title: 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.
  
  
  CONCLUSIONS
  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.affiliation: Philip Morris International Research and Development, Philip Morris Products S.A, Quai Jeanrenaud 5, 2000, Neuchâtel, Switzerland.
authors.forename: Maciej
authors.initials: M
authors.lastname: Cabanski
authors.forename: Brett
authors.initials: B
authors.lastname: Fields
authors.forename: Stephanie
authors.initials: S
authors.lastname: Boue
authors.forename: Natalia
authors.initials: N
authors.lastname: Boukharov
authors.forename: Hector
authors.initials: H
authors.lastname: DeLeon
authors.forename: Natalie
authors.initials: N
authors.lastname: Dror
authors.forename: Marcel
authors.initials: M
authors.lastname: Geertz
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Guedj
authors.forename: Anita
authors.initials: A
authors.lastname: Iskandar
authors.forename: Ulrike
authors.initials: U
authors.lastname: Kogel
authors.forename: Celine
authors.initials: C
authors.lastname: Merg
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Peck
authors.forename: Carine
authors.initials: C
authors.lastname: Poussin
authors.forename: Walter K
authors.initials: WK
authors.lastname: Schlage
authors.forename: Marja
authors.initials: M
authors.lastname: Talikka
authors.forename: Nikolai V
authors.initials: NV
authors.lastname: Ivanov
authors.forename: Julia
authors.initials: J
authors.lastname: Hoeng
authors.forename: Manuel C
authors.initials: MC
authors.lastname: Peitsch
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D015984:Causality; D020869:Gene Expression Profiling; D019570:Inhalation Exposure; D008168:Lung / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018181:Mice, Inbred CFTR; D018345:Mice, Knockout; D016133:Polymerase Chain Reaction; D040901:Proteomics; D011656:Pulmonary Emphysema / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology*; D012906:Smoke; D012907:Smoking; D013045:Species Specificity; D014026:Nicotiana
chemical_list: D001057:Apolipoproteins E; D012906:Smoke