title: Network analysis of temporal effects of intermittent and sustained hypoxia on rat lungs.
abstract: The molecular networks underlying the lung response to hypoxia are not fully understood. We employed systems biology approaches to study temporal effects of intermittent or sustained hypoxia on gene expression in rat lungs. We obtained gene expression profiles from rats exposed to intermittent or sustained hypoxia lasting 0-30 days and identified differentially expressed genes, their patterns, biological processes, and regulatory networks critical for lung response to intermittent or sustained hypoxia. We validated selected genes with quantitative real-time PCR. Intermittent and sustained hypoxia induced two distinct sets of genes in rat lungs that displayed different temporal expression patterns. Intermittent hypoxia induced genes mostly involved in ion transport and homeostasis, neurological processes, and steroid hormone receptor activity, while sustained hypoxia induced genes principally participating in immune responses. The intermittent hypoxia-activated network suggested a role for cross talk between estrogen receptor 1 (ESR1) and other key proteins in hypoxic responses. The sustained hypoxia-activated network was indicative of vascular remodeling and pulmonary hypertension. We confirmed the temporal expression changes of 12 genes (including the Esr1 gene and 4 ESR1 target genes) in intermittent hypoxia and 8 genes in sustained hypoxia with quantitative real-time PCR.
  
  
  CONCLUSIONS
  intermittent and sustained hypoxia induced distinct gene expression patterns in rat lungs. The functional characteristics of genes activated by these two distinct perturbations suggest their roles in the downstream physiological effects of intermittent and sustained hypoxia. Our results demonstrate the discovery potential of applying systems biology approaches to the understanding of mechanisms underlying hypoxic lung response.
authors.affiliation: Dorothy P. and Richard P. Simmons Center for Interstitial Lung Disease, Div. of Pulmonary, Allergy, and Critical Care Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA. wuw2@upmc.edu
authors.forename: Wei
authors.initials: W
authors.lastname: Wu
authors.forename: Nilesh B
authors.initials: NB
authors.lastname: Dave
authors.forename: Guoying
authors.initials: G
authors.lastname: Yu
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Strollo
authors.forename: Elizabeta
authors.initials: E
authors.lastname: Kovkarova-Naumovski
authors.forename: Stefan W
authors.initials: SW
authors.lastname: Ryter
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Reeves
authors.forename: Ehab
authors.initials: E
authors.lastname: Dayyat
authors.forename: Yang
authors.initials: Y
authors.lastname: Wang
authors.forename: Augustine M K
authors.initials: AM
authors.lastname: Choi
authors.forename: David
authors.initials: D
authors.lastname: Gozal
authors.forename: Naftali
authors.initials: N
authors.lastname: Kaminski
mesh_terms: D000818:Animals; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D053263:Gene Regulatory Networks; D000860:Hypoxia / Q000235:genetics* / Q000378:metabolism; D008168:Lung / Q000378:metabolism*; D008297:Male; D046228:Microarray Analysis; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D047628:Estrogen Receptor alpha