Transcriptional profiling and targeted proteomics reveals common molecular changes associated with cigarette smoke-induced lung emphysema development in five susceptible mouse strains

Authored by  M Cabanski, B Fields*, S Boue, N Boukharov*, H De Leon, N Dror*, M Geertz, E Guedj, A Iskandar, U Kogel, C Merg, M Peck, C Poussin, W Schlage, M Talikka, NV Ivanov, J Hoeng, M Peitsch

Published in Inflammation Research     
* This author is not affiliated with PMI.


Background: Mouse models are useful for studying cigarette smoke (CS)-induced chronic pulmonary pathologies such as lung emphysema. To enhance translation of large-scale omics data from mechanistic studies into pathophysiological changes, we have developed computational tools based on reverse causal reasoning (RCR).

Objective: In the present study we applied a systems biology approach leveraging RCR to identify molecular mechanistic explanations of pathophysiological changes associated with CS-induced lung emphysema in susceptible mice.MethodsThe lung transcriptomes of five mouse models (C57BL/6, ApoE −/− , A/J, CD1, and Nrf2 −/− ) were analyzed following 5–7 months of CS exposure.

Results: We predicted 39 molecular changes mostly related to inflammatory processes including known key emphysema drivers such as NF-κB and TLR4 signaling, and increased levels of TNF-α, CSF2, and several interleukins. More importantly, RCR predicted potential molecular mechanisms that are less well-established, including increased transcriptional activity of PU.1, STAT1, C/EBP, FOXM1, YY1, and N-COR, and reduced protein abundance of ITGB6 and CFTR. We corroborated several predictions using targeted proteomic approaches, demonstrating increased abundance of CSF2,C/EBPα, C/EBPβ, PU.1, BRCA1, and STAT1.

Conclusion: These systems biology-derived candidate mechanisms common to susceptible mouse models may enhance understanding of CS-induced molecular processes underlying emphysema development in mice and their relevancy for human chronic obstructive pulmonary disease.