Gene expression profiling identifies MMP-12 and ADAMDEC1 as potential pathogenic mediators of pulmonary sarcoidosis.
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.
Crouser
Elliott D
ED
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
Culver
Daniel A
DA
Knox
Kenneth S
KS
Julian
Mark W
MW
Shao
Guohong
G
Abraham
Susamma
S
Liyanarachchi
Sandya
S
Macre
Jennifer E
JE
Wewers
Mark D
MD
Gavrilin
Mikhail A
MA
Ross
Patrick
P
Abbas
Abbas
A
Eng
Charis
C
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
D016207:Cytokines; D051722:ADAM Proteins; D008666:Metalloendopeptidases; C108169:decysin; D053508:Matrix Metalloproteinase 12