Endothelial nitric oxide synthase deficient mice are protected from lipopolysaccharide induced acute lung injury

Christine M. Gross, Ruslan Rafikov, Sanjiv Kumar, Saurabh Aggarwal, P. Benson Ham, Mary Louise Meadows, Mary Cherian-Shaw, Archana Kangath, Supriya Sridhar, Rudolf Lucas, Stephen Matthew Black

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

Lipopolysaccharide (LPS) derived from the outer membrane of gram-negative bacteria induces acute lung injury (ALI) in mice. This injury is associated with lung edema, inflammation, diffuse alveolar damage, and severe respiratory insufficiency. We have previously reported that LPS-mediated nitric oxide synthase (NOS) uncoupling, through increases in asymmetric dimethylarginine (ADMA), plays an important role in the development of ALI through the generation of reactive oxygen and nitrogen species. Therefore, the focus of this study was to determine whether mice deficient in endothelial NOS (eNOS-/-) are protected against ALI. In both wild-type and eNOS-/- mice, ALI was induced by the intratracheal instillation of LPS (2 mg/kg). After 24 hours, we found that eNOS-/- mice were protected against the LPS mediated increase in inflammatory cell infiltration, inflammatory cytokine production, and lung injury. In addition, LPS exposed eNOS-/- mice had increased oxygen saturation and improved lung mechanics. The protection in eNOS-/- mice was associated with an attenuated production of NO, NOS derived superoxide, and peroxynitrite. Furthermore, we found that eNOS-/- mice had less RhoA activation that correlated with a reduction in RhoA nitration at Tyr34. Finally, we found that the reduction in NOS uncoupling in eNOS-/- mice was due to a preservation of dimethylarginine dimethylaminohydrolase (DDAH) activity that prevented the LPS-mediated increase in ADMA. Together our data suggest that eNOS derived reactive species play an important role in the development of LPS-mediated lung injury.

Original languageEnglish (US)
Article numbere0119918
JournalPloS one
Volume10
Issue number3
DOIs
StatePublished - Mar 18 2015

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Acute Lung Injury
Nitric Oxide Synthase Type III
lipopolysaccharides
Lipopolysaccharides
lungs
mice
Nitric Oxide Synthase
Lung Injury
nitric oxide synthase
Nitration
Reactive Nitrogen Species
Peroxynitrous Acid
oxygen
endothelial nitric oxide synthase
Infiltration
Superoxides
Mechanics
Gram-Negative Bacteria
mechanics
Gram-negative bacteria

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

Cite this

Gross, C. M., Rafikov, R., Kumar, S., Aggarwal, S., Ham, P. B., Meadows, M. L., ... Black, S. M. (2015). Endothelial nitric oxide synthase deficient mice are protected from lipopolysaccharide induced acute lung injury. PloS one, 10(3), [e0119918]. https://doi.org/10.1371/journal.pone.0119918

Endothelial nitric oxide synthase deficient mice are protected from lipopolysaccharide induced acute lung injury. / Gross, Christine M.; Rafikov, Ruslan; Kumar, Sanjiv; Aggarwal, Saurabh; Ham, P. Benson; Meadows, Mary Louise; Cherian-Shaw, Mary; Kangath, Archana; Sridhar, Supriya; Lucas, Rudolf; Black, Stephen Matthew.

In: PloS one, Vol. 10, No. 3, e0119918, 18.03.2015.

Research output: Contribution to journalArticle

Gross, CM, Rafikov, R, Kumar, S, Aggarwal, S, Ham, PB, Meadows, ML, Cherian-Shaw, M, Kangath, A, Sridhar, S, Lucas, R & Black, SM 2015, 'Endothelial nitric oxide synthase deficient mice are protected from lipopolysaccharide induced acute lung injury', PloS one, vol. 10, no. 3, e0119918. https://doi.org/10.1371/journal.pone.0119918
Gross, Christine M. ; Rafikov, Ruslan ; Kumar, Sanjiv ; Aggarwal, Saurabh ; Ham, P. Benson ; Meadows, Mary Louise ; Cherian-Shaw, Mary ; Kangath, Archana ; Sridhar, Supriya ; Lucas, Rudolf ; Black, Stephen Matthew. / Endothelial nitric oxide synthase deficient mice are protected from lipopolysaccharide induced acute lung injury. In: PloS one. 2015 ; Vol. 10, No. 3.
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