| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH |
|
|
|
|||||||
|
|||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1 Division of Pulmonary Allergy and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
2 Department of Surgery, Harvard Medical School/Beth Israel Deaconess Medical Center, Boston, MA, USA
3 Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
4 Division of Gastroenterology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
5 Department of Surgery, Innsbruck Medical University, Innsbruck, Austria
* To whom correspondence should be addressed. E-mail: lotterbe{at}bidmc.harvard.edu.
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 then rapidly converted to bilirubin by biliverdin reductase. We tested the hypothesis that BV administration could substitute for the effects observed with HO-1. Using the well-described rat model of lipopolysaccharide (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 prior to a lethal dose of LPS leads to a significant improvement in long-term survival of 87% versus 20% survival in sham-treated controls. BV treatment suppressed LPS-induced increases in lung permeability and lung alveolitis, as well as significantly reduced serum levels of the LPS-induced pro-inflammatory 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.
This article has been cited by other articles:
|
|
 |
|
  K. Patil, L. Bellner, G. Cullaro, K. H. Gotlinger, M. W. Dunn, and M. L. Schwartzman Heme Oxygenase-1 Induction Attenuates Corneal Inflammation and Accelerates Wound Healing after Epithelial Injury Invest. Ophthalmol. Vis. Sci., August 1, 2008; 49(8): 3379 - 3386. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Yoshida and R. M. Tuder Pathobiology of Cigarette Smoke-Induced Chronic Obstructive Pulmonary Disease Physiol Rev, July 1, 2007; 87(3): 1047 - 1082. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. E. Fredenburgh, M. A. Perrella, and S. A. Mitsialis The Role of Heme Oxygenase-1 in Pulmonary Disease Am. J. Respir. Cell Mol. Biol., February 1, 2007; 36(2): 158 - 165. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. W. Ryter, D. Morse, and A. M. K. Choi Carbon Monoxide and Bilirubin: Potential Therapies for Pulmonary/Vascular Injury and Disease Am. J. Respir. Cell Mol. Biol., February 1, 2007; 36(2): 175 - 182. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH |
| Visit Other APS Journals Online |
