We have analyzed changes in similar to4000 lung mRNAs, with GeneChips, in mice exposed to I ppm O-3 for three consecutive nights (8 h per night). Differential gene expression analysis identified similar to260 O-3 sensitive genes; similar to80% of these were repressed and similar to20% 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 (similar to7-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 similar to30 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. (C) 2003 Elsevier Science (USA). All rights reserved.