Multiple contributing roles for NOS2 in LPS-induced acute airway inflammation in mice

Tatsuya Okamoto, Kishorchandra Gohil, Erik I. Finkelstein, Peter Bove, Takaaki Akaike, Albert Van Der Vliet

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90 Citations (Scopus)


Acute lung inflammation and injury were induced by intranasal instillation of lipopolysaccharide (LPS) in normal and type 2 nitric oxide synthase (NOS2)-deficient (NOS2-/-) C57BL/6 mice. LPS-induced increases in extravasated airway neutrophils and in lung lavage fluid of TNF-α and macrophage inflammatory protein-2 were markedly lower in NOS2-/- than in wild-type mice, indicating that NOS2-derived nitric oxide (NO·) participates in inflammatory cytokine production and neutrophil recruitment. Instillation of LPS also increased total lung lavage protein and induced matrix metalloproteinase-9 and mucin 5AC, as indexes of lung epithelial injury and/or mucus hyperplasia, and increased tyrosine nitration of lung lavage proteins, a marker of oxidative injury. All these responses were less pronounced in NOS2-/- than in wild-type mice. Inhibition of NOS activity also suppressed production of TNF-α and macrophage inflammatory protein-2 by LPS-stimulated mouse alveolar MH-S macrophages, and this was restored by NO· donors, illustrating involvement of NO· in macrophage cytokine signaling. Oligonucleotide microarray (GeneChip) analysis of global lung gene expression revealed that LPS inhalation induced a range of transcripts encoding proinflammatory cytokines and chemokines, stress-inducible factors, and other extracellular factors and suppressed mRNAs encoding certain cytoskeletal proteins and signaling proteins, responses that were generally attenuated in NOS2-/- mice. Comparison of both mouse strains revealed altered expression of several cytoskeletal proteins, cell surface proteins, and signaling proteins in NOS2-/- mice, changes that may partly explain the reduced responsiveness to LPS. Collectively, our results suggest that NOS2 participates in the acute inflammatory response to LPS by multiple mechanisms: involvement in proinflammatory cytokine signaling and alteration of the expression of various genes that affect inflammatory-immune responses to LPS.

Original languageEnglish
Pages (from-to)L198-L209
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Issue number1 30-1
Publication statusPublished - 2004 Jan
Externally publishedYes


  • Cytokines
  • Injury
  • Neutrophils
  • Nitric oxide
  • Oligonucleotide microarray

ASJC Scopus subject areas

  • Physiology
  • Pulmonary and Respiratory Medicine
  • Physiology (medical)
  • Cell Biology


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