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.