title: Expression of hypoxia-inducible factor (HIF)-1a-vascular endothelial growth factor (VEGF)-inhibitory growth factor (ING)-4- axis in sarcoidosis patients.
abstract: BACKGROUND
  Sarcoidosis is a granulomatous disorder of unknown etiology. The term of immunoangiostasis has been addressed by various studies as potentially involved in the disease pathogenesis. The aim of the study was to investigate the expression of the master regulator of angiogenesis hypoxia inducible factor (HIF)-1a - vascular endothelial growth factor (VEGF)- inhibitor of growth factor 4-(ING4) - axis within sarcoid granuloma.
  
  
  METHODS
  A total of 37 patients with sarcoidosis stages II-III were recruited in our study. Tissue microarray technology coupled with immunohistochemistry analysis were applied to video-assisted thoracoscopic surgery (VATS) lung biopsy samples collected from 37 sarcoidosis patients and 24 controls underwent surgery for benign lesions of the lung. Computerized image analysis was used to quantify immunohistochemistry results. qRT-PCR was used to assess HIF-1a and ING4 expression in 10 sarcoidosis mediastinal lymph node and 10 control lung samples.
  
  
  RESULTS
  HIF-1a and VEGF-ING4 expression, both in protein and mRNA level, was found to be downregulated and upregulated, respectively, in sarcoidosis samples compared to controls. Immunohistochemistry coupled with computerized image analysis revealed minimal expression of HIF-1a within sarcoid granulomas whereas an abundant staining of ING4 and VEGF in epithelioid cells was also visualized.
  
  
  CONCLUSIONS
  Our data suggest an impairment of the HIF-1a - VEGF axis, potentialy arising by ING4 overexpression and ultimately resulting in angiostasis and monocyte recruitment within granulomas. The concept of immunoangiostasis as a possible protection mechanism against antigens of infectious origin needs further research to be verified.
authors.affiliation: Department of Pneumonology, University Hospital of Alexandroupolis, Medical school, Democritus University of Thrace, Thrace, Greece. atzouvelekis@yahoo.gr
authors.forename: Argyris
authors.initials: A
authors.lastname: Tzouvelekis
authors.forename: Paschalis
authors.initials: P
authors.lastname: Ntolios
authors.forename: Andreas
authors.initials: A
authors.lastname: Karameris
authors.forename: Anastasios
authors.initials: A
authors.lastname: Koutsopoulos
authors.forename: Panagiotis
authors.initials: P
authors.lastname: Boglou
authors.forename: Andreas
authors.initials: A
authors.lastname: Koulelidis
authors.forename: Kostas
authors.initials: K
authors.lastname: Archontogeorgis
authors.forename: George
authors.initials: G
authors.lastname: Zacharis
authors.forename: Fotis
authors.initials: F
authors.lastname: Drakopanagiotakis
authors.forename: Paschalis
authors.initials: P
authors.lastname: Steiropoulos
authors.forename: Stavros
authors.initials: S
authors.lastname: Anevlavis
authors.forename: Vlassis
authors.initials: V
authors.lastname: Polychronopoulos
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Mikroulis
authors.forename: Demosthenes
authors.initials: D
authors.lastname: Bouros
mesh_terms: D000328:Adult; D000368:Aged; D001706:Biopsy; D016022:Case-Control Studies; D018797:Cell Cycle Proteins / Q000032:analysis* / Q000235:genetics; D015536:Down-Regulation; D005260:Female; D057166:High-Throughput Screening Assays; D018398:Homeodomain Proteins / Q000032:analysis* / Q000235:genetics; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000032:analysis* / Q000235:genetics; D007090:Image Interpretation, Computer-Assisted; D007150:Immunohistochemistry; D008168:Lung / Q000737:chemistry* / Q000473:pathology / Q000601:surgery; D008297:Male; D008875:Middle Aged; D012333:RNA, Messenger / Q000032:analysis; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017565:Sarcoidosis, Pulmonary / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D020775:Thoracic Surgery, Video-Assisted; D046888:Tissue Array Analysis; D025521:Tumor Suppressor Proteins / Q000032:analysis* / Q000235:genetics; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000032:analysis / Q000235:genetics
chemical_list: D018797:Cell Cycle Proteins; C497442:HIF1A protein, human; D018398:Homeodomain Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C483230:ING4 protein, human; D012333:RNA, Messenger; D025521:Tumor Suppressor Proteins; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A