title: Dimethylarginine dimethylaminohydrolase II overexpression attenuates LPS-mediated lung leak in acute lung injury.
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.
authors.affiliation: Pulmonary Disease Program, Vascular Biology Center, Georgia Regents University, Augusta, Georgia.
authors.forename: Saurabh
authors.initials: S
authors.lastname: Aggarwal
authors.forename: Christine M
authors.initials: CM
authors.lastname: Gross
authors.forename: Sanjiv
authors.initials: S
authors.lastname: Kumar
authors.forename: Christiana
authors.initials: C
authors.lastname: Dimitropoulou
authors.forename: Shruti
authors.initials: S
authors.lastname: Sharma
authors.forename: Boris A
authors.initials: BA
authors.lastname: Gorshkov
authors.forename: Supriya
authors.initials: S
authors.lastname: Sridhar
authors.forename: Qing
authors.initials: Q
authors.lastname: Lu
authors.forename: Natalia V
authors.initials: NV
authors.lastname: Bogatcheva
authors.forename: Agnieszka J
authors.initials: AJ
authors.lastname: Jezierska-Drutel
authors.forename: Rudolf
authors.initials: R
authors.lastname: Lucas
authors.forename: Alexander D
authors.initials: AD
authors.lastname: Verin
authors.forename: John D
authors.initials: JD
authors.lastname: Catravas
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Black
mesh_terms: D055371:Acute Lung Injury / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics / Q000517:prevention & control*; D000581:Amidohydrolases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000378:metabolism; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D002199:Capillary Permeability; D002478:Cells, Cultured; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000201:enzymology* / Q000473:pathology; D015316:Genetic Therapy; D006801:Humans; D008070:Lipopolysaccharides; D008168:Lung / Q000098:blood supply* / Q000201:enzymology / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D055806:Microvessels / Q000201:enzymology* / Q000473:pathology; D018384:Oxidative Stress; D030421:Peroxynitrous Acid / Q000378:metabolism; D011654:Pulmonary Edema / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics / Q000517:prevention & control*; D013481:Superoxides / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D015854:Up-Regulation
chemical_list: D008070:Lipopolysaccharides; D013481:Superoxides; D030421:Peroxynitrous Acid; C018524:N,N-dimethylarginine; D001120:Arginine; D000581:Amidohydrolases; C059999:dimethylargininase