title: Gene expression profiling identifies MMP-12 and ADAMDEC1 as potential pathogenic mediators of pulmonary sarcoidosis.
abstract: BACKGROUND
  Little is known about the genetic regulation of granulomatous inflammation in sarcoidosis.
  
  
  OBJECTIVE
  To determine if tissue gene array analysis would identify novel genes engaged in inflammation and lung remodeling in patients with sarcoidosis.
  
  
  METHODS
  Gene expression analysis was performed on tissues obtained from patients with sarcoidosis at the time of diagnosis (untreated) (n = 6) compared with normal lung tissue (n = 6). Expression of select genes was further confirmed in lung tissue from a second series of patients with sarcoidosis and disease-free control subjects (n = 11 per group) by semi-quantitative RT-PCR. Interactive gene networks were identified in patients with sarcoidosis using Ingenuity Pathway Analysis (Ingenuity Systems, Inc., Redwood, CA) software. The expression of proteins corresponding to selected overexpressed genes was determined using fluorokine multiplex analysis, and immunohistochemistry. Selected genes and proteins were then analyzed in bronchoalveolar lavage fluid in an independent series of patients with sarcoidosis (n = 36) and control subjects (n = 12).
  
  
  RESULTS
  A gene network engaged in Th1-type responses was most significantly overexpressed in the sarcoidosis lung tissues, including genes not previously reported in the context of sarcoidosis (e.g., IL-7). MMP-12 and ADAMDEC1 transcripts were most highly expressed (> 25-fold) in sarcoidosis lung tissues, corresponding with increased protein expression by immunohistochemistry. MMP-12 and ADAMDEC1 gene and protein expression were increased in bronchoalveolar lavage samples from patients with sarcoidosis, correlating with disease severity.
  
  
  CONCLUSIONS
  Tissue gene expression analyses provide novel insights into the pathogenesis of pulmonary sarcoidosis. MMP-12 and ADAMDEC1 emerge as likely mediators of lung damage and/or remodeling and may serve as markers of disease activity.
authors.affiliation: Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, The Dorothy M. Davis Heart and Lung Research Institute, Columbus, Ohio 43210-1252, USA. Elliott.Crouser@osumc.edu
authors.forename: Elliott D
authors.initials: ED
authors.lastname: Crouser
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Culver
authors.forename: Kenneth S
authors.initials: KS
authors.lastname: Knox
authors.forename: Mark W
authors.initials: MW
authors.lastname: Julian
authors.forename: Guohong
authors.initials: G
authors.lastname: Shao
authors.forename: Susamma
authors.initials: S
authors.lastname: Abraham
authors.forename: Sandya
authors.initials: S
authors.lastname: Liyanarachchi
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Macre
authors.forename: Mark D
authors.initials: MD
authors.lastname: Wewers
authors.forename: Mikhail A
authors.initials: MA
authors.lastname: Gavrilin
authors.forename: Patrick
authors.initials: P
authors.lastname: Ross
authors.forename: Abbas
authors.initials: A
authors.lastname: Abbas
authors.forename: Charis
authors.initials: C
authors.lastname: Eng
mesh_terms: D051722:ADAM Proteins; D000328:Adult; D000367:Age Factors; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D016022:Case-Control Studies; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006099:Granuloma / Q000201:enzymology / Q000235:genetics; D006801:Humans; D008297:Male; D053508:Matrix Metalloproteinase 12 / Q000096:biosynthesis / Q000235:genetics*; D008666:Metalloendopeptidases / Q000096:biosynthesis / Q000235:genetics*; D046228:Microarray Analysis; D008875:Middle Aged; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017565:Sarcoidosis, Pulmonary / Q000201:enzymology / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D012737:Sex Factors; D018417:Th1 Cells / Q000276:immunology
chemical_list: D016207:Cytokines; D051722:ADAM Proteins; D008666:Metalloendopeptidases; C108169:decysin; D053508:Matrix Metalloproteinase 12