title: Computational identification of key biological modules and transcription factors in acute lung injury.
abstract: BACKGROUND
  Mechanical ventilation augments the acute lung injury (ALI) caused by bacterial products. The molecular pathogenesis of this synergistic interaction remains incompletely understood.
  
  
  OBJECTIVE
  We sought to develop a computational framework to systematically identify gene regulatory networks activated in ALI.
  
  
  METHODS
  We have developed a mouse model in which the combination of mechanical ventilation and intratracheal LPS produces significantly more injury to the lung than either insult alone. We used global gene ontology analysis to determine overrepresented biological modules and computational transcription factor analysis to identify putative regulatory factors involved in this model of ALI.
  
  
  RESULTS
  By integrating expression profiling with gene ontology and promoter analysis, we constructed a large-scale regulatory modular map of the important processes activated in ALI. This map assigned differentially expressed genes to highly overrepresented biological modules, including "defense response," "immune response," and "oxidoreductase activity." These modules were then systematically incorporated into a gene regulatory network that consisted of putative transcription factors, such as IFN-stimulated response element, IRF7, and Sp1, that may regulate critical processes involved in the pathogenesis of ALI.
  
  
  CONCLUSIONS
  We present a novel, unbiased, and powerful computational approach to investigate the synergistic effects of mechanical ventilation and LPS in promoting ALI. Our methodology is applicable to any expression profiling experiment involving eukaryotic organisms.
authors.affiliation: Department of Medicine, University of Washington, Seattle, WA, USA. sagharib@u.washington.edu
authors.forename: Sina A
authors.initials: SA
authors.lastname: Gharib
authors.forename: W Conrad
authors.initials: WC
authors.lastname: Liles
authors.forename: Gustavo
authors.initials: G
authors.lastname: Matute-Bello
authors.forename: Robb W
authors.initials: RW
authors.lastname: Glenny
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Martin
authors.forename: William A
authors.initials: WA
authors.lastname: Altemeier
mesh_terms: D000818:Animals; D019295:Computational Biology / Q000379:methods*; D004195:Disease Models, Animal; D018450:Disease Progression; D020869:Gene Expression Profiling; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D012313:RNA / Q000235:genetics*; D012121:Respiration, Artificial / Q000009:adverse effects; D012128:Respiratory Distress Syndrome / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics*; D014158:Transcription, Genetic
chemical_list: D008070:Lipopolysaccharides; D014157:Transcription Factors; D012313:RNA