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1 Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of California, Davis, CA, USA; Department of Internal Medicine-1, and Department of Microbiology, Kumamoto University School of Medicine, Kumamoto, Japan
2 Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of California, Davis, CA, USA
3 Department of Pathology, University of Vermont, Burlington, VT, USA
4 Department of Internal Medicine-1, and Department of Microbiology, Kumamoto University School of Medicine, Kumamoto, Japan
* To whom correspondence should be addressed. E-mail: avanderv{at}zoo.uvm.edu.
Acute lung inflammation and injury was induced by intranasal instillation of lipopolysaccaride (LPS) in normal and NOS2-deficient (NOS2-/-) C57BL/6 mice. LPS-induced increases in extravasated airway neutrophils, and in lung lavage fluid levels of tumor necrosis factor-
(TNF-) and macrophage inflammatory protein-2 (MIP-2), were markedly lower in NOS2-/- mice compared to wild-type mice, indicating that NOS2-derived nitric oxide (NO.) participates in inflammatory cytokine production and neutrophil recruitment. Instillation of LPS also caused increased total lung lavage protein levels and induction of matrix metalloproteinase-9 (MMP-9) and mucin (MUC) 5AC, as indices 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-/- mice compared to wild-type mice. Inhibition of NOS activity also suppressed production of TNF- and MIP-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 pro-inflammatory 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, by involvement in pro-inflammatory cytokine signaling and by altering the expression of various genes that affect inflammatory-immune responses to LPS.
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