Published ahead of print on September 22, 2006, doi:10.1164/rccm.200601-062OC
Am. J. Respir. Crit. Care Med., Volume 175, Number 1, January 2007, 45-54
A more recent version of this article appeared on January 1, 2007
Submitted on January 15, 2006
Accepted on September 22, 2006
Gene Expression Profiling of Familial and Sporadic Cases of Interstitial Pneumonia
Ivana V Yang1*, Lauranell H Burch1, Mark P Steele2, Jordan D Savov3, John W Hollingsworth2, Erin McElvania-Tekippe3, Katherine G Berman3, Marcy C Speer3, Thomas A Sporn3, Kevin K Brown4, Marvin I Schwarz5, and David A Schwartz2
1 Laboratory of Respiratory Biology, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA,
2 Laboratory of Respiratory Biology, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA; Department of Medicine, Duke University Medical Center, Durham, NC, USA,
3 Department of Medicine, Duke University Medical Center, Durham, NC, USA,
4 National Jewish Medical and Research Center, Denver, CO, USA; University of Colorado at Denver and Health Sciences Center, Denver, CO, USA,
5 University of Colorado at Denver and Health Sciences Center, Denver, CO, USA
* To whom correspondence should be addressed. E-mail: yangi{at}niehs.nih.gov.
Rationale: Idiopathic interstitial pneumonia (IIP) and its' familial variants are progressive and largely untreatable disorders with poorly understood molecular
mechanisms. Both the genetics and the histologic type of IIP play a role in understanding the etiology and pathogenesis of interstitial lung disease, but transcriptional signatures of these subtypes are unknown. Objectives: To evaluate gene expression in the lung tissue from patients with usual interstitial pneumonia (UIP) and non-specific interstitial pneumonia (NSIP) that were either familial or non-familial in origin and compare them to gene expression from normal lung parenchyma. Methods: We profiled RNA from lungs of 16 patients with sporadic IIP, 10 with familial IIP, and 9 normal controls on a whole human genome oligonucleotide microarray. Results: Significant transcriptional differences exist in familial and sporadic IIPs. The genes distinguishing the genetic subtypes belong to the same functional categories as transcripts that distinguish IIP from normal samples. Relevant categories include chemokines and growth factors and their receptors, complement components, genes associated with cell proliferation and death, and genes in the Wnt pathway. The role of the chemokine CXCL12 in disease pathogenesis was confirmed in the murine bleomycin model of lung injury, with C57BL/6CXCR4+/- mice demonstrating significantly less collagen deposition than C57BL/6CXCCR4+/+ mice. While substantial differences exist between familial and sporadic IIPs, we identified only minor gene expression changes between UIP and NSIP. Conclusions: Taken together, our findings indicate that the differences in gene expression profiles of familial and sporadic IIPs may provide clues to the etiology and pathogenesis of IIP.
Key words: interstitial lung disease, familial interstitial pneumonia, lung fibrosis, global transcription analysis, microarrays
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