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Gene Expression Profiling Identifies MMP-12 and ADAMDEC1 as Potential Pathogenic Mediators of Pulmonary Sarcoidosis

¹ Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, The Dorothy M. Davis Heart and Lung Research Institute, Columbus, Ohio; ² Department of Pulmonary and Critical Care Medicine, Lerner Research Institute, and Taussig Cancer Institute, Cleveland Clinic Foundation, Cleveland, Ohio; ³ Department of Medicine, Indiana University School of Medicine, Richard L. Roudebush VA Medical Center, Indianapolis, Indiana; ⁴ The Arthur G. James Comprehensive Cancer Center and ⁵ Division of Thoracic Surgery, The Ohio State University Medical Center, Columbus, Ohio; ⁶ Genomic Medicine Institute, Lerner Research Institute, and Taussig Cancer Institute, Cleveland Clinic Foundation; and ⁷ Department of Genetics and CASE Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio

Correspondence and request for reprints should be addressed to Elliott D. Crouser, M.D., The Ohio State University Medical Center, Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, 201 Davis Heart and Lung Research Institute, 473 West 12th Avenue, Columbus, OH 43210-1252. E-mail: Elliott.Crouser{at}osumc.edu

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.

Key Words: genetic • gene array • granuloma • lung • BAL

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject The pathogenesis of sarcoidosis remains poorly understood, including the genetic factors regulating granulomatous inflammation at the tissue level. Genome-wide gene expression profiling can provide novel insights into interactive gene networks involved in the pathogenesis of disease. What This Study Adds to the Field Using gene expression profiling, highly interactive gene networks were identified, including genes and gene products not previously linked to the pathogenesis of sarcoidosis. Among these, gene and protein expression of proteases MMP-12 and ADAMDEC1 were greatly increased at the tissue level and in bronchoalveolar fluid of patients with sarcoidosis and correlated with the severity of lung disease.