Endotoxic shock is a disease process caused by a severe underlying infection. If left unchecked, this process may progress to refractory hypotension, multiple organ system failure, and death. Other than the cardiovascular response and its associated hypotension, abnormalities of the renal, hepatic, pulmonary, and hematologic systems are common during endotoxemia. The development of multiple organ failure contributes significantly to morbidity and mortality. In addition, oxygen-derived free radicals contribute to the cellular and tissue injury associated with endotoxin-induced inflammation. Heme oxygenase (HO)-1 is a cytoprotective enzyme that is induced by stimuli associated with oxidative stress. HO-1 degrades heme (a potent oxidant) to generate carbon monoxide (CO, a vasodilatory gas that has anti-inflammatory properties), bilirubin (an antioxidant derived from biliverdin), and iron. Due to properties of HO-1 and its products, it is believed that HO-1 may play an important role in protecting cells and tissues in the settings of increased oxidative stress, such as during endotoxemia. Studies from our laboratory using HO-1 null (-/-) mice confirmed this hypothesis by showing that endotoxemia produced increased oxidative stress, end-organ damage, and death in mice lacking HO-1 compared with wild-type mice. This detrimental outcome did not correlate with the blood pressure response, as HO-1-/- mice had a significantly higher systolic blood pressure in the setting of increased mortality. These data led us to hypothesize that the upregulation of HO-1, and its subsequent cytoprotective effects (outweighing the potential vasodiIatory/hypotensive effects), may play an important role in preventing the pathophysiology of endotoxic shock. Thus, the goals of this proposal are 1) to determine whether vascular overexpression of HO-1 may have beneficial consequences in endotoxin-induced tissue injury and death by using a vasculai smooth muscle cell-targeted promoter to generate transgenic mice, 2) to elucidate the role of HO-1 in bone marrow-derived inflammatory cells versus parenchymal cells during endotoxin-induced end-organ damage and death, and 3) to further identify DNA sequences (cis-acting elements) and their cognate DNA-binding proteins (trans-acting factors), that in conjunction with the architectural transcription factor HMG-I/Y, are important for regulating HO-1 transcription during an inflammatory stimulus

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL060788-09
Application #
7066093
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Goldman, Stephen
Project Start
1998-07-01
Project End
2007-08-31
Budget Start
2006-07-01
Budget End
2007-08-31
Support Year
9
Fiscal Year
2006
Total Cost
$386,694
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Tsoyi, Konstantin; Geldart, Adriana M; Christou, Helen et al. (2015) Elk-3 is a KLF4-regulated gene that modulates the phagocytosis of bacteria by macrophages. J Leukoc Biol 97:171-80
Sanada, Fumihiro; Kim, Junghyun; Czarna, Anna et al. (2014) c-Kit-positive cardiac stem cells nested in hypoxic niches are activated by stem cell factor reversing the aging myopathy. Circ Res 114:41-55
Hall, Sean R R; Tsoyi, Konstantin; Ith, Bonna et al. (2013) Mesenchymal stromal cells improve survival during sepsis in the absence of heme oxygenase-1: the importance of neutrophils. Stem Cells 31:397-407
Chung, Su Wol; Kwon, Min-Young; Kang, Young-Ho et al. (2012) Transforming growth factor-?1 suppression of endotoxin-induced heme oxygenase-1 in macrophages involves activation of Smad2 and downregulation of Ets-2. J Cell Physiol 227:351-60
Kwon, Min-Young; Liu, Xiaoli; Lee, Seon-Jin et al. (2011) Nucleotide-binding oligomerization domain protein 2 deficiency enhances neointimal formation in response to vascular injury. Arterioscler Thromb Vasc Biol 31:2441-7
Fredenburgh, Laura E; Velandia, Margarita M Suárez; Ma, Jun et al. (2011) Cyclooxygenase-2 deficiency leads to intestinal barrier dysfunction and increased mortality during polymicrobial sepsis. J Immunol 187:5255-67
Baron, Rebecca M; Lopez-Guzman, Silvia; Riascos, Dario F et al. (2010) Distamycin A inhibits HMGA1-binding to the P-selectin promoter and attenuates lung and liver inflammation during murine endotoxemia. PLoS One 5:e10656
Hung, Chi-Chih; Liu, Xiaoli; Kwon, Min-Young et al. (2010) Regulation of heme oxygenase-1 gene by peptidoglycan involves the interaction of Elk-1 and C/EBPalpha to increase expression. Am J Physiol Lung Cell Mol Physiol 298:L870-9
Liu, Xiaoli; Ramjiganesh, Tripurasundari; Chen, Yen-Hsu et al. (2009) Disruption of striated preferentially expressed gene locus leads to dilated cardiomyopathy in mice. Circulation 119:261-8
Takamiya, Rina; Hung, Chi-Chih; Hall, Sean R et al. (2009) High-mobility group box 1 contributes to lethality of endotoxemia in heme oxygenase-1-deficient mice. Am J Respir Cell Mol Biol 41:129-35

Showing the most recent 10 out of 42 publications