Dimethylarginine dimethylaminohydrolase II overexpression attenuates LPS-mediated lung leak in acute lung injury

Saurabh Aggarwal, Christine M. Gross, Sanjiv Kumar, Christiana Dimitropoulou, Shruti Sharma, Boris A Gorshkov, Supriya Sridhar, Qing Lu, Natalia V. Bogatcheva, Agnieszka J. Jezierska-Drutel, Rudolf Lucas, Alexander Dmitriyevich Verin, John D. Catravas, Stephen Matthew Black

Research output: Contribution to journalArticle

20 Scopus citations

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 languageEnglish (US)
Pages (from-to)614-625
Number of pages12
JournalAmerican journal of respiratory cell and molecular biology
Volume50
Issue number3
DOIs
StatePublished - Mar 2014

Keywords

  • Acute lung injury
  • Asymmetric dimethylarginine
  • Dimethylarginine dimethylaminohydrolase II
  • Gene delivery
  • Nitrative stress

ASJC Scopus subject areas

  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology

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  • Cite this

    Aggarwal, S., Gross, C. M., Kumar, S., Dimitropoulou, C., Sharma, S., Gorshkov, B. A., Sridhar, S., Lu, Q., Bogatcheva, N. V., Jezierska-Drutel, A. J., Lucas, R., Verin, A. D., Catravas, J. D., & Black, S. M. (2014). Dimethylarginine dimethylaminohydrolase II overexpression attenuates LPS-mediated lung leak in acute lung injury. American journal of respiratory cell and molecular biology, 50(3), 614-625. https://doi.org/10.1165/rcmb.2013-0193OC