Abstract
Acute lung injury (ALI) is a severe hypoxemic respiratory insufficiency associated with lung leak, diffuse alveolar damage, inflammation, and loss of lung function. Decreased dimethylaminohydrolase (DDAH) activity and increases in asymmetric dimethylarginine (ADMA), together with exaggerated oxidative/nitrative stress, contributes to the development of ALI in mice exposed to LPS. Whether restoring DDAH function and suppressing ADMA levels can effectively ameliorate vascular hyperpermeability and lung injury in ALI is unknown, and was the focus of this study. In human lung microvascular endothelial cells, DDAH II overexpression prevented the LPS-dependent increase in ADMA, superoxide, peroxynitrite, and protein nitration. DDAH II also attenuated the endothelial barrier disruption associated with LPS exposure. Similarly, in vivo, we demonstrated that the targeted overexpression of DDAH II in the pulmonary vasculature significantly inhibited the accumulation of ADMA and the subsequent increase in oxidative/nitrative stress in the lungs of mice exposed to LPS. In addition, augmenting pulmonary DDAH II activity before LPS exposure reduced lung vascular leak and lung injury and restored lung function when DDAH activity was increased after injury. Together, these data suggest that enhancing DDAH II activity may prove a useful adjuvant therapy to treat patients with ALI.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 614-625 |
| Number of pages | 12 |
| Journal | American Journal of Respiratory Cell and Molecular Biology |
| Volume | 50 |
| Issue number | 3 |
| DOIs | |
| State | Published - 2014 |
| Externally published | Yes |
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Keywords
- Acute lung injury
- Asymmetric dimethylarginine
- Dimethylarginine dimethylaminohydrolase II
- Gene delivery
- Nitrative stress
ASJC Scopus subject areas
- Cell Biology
- Pulmonary and Respiratory Medicine
- Molecular Biology
- Clinical Biochemistry
Cite this
Dimethylarginine dimethylaminohydrolase II overexpression attenuates LPS-mediated lung leak in acute lung injury. / Aggarwal, Saurabh; Gross, Christine M.; Kumar, Sanjiv; Dimitropoulou, Christiana; Sharma, Shruti; Gorshkov, Boris A.; Sridhar, Supriya; Lu, Qing; Bogatcheva, Natalia; Jezierska-Drutel, Agnieszka J.; Lucas, Rudolf; Verin, Alexander D.; Catravas, John D.; Black, Stephen M.
In: American Journal of Respiratory Cell and Molecular Biology, Vol. 50, No. 3, 2014, p. 614-625.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Dimethylarginine dimethylaminohydrolase II overexpression attenuates LPS-mediated lung leak in acute lung injury
AU - Aggarwal, Saurabh
AU - Gross, Christine M.
AU - Kumar, Sanjiv
AU - Dimitropoulou, Christiana
AU - Sharma, Shruti
AU - Gorshkov, Boris A.
AU - Sridhar, Supriya
AU - Lu, Qing
AU - Bogatcheva, Natalia
AU - Jezierska-Drutel, Agnieszka J.
AU - Lucas, Rudolf
AU - Verin, Alexander D.
AU - Catravas, John D.
AU - Black, Stephen M.
PY - 2014
Y1 - 2014
N2 - Acute lung injury (ALI) is a severe hypoxemic respiratory insufficiency associated with lung leak, diffuse alveolar damage, inflammation, and loss of lung function. Decreased dimethylaminohydrolase (DDAH) activity and increases in asymmetric dimethylarginine (ADMA), together with exaggerated oxidative/nitrative stress, contributes to the development of ALI in mice exposed to LPS. Whether restoring DDAH function and suppressing ADMA levels can effectively ameliorate vascular hyperpermeability and lung injury in ALI is unknown, and was the focus of this study. In human lung microvascular endothelial cells, DDAH II overexpression prevented the LPS-dependent increase in ADMA, superoxide, peroxynitrite, and protein nitration. DDAH II also attenuated the endothelial barrier disruption associated with LPS exposure. Similarly, in vivo, we demonstrated that the targeted overexpression of DDAH II in the pulmonary vasculature significantly inhibited the accumulation of ADMA and the subsequent increase in oxidative/nitrative stress in the lungs of mice exposed to LPS. In addition, augmenting pulmonary DDAH II activity before LPS exposure reduced lung vascular leak and lung injury and restored lung function when DDAH activity was increased after injury. Together, these data suggest that enhancing DDAH II activity may prove a useful adjuvant therapy to treat patients with ALI.
AB - Acute lung injury (ALI) is a severe hypoxemic respiratory insufficiency associated with lung leak, diffuse alveolar damage, inflammation, and loss of lung function. Decreased dimethylaminohydrolase (DDAH) activity and increases in asymmetric dimethylarginine (ADMA), together with exaggerated oxidative/nitrative stress, contributes to the development of ALI in mice exposed to LPS. Whether restoring DDAH function and suppressing ADMA levels can effectively ameliorate vascular hyperpermeability and lung injury in ALI is unknown, and was the focus of this study. In human lung microvascular endothelial cells, DDAH II overexpression prevented the LPS-dependent increase in ADMA, superoxide, peroxynitrite, and protein nitration. DDAH II also attenuated the endothelial barrier disruption associated with LPS exposure. Similarly, in vivo, we demonstrated that the targeted overexpression of DDAH II in the pulmonary vasculature significantly inhibited the accumulation of ADMA and the subsequent increase in oxidative/nitrative stress in the lungs of mice exposed to LPS. In addition, augmenting pulmonary DDAH II activity before LPS exposure reduced lung vascular leak and lung injury and restored lung function when DDAH activity was increased after injury. Together, these data suggest that enhancing DDAH II activity may prove a useful adjuvant therapy to treat patients with ALI.
KW - Acute lung injury
KW - Asymmetric dimethylarginine
KW - Dimethylarginine dimethylaminohydrolase II
KW - Gene delivery
KW - Nitrative stress
UR - http://www.scopus.com/inward/record.url?scp=84895519654&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84895519654&partnerID=8YFLogxK
U2 - 10.1165/rcmb.2013-0193OC
DO - 10.1165/rcmb.2013-0193OC
M3 - Article
VL - 50
SP - 614
EP - 625
JO - American Journal of Respiratory Cell and Molecular Biology
JF - American Journal of Respiratory Cell and Molecular Biology
SN - 1044-1549
IS - 3
ER -