ajplung.00458.2004