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This Article Full Text Full Text (PDF) All Versions of this Article: 286/1/L198    most recent 00136.2003v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (21) Citing Articles via Google Scholar Google Scholar Articles by Okamoto, T. Articles by van der Vliet, A. Search for Related Content PubMed PubMed Citation Articles by Okamoto, T. Articles by van der Vliet, A.

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

¹Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of California, Davis, Davis, California 95616; ²Department of Internal Medicine-1 and ⁴Department of Microbiology, Kumamoto University School of Medicine, Kumamoto, Japan 860-0811; and ³Department of Pathology, University of Vermont, Burlington, Vermont 05405

Submitted 2 May 2003 ; accepted in final form 31 August 2003

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- 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- 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.

nitric oxide; injury; neutrophils; cytokines; oligonucleotide microarray

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