E-GEOD-52854 - Inhibition of MEK and PI3K alone or in combination alters the transcriptome of the lung during TGFα-induced pulmonary fibrosis

Status
Released on 3 December 2013, last updated on 16 January 2014
Organism
Mus musculus
Samples (20)
Protocols (2)
Description
Pulmonary fibrosis is often triggered by an epithelial injury resulting in the formation of fibrotic lesions in the lung, which progress to impair gas exchange and ultimately cause death. Recent clinical trials using drugs that target either inflammation or a specific molecule have failed, suggesting that multiple pathways and cellular processes need to be attenuated for effective reversal of established and progressive fibrosis. Although activation of MAPK and PI3K pathways have been detected in human fibrotic lung samples, the therapeutic benefits of in vivo modulation of the MAPK and PI3K pathways in combination are unknown. Overexpression of TGFα in the lung epithelium of transgenic mice results in the formation of fibrotic lesions similar to those found in human pulmonary fibrosis, and previous work from our group shows that inhibitors of either the MAPK or PI3K pathway can alter the progression of fibrosis. In this study, we sought to determine whether simultaneous inhibition of the MAPK and PI3K signaling pathways is a more effective therapeutic strategy for established and progressive pulmonary fibrosis. Our results showed that inhibiting both pathways had additive effects compared to inhibiting either pathway alone in reducing fibrotic burden, including reducing lung weight, pleural thickness, and total collagen in the lungs of TGFα mice. This study demonstrates that inhibiting MEK and PI3K in combination abolishes proliferative gene changes associated with fibrosis and myfibroblast accumulation and thus may serve as a therapeutic option in the treatment of human fibrotic lung disease where these pathways play a role. mRNA profiles of CCSP/TGFalpha mice treated with vehicle, ARRY, PX-866, ARRY/PX-866
Experiment type
RNA-seq of coding RNA 
Contacts
Jing Chen <geo@ncbi.nlm.nih.gov>, Cynthia Davidson, Kimberly Wagner, Mario Medvedovic, Mukta Phatak, Ramakrishna Edukulla, Satish K Madala, Stephanie Schmidt, Thomas H Acciani, Thomas R Korfhagen, Timothy D LeCras, William D Hardie
MINSEQE
Exp. designProtocolsVariablesProcessedSeq. reads
Files
Investigation descriptionE-GEOD-52854.idf.txt
Sample and data relationshipE-GEOD-52854.sdrf.txt
Links