Identification of key events at the transcriptional level can facilitate the identification of processes that are critical for disease initiation and progression, thus allowing information from animal experiments to be queried and used for extrapolation to human scenarios (Edwards and Preston, 2008). Comparison of our data with specific models of lung disease, including bacterial infection, airway hypersensitivity and lung injury revealed that CBNPs induced Ibrutinib price responses that were more closely related to lung injury and fibrosis than to other models. This finding was further supported
by comparison of the expression profiles of CBNP exposed mice to those of curated studies of animals and humans exhibiting a myriad of pulmonary disease phenotypes. This analysis demonstrates that CBNP exposure perturbs genes that are Dasatinib supplier known to be involved in tissue injury and fibrosis in mice. Although it is unclear if CBNP exposure would result in the same gene expression profile
in humans, similar pathways including many involved in fibrotic responses were found in both mice and humans (52% of the top 50 pathways found were common between mouse and human). Despite concordance of pathways, the top ranked genes differed considerably between both species. However, many of the genes found in mice and humans had similar functions, including inflammatory and acute phase responses (e.g., Saa3, Socs3 and Mt2 in mice and CP, VNN2 and CXCL10 in humans), cell cycle progression (Cdkn1a in mice and KLF4 in humans) and bone and tissue modelling
(Mmp14, Timp1, Eln and Ogn in mice and SPP1 in humans). Thus, despite discordance in the gene expression profiles between species, the similar functions Oxymatrine of top ranked genes and concordance between pathways supports the likelihood of similar responses in the event of CBNP exposure in humans. In addition, fibrosis has been identified as an outcome of exposure to various particles and NPs in animals ( Bermudez et al., 2004 and Shvedova et al., 2008), including Printex 90 (e.g., 28-day nose only inhalation in Wistar WU rats) ( Bellmann et al., 2009), as well as in humans ( Lkhasuren et al., 2007 and Wang and Christiani, 2003). The process of pulmonary fibrosis is closely related to progression of carcinogenic outcome ( Hubbard et al., 2000). These data demonstrating very similar fibrotic pathways in mice and humans and a significant overlap with CBNP-induced gene expression changes thus support the use of pathway-based approaches in identifying molecular mechanisms of disease onset and progression, and using gene expression profiles to support HHRA. This study confirms several key elements that are necessary for the application of gene expression profiling for HHRA of toxicant exposures in general. First, transcriptional profiles can effectively predict the biological effects of chemical exposures.