title: Gene expression profiling in lung tissues from mice exposed to cigarette smoke, lipopolysaccharide, or smoke plus lipopolysaccharide by inhalation.
abstract: The purpose of this study was to investigate whether coexposure to lipopolysacchride (LPS) will heighten the inflammatory response and other pulmonary lesions in mice exposed to cigarette smoke, and thus to evaluate the potential use of this LPS-compromised mouse model as a model for chronic obstructive pulmonary disease (COPD) investigation. AKR/J male mice were exposed to HEPA-filtered air (sham control group), cigarette smoke (smoke group), LPS (LPS group), or smoke plus LPS (smoke-LPS group) by nose-only inhalation. Lungs were collected at the end of the 3-wk exposure and processed for microarray analysis. Clustering and network analysis showed decreased heat-shock response and chaperone activity, increased immune and inflammatory response, and increased mitosis in all three exposed groups. Two networks/function modules were exclusively found in the smoke-LPS group, that is, the downregulated muscle development/muscle contraction process and the upregulated reactive oxygen species production process. Notably, the number of genes and function modules/networks associated with inflammation was reduced in the smoke-LPS group compared to the LPS group. The most upregulated gene in the smoke group, MMP12, is a matrix metalloproteinase that preferentially degrades elastin and has been implicated in COPD development. NOXO1, which was upregulated in all three treatment groups, positively regulates the expression of a subunit of NADPH oxidase (NOX1), a major source of reactive oxygen species, and may play an important role in the pathogenesis of COPD. Serum amyloid A1, which is an acute-phase systemic inflammation marker and can be induced by LPS exposure, was significantly upregulated in the LPS and smoke-LPS groups. MARCO, a scavenger receptor expressed in macrophages that may play a significant role in LPS-induced inflammatory response, was upregulated in the LPS group and the smoke-LPS group, but not in the smoke group. In conclusion, gene expression profiling identified genes and function modules that may be related to COPD pathogenesis and may be useful as biomarkers to monitor COPD progression. In addition, an LPS-compromised mouse model showed potential as a useful tool for studying cigarette smoke-associated COPD.
authors.affiliation: Battelle Toxicology Northwest, Richland, Washington, USA.
authors.forename: Q R
authors.initials: QR
authors.lastname: Meng
authors.forename: K M
authors.initials: KM
authors.lastname: Gideon
authors.forename: S J
authors.initials: SJ
authors.lastname: Harbo
authors.forename: R A
authors.initials: RA
authors.lastname: Renne
authors.forename: M K
authors.initials: MK
authors.lastname: Lee
authors.forename: A M
authors.initials: AM
authors.lastname: Brys
authors.forename: R
authors.initials: R
authors.lastname: Jones
mesh_terms: D000280:Administration, Inhalation; D000818:Animals; D016000:Cluster Analysis; D004195:Disease Models, Animal; D005069:Evaluation Studies as Topic; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides / Q000008:administration & dosage*; D008168:Lung / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D053508:Matrix Metalloproteinase 12 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008806:Mice, Inbred AKR; D018832:Molecular Chaperones; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D025341:Principal Component Analysis; D029424:Pulmonary Disease, Chronic Obstructive / Q000139:chemically induced; D012333:RNA, Messenger / Q000378:metabolism; D000685:Serum Amyloid A Protein / Q000235:genetics / Q000378:metabolism; D012906:Smoke / Q000009:adverse effects*; D014026:Nicotiana / Q000633:toxicity*; D014028:Tobacco Smoke Pollution / Q000009:adverse effects
chemical_list: D006360:Heat-Shock Proteins; C486113:Hsbp1 protein, mouse; D008070:Lipopolysaccharides; D018832:Molecular Chaperones; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D000685:Serum Amyloid A Protein; D012906:Smoke; D014028:Tobacco Smoke Pollution; D053508:Matrix Metalloproteinase 12