Ozone-induced disruptions of lung transcriptomes.
We have analyzed changes in approximately 4000 lung mRNAs, with GeneChips, in mice exposed to 1 ppm O(3) for three consecutive nights (8 h per night). Differential gene expression analysis identified approximately 260 O(3) sensitive genes; approximately 80% of these were repressed and approximately 20% were induced in O(3)-exposed mice compared to the air-exposed controls. A 20-fold induction of serum amyloid A3 mRNA by O(3) suggested activation of NF-kappaB and CCAAT/enhancer binding protein-mediated pathways by inflammatory cytokines. Induction (up to 14-fold) of 12 genes that increase DNA synthesis and cell cycle progression, and increase (approximately 7-fold) in CD44 mRNA and macrophage metalloelastase suggested a state of O(3)-induced hyperplasia and lung remodeling. Several mRNAs encoding enzymes of xenobiotic metabolism and cytoskeletal functions were repressed and may suggest cytokine mediated suppression of cytochrome P450 expression and cachexia-like inflammatory state in ozone-exposed lungs. The expressions of approximately 30 genes of immune response were also repressed. Collectively this genome-wide analysis of lungs identified ozone-induced disruption of gene transcriptional profile indicative of increased cellular proliferation under suppressed immune surveillance and xenobiotic metabolism.
Gohil
Kishorchandra
K
Center for Comparative Respiratory and Medicine, Department of Internal Medicine, University of California, Davis, CA 95616, USA. kgohil@ucdavis.edu
Cross
Carroll E
CE
Last
Jerold A
JA
D000388:Air; D000818:Animals; D002453:Cell Cycle; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D016678:Genome; D006649:Histocompatibility Antigens / Q000235:genetics / Q000378:metabolism; D007249:Inflammation / Q000139:chemically induced; D008168:Lung / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D008214:Lymphocytes / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000502:physiology; D020411:Oligonucleotide Array Sequence Analysis; D010083:Oxidants, Photochemical / Q000494:pharmacology*; D010126:Ozone / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism*; D014158:Transcription, Genetic
D006649:Histocompatibility Antigens; D016328:NF-kappa B; D010083:Oxidants, Photochemical; D012333:RNA, Messenger; D010126:Ozone; D003577:Cytochrome P-450 Enzyme System