title: Gene expression profiling in the lungs of patients with pulmonary hypertension associated with pulmonary fibrosis.
abstract: BACKGROUND
  Pulmonary hypertension (PH) associated with pulmonary fibrosis (PF) is a severe condition with poor outcome. It is unknown whether patients with PF with associated PH (APH) represent a distinct phenotype of the disease. We hypothesized that the lung tissue gene expression pattern of patients with APH has a characteristic profile when compared with patients with PF without APH. We sought to determine if different gene expression signatures in PF could be determined based on pulmonary arterial pressures (PAPs) and to provide new insights into the pathobiology of APH.
  
  
  METHODS
  Microarray analysis (Affymetrix) was performed after RNA was extracted from explanted lungs in 116 consecutive patients with PF (development set, n = 84; validation set, n = 32) and seven subjects with idiopathic pulmonary arterial hypertension undergoing lung transplant (LTx). PAP were recorded intraoperatively immediately before starting LTx. The development set was divided into three groups according to mean PAP (mPAP): severe PH group (mPAP ≥ 40 mm Hg, n = 17); intermediate PH group (mPAP 21-39 mm Hg, n = 45); NoPH group (mPAP ≤ 20 mm Hg, n = 22).
  
  
  RESULTS
  Distinct gene signatures were observed. Patients in the severe PH group showed increased expression of genes, gene sets, and networks related to myofibroblast proliferation and vascular remodeling, whereas patients in the NoPH group strongly expressed proinflammatory genes. Two-dimensional hierarchic clustering based on 222 differentially expressed genes (severe PH vs no PH) dichotomized subjects into two phenotypes in the intermediate PH group and in the validation set. Real-time polymerase chain reaction confirmed the differential expression of selected genes.
  
  
  CONCLUSIONS
  Gene expression profiles distinguish PF phenotypes with and without APH. This observation can have important implications for future trials.
authors.affiliation: Latner Thoracic Surgery Research Laboratories, University of Toronto, Toronto, ON, Canada; Toronto Lung Transplant Program, University of Toronto, Toronto, ON, Canada; Pulmonary Hypertension Program, University of Toronto, Toronto, ON, Canada.
authors.forename: Marco
authors.initials: M
authors.lastname: Mura
authors.affiliation: Latner Thoracic Surgery Research Laboratories, University of Toronto, Toronto, ON, Canada; Toronto Lung Transplant Program, University of Toronto, Toronto, ON, Canada.
authors.forename: Masaki
authors.initials: M
authors.lastname: Anraku
authors.affiliation: Latner Thoracic Surgery Research Laboratories, University of Toronto, Toronto, ON, Canada.
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Yun
authors.affiliation: Toronto Lung Transplant Program, University of Toronto, Toronto, ON, Canada.
authors.forename: Karen
authors.initials: K
authors.lastname: McRae
authors.affiliation: Latner Thoracic Surgery Research Laboratories, University of Toronto, Toronto, ON, Canada.
authors.forename: Mingyao
authors.initials: M
authors.lastname: Liu
authors.affiliation: Latner Thoracic Surgery Research Laboratories, University of Toronto, Toronto, ON, Canada; Toronto Lung Transplant Program, University of Toronto, Toronto, ON, Canada.
authors.forename: Thomas K
authors.initials: TK
authors.lastname: Waddell
authors.affiliation: Toronto Lung Transplant Program, University of Toronto, Toronto, ON, Canada.
authors.forename: Lianne G
authors.initials: LG
authors.lastname: Singer
authors.affiliation: Toronto Lung Transplant Program, University of Toronto, Toronto, ON, Canada; Pulmonary Hypertension Program, University of Toronto, Toronto, ON, Canada.
authors.forename: John T
authors.initials: JT
authors.lastname: Granton
authors.affiliation: Latner Thoracic Surgery Research Laboratories, University of Toronto, Toronto, ON, Canada; Toronto Lung Transplant Program, University of Toronto, Toronto, ON, Canada.
authors.forename: Shaf
authors.initials: S
authors.lastname: Keshavjee
authors.affiliation: Latner Thoracic Surgery Research Laboratories, University of Toronto, Toronto, ON, Canada; Toronto Lung Transplant Program, University of Toronto, Toronto, ON, Canada; Pulmonary Hypertension Program, University of Toronto, Toronto, ON, Canada. Electronic address: marc.deperrot@uhn.ca.
authors.forename: Marc
authors.initials: M
authors.lastname: de Perrot
mesh_terms: D000328:Adult; D000368:Aged; D001794:Blood Pressure; D015897:Comorbidity; D003937:Diagnosis, Differential; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D006976:Hypertension, Pulmonary / Q000175:diagnosis / Q000453:epidemiology* / Q000235:genetics*; D008168:Lung / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D016040:Lung Transplantation; D008297:Male; D046228:Microarray Analysis; D008875:Middle Aged; D010641:Phenotype; D011658:Pulmonary Fibrosis / Q000175:diagnosis / Q000453:epidemiology* / Q000235:genetics*