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
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume289
Issue number6 33-6
DOIs
Publication statusPublished - Dec 2005
Externally publishedYes

Fingerprint

Biliverdine
Acute Lung Injury
Endotoxins
Heme Oxygenase-1
Lung
biliverdin reductase
Bilirubin
Pneumonia
Cytokines
Endotoxemia
Cytoprotection
Lung Injury
Heme
Interleukin-10
Lung Diseases
Shock
Permeability
Interleukin-6
Sepsis
Anti-Inflammatory Agents

Keywords

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

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Cell Biology
  • Physiology

Cite this

Biliverdin administration protects against endotoxin-induced acute lung injury in rats. / Sarady-Andrews, Judit K.; Liu, Fang; Gallo, David; Nakao, Atsunori; Overhaus, Marcus; Öllinger, Robert; Choi, Augustine M.; Otterbein, Leo E.

In: American Journal of Physiology - Lung Cellular and Molecular Physiology, Vol. 289, No. 6 33-6, 12.2005.

Research output: Contribution to journalArticle

Sarady-Andrews, Judit K. ; Liu, Fang ; Gallo, David ; Nakao, Atsunori ; Overhaus, Marcus ; Öllinger, Robert ; Choi, Augustine M. ; Otterbein, Leo E. / Biliverdin administration protects against endotoxin-induced acute lung injury in rats. In: American Journal of Physiology - Lung Cellular and Molecular Physiology. 2005 ; Vol. 289, No. 6 33-6.
@article{4826e1c0063642589dd177f66a9a6d72,
title = "Biliverdin administration protects against endotoxin-induced acute lung injury in rats",
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.",
keywords = "Biliverdin reductase, Heme oxygenase-1, Inflammation, Oxidative stress",
author = "Sarady-Andrews, {Judit K.} and Fang Liu and David Gallo and Atsunori Nakao and Marcus Overhaus and Robert {\"O}llinger and Choi, {Augustine M.} and Otterbein, {Leo E.}",
year = "2005",
month = "12",
doi = "10.1152/ajplung.00458.2004",
language = "English",
volume = "289",
journal = "American Journal of Physiology - Lung Cellular and Molecular Physiology",
issn = "1040-0605",
publisher = "American Physiological Society",
number = "6 33-6",

}

TY - JOUR

T1 - Biliverdin administration protects against endotoxin-induced acute lung injury in rats

AU - Sarady-Andrews, Judit K.

AU - Liu, Fang

AU - Gallo, David

AU - Nakao, Atsunori

AU - Overhaus, Marcus

AU - Öllinger, Robert

AU - Choi, Augustine M.

AU - Otterbein, Leo E.

PY - 2005/12

Y1 - 2005/12

N2 - 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.

AB - 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.

KW - Biliverdin reductase

KW - Heme oxygenase-1

KW - Inflammation

KW - Oxidative stress

UR - http://www.scopus.com/inward/record.url?scp=27944467221&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=27944467221&partnerID=8YFLogxK

U2 - 10.1152/ajplung.00458.2004

DO - 10.1152/ajplung.00458.2004

M3 - Article

C2 - 16155084

AN - SCOPUS:27944467221

VL - 289

JO - American Journal of Physiology - Lung Cellular and Molecular Physiology

JF - American Journal of Physiology - Lung Cellular and Molecular Physiology

SN - 1040-0605

IS - 6 33-6

ER -