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

Abstract

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.

METHODS:

The 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.

• Authors: Maciej Cabanski, Brett Fields, Stephanie Boue, Natalia Boukharov, Hector DeLeon, Natalie Dror, Marcel Geertz, Emmanuel Guedj, Anita Iskandar, Ulrike Kogel, Celine Merg, Michael J Peck, Carine Poussin, Walter K Schlage, Marja Talikka, Nikolai V Ivanov, Julia Hoeng, Manuel C Peitsch
• Journal: Inflammation research : official journal of the European Histamine Research Society ... [et al.] (Inflamm Res) Vol. 64 Issue 7 Pg. 471-86 (Jul 2015) ISSN: 1420-908X [Electronic] Switzerland
• PMID: 25962837 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Apolipoproteins E
• Smoke

Topics

• Animals
• Apolipoproteins E (genetics)
• Bronchoalveolar Lavage Fluid (chemistry, cytology)
• Causality
• Gene Expression Profiling
• Inhalation Exposure
• Lung (pathology)
• Mice
• Mice, Inbred C57BL
• Mice, Inbred CFTR
• Mice, Knockout
• Polymerase Chain Reaction
• Proteomics
• Pulmonary Emphysema (chemically induced, genetics, pathology)
• Smoke
• Smoking
• Species Specificity
• Nicotiana