Gene expression profiling identifies MMP-12 and ADAMDEC1 as potential pathogenic mediators of pulmonary sarcoidosis

Elliott D. Crouser, Daniel A. Culver, Kenneth S Knox, Mark W. Julian, Guohong Shao, Susamma Abraham, Sandya Liyanarachchi, Jennifer E. Macre, Mark D. Wewers, Mikhail A. Gavrilin, Patrick Ross, Abbas Abbas, Charis Eng

Research output: Contribution to journalArticle

79 Citations (Scopus)

Abstract

Rationale: Little is known about the genetic regulation of granulomatous inflammation in sarcoidosis. Objectives: 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). Measurements and Main 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.

Original languageEnglish (US)
Pages (from-to)929-938
Number of pages10
JournalAmerican Journal of Respiratory and Critical Care Medicine
Volume179
Issue number10
DOIs
StatePublished - May 15 2009
Externally publishedYes

Fingerprint

Pulmonary Sarcoidosis
Gene Expression Profiling
Sarcoidosis
Matrix Metalloproteinases
Lung
Gene Expression
Gene Regulatory Networks
Genes
Proteins
Sequoia
Immunohistochemistry
Tissue Array Analysis
Interleukin-7
Bronchoalveolar Lavage Fluid
Bronchoalveolar Lavage
Pneumonia
Software

Keywords

  • BAL
  • Gene array
  • Genetic
  • Granuloma
  • Lung

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

Cite this

Gene expression profiling identifies MMP-12 and ADAMDEC1 as potential pathogenic mediators of pulmonary sarcoidosis. / Crouser, Elliott D.; Culver, Daniel A.; Knox, Kenneth S; Julian, Mark W.; Shao, Guohong; Abraham, Susamma; Liyanarachchi, Sandya; Macre, Jennifer E.; Wewers, Mark D.; Gavrilin, Mikhail A.; Ross, Patrick; Abbas, Abbas; Eng, Charis.

In: American Journal of Respiratory and Critical Care Medicine, Vol. 179, No. 10, 15.05.2009, p. 929-938.

Research output: Contribution to journalArticle

Crouser, ED, Culver, DA, Knox, KS, Julian, MW, Shao, G, Abraham, S, Liyanarachchi, S, Macre, JE, Wewers, MD, Gavrilin, MA, Ross, P, Abbas, A & Eng, C 2009, 'Gene expression profiling identifies MMP-12 and ADAMDEC1 as potential pathogenic mediators of pulmonary sarcoidosis', American Journal of Respiratory and Critical Care Medicine, vol. 179, no. 10, pp. 929-938. https://doi.org/10.1164/rccm.200803-490OC
Crouser, Elliott D. ; Culver, Daniel A. ; Knox, Kenneth S ; Julian, Mark W. ; Shao, Guohong ; Abraham, Susamma ; Liyanarachchi, Sandya ; Macre, Jennifer E. ; Wewers, Mark D. ; Gavrilin, Mikhail A. ; Ross, Patrick ; Abbas, Abbas ; Eng, Charis. / Gene expression profiling identifies MMP-12 and ADAMDEC1 as potential pathogenic mediators of pulmonary sarcoidosis. In: American Journal of Respiratory and Critical Care Medicine. 2009 ; Vol. 179, No. 10. pp. 929-938.
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abstract = "Rationale: Little is known about the genetic regulation of granulomatous inflammation in sarcoidosis. Objectives: 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). Measurements and Main 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.",
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T1 - Gene expression profiling identifies MMP-12 and ADAMDEC1 as potential pathogenic mediators of pulmonary sarcoidosis

AU - Crouser, Elliott D.

AU - Culver, Daniel A.

AU - Knox, Kenneth S

AU - Julian, Mark W.

AU - Shao, Guohong

AU - Abraham, Susamma

AU - Liyanarachchi, Sandya

AU - Macre, Jennifer E.

AU - Wewers, Mark D.

AU - Gavrilin, Mikhail A.

AU - Ross, Patrick

AU - Abbas, Abbas

AU - Eng, Charis

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N2 - Rationale: Little is known about the genetic regulation of granulomatous inflammation in sarcoidosis. Objectives: 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). Measurements and Main 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.

AB - Rationale: Little is known about the genetic regulation of granulomatous inflammation in sarcoidosis. Objectives: 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). Measurements and Main 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.

KW - BAL

KW - Gene array

KW - Genetic

KW - Granuloma

KW - Lung

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