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Bioinforrnatics of Gene Expression Profiling Data Provide Mechanistic Understanding of Acute Ozone-Induced Lung injury
Citation:
Ward, W. O., M. SCHLADWEILER, A. D. LEDBETTER, AND U. P. KODAVANTI. Bioinforrnatics of Gene Expression Profiling Data Provide Mechanistic Understanding of Acute Ozone-Induced Lung injury. Presented at Society of Toxicology (SOT) Annual Meeting, San Francisco, CA, March 11 - 15, 2012.
Impact/Purpose:
In this abstract gene expression data was examined extensively using various bioinformatics approaches to provide mechanistic undertsanding of how ozone might induce inflammation and repair. The processes of endocytosis, cell adhesion, transcription factor activation, cell growth and cell cycle control were identified to be involved in ozone responsiveness.
Description:
Acute ozone-induced pulmonary injury and inflammation are well characterized. A few studies have used gene expression profiling to determine the types of changes induced by ozone; however the mechanisms or the pathways involved are less well understood. We presumed that robust bioinformatics of the transcriptional data will allow us to better understand the mechanism of pulmonary injury caused by acute ozone exposure. Male Wistar Kyoto rats (10-12 wk) were exposed to air, or ozone (0.25, 0.5 or 1.0 ppm) and pulmonary injury and inflammation were assessed 4 and 20 h later and lung gene expression profiling was assessed 4 h later (air and 1.0 ppm ozone). At 20 h BAL fluid protein and neutrophils increased at 1 ppm ozone. Numerous genes involved in acute inflammatory response were upregulated along with changes in genes regulating processes such as cell adhesion and migration, steroid metabolism, apoptosis, cell cycle control and cell growth. The NFKB (Rela), SP1 and TP3 transcription factors were identified to be mediating activation of genes for these processes. Upstream signaling involving ErbB, toll-like receptors, Wnt, TGF-ß, NOD-like receptor and others were predicted based on downstream changes in expression. Because many of these genes regulating various inflammatory and repair processes are also involved in cancer, this pathway was also identified as being significantly changed by ozone. Remarkable changes in the genes regulating endocytosis and glucocorticoid receptor activities as evident by KEGG pathway analysis provides the insight that ozone-induced lung injury is initiated by changes in cell membrane and receptors together likely involving clearance of oxidatively modified lung lining lipids and proteins. Thus, gene expression profiling data could predict mechanisms of ozone-induced lung injury and provide the understanding of how different cellular processes such as endocytosis, activation of transcription factors, cell migration, apoptosis, cytokines release, and growth orchestrate the inflammatory and repair processes in the lung. (Does not reflect the US EPA policy).