Role of inducible nitric oxide synthase-derived nitric oxide in lipopolysaccharide plus interferon-γ-induced pulmonary inflammation

• Published in: Toxicology and applied pharmacology Vol. 195; no. 1; pp. 45 - 54
• Main Authors: Zeidler, Patti C., Millecchia, Lyndell M., Castranova, Vincent
• Format: Journal Article
• Language: English
• Published: San Diego, CA Elsevier Inc 15.02.2004; Elsevier
• Subjects: Albumins - metabolism; Animals; Bacteriology; Biological and medical sciences; Bronchoalveolar Lavage Fluid - chemistry; Bronchoalveolar Lavage Fluid - cytology; Cell Count; Chemokine CXCL2; Drug Synergism; Fundamental and applied biological sciences. Psychology; Inducible nitric oxide synthase; Interferon-gamma; Interferon-gamma - toxicity; L-Lactate Dehydrogenase - metabolism; Lipopolysaccharide; Lipopolysaccharides - toxicity; Lung - drug effects; Lung - enzymology; Lung - metabolism; Lung inflammation; Macrophages, Alveolar - cytology; Male; Mice; Mice, Knockout; Microbiology; Monokines - metabolism; Neutrophils - cytology; Nitric Oxide - metabolism; Nitric Oxide Synthase - genetics; Nitric Oxide Synthase - metabolism; Nitric Oxide Synthase Type II; Pathogenicity, virulence, toxins, bacteriocins, pyrogens, host-bacteria relations, miscellaneous strains; Pneumonia - chemically induced; Pneumonia - metabolism; Tumor Necrosis Factor-alpha - metabolism; Lipopolysaccharide; Interferon-gamma; Lung inflammation; Inducible nitric oxide synthase; Enzyme; Toxicity; Lung; Rodentia; Inflammation; Nitric-oxide synthase; Vertebrata; Mammalia; Mouse; Animal; Nitric oxide; Oxidoreductases; Gamma interferon
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1016/j.taap.2003.10.005

Exposure of mice to lipopolysaccharide (LPS) plus interferon-γ (IFN-γ) increases nitric oxide (NO) production, which is proposed to play a role in the resulting pulmonary damage and inflammation. To determine the role of inducible nitric oxide synthase (iNOS)-induced NO in this lung reaction, the responses of inducible nitric oxide synthase knockout (iNOS KO) versus C57BL/6J wild-type (WT) mice to aspirated LPS + IFN-γ were compared. Male mice (8–10 weeks) were exposed to LPS (1.2 mg/kg) + IFN-γ (5000 U/mouse) or saline. At 24 or 72 h postexposure, lungs were lavaged with saline and the acellular fluid from the first bronchoalveolar lavage (BAL) was analyzed for total antioxidant capacity (TAC), lactate dehydrogenase (LDH) activity, albumin, tumor necrosis factor-α (TNF-α), and macrophage inflammatory protein-2 (MIP-2). The cellular fraction of the total BAL was used to determine alveolar macrophage (AM) and polymorphonuclear leukocyte (PMN) counts, and AM zymosan-stimulated chemiluminescence (AM-CL). Pulmonary responses 24 h postexposure to LPS + IFN-γ were characterized by significantly decreased TAC, increased BAL AMs and PMNs, LDH, albumin, TNF-α, and MIP-2, and enhanced AM-CL to the same extent in both WT and iNOS KO mice. Responses 72 h postexposure were similar; however, significant differences were found between WT and iNOS KO mice. iNOS KO mice demonstrated a greater decline in total antioxidant capacity, greater BAL PMNs, LDH, albumin, TNF-α, and MIP-2, and an enhanced AM-CL compared to the WT. These data suggest that the role of iNOS-derived NO in the pulmonary response to LPS + IFN-γ is anti-inflammatory, and this becomes evident over time.