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Gene Expression Profiling of Familial and Sporadic Interstitial Pneumonia

Laboratory of Respiratory Biology, National Institute of Environmental Health Sciences, Research Triangle Park; Department of Medicine, Duke University Medical Center, Durham, North Carolina; National Jewish Medical and Research Center, Denver; and University of Colorado at Denver and Health Sciences Center, Denver, Colorado

Correspondence and requests for reprints should be addressed to Ivana V. Yang, Ph.D., Laboratory of Respiratory Biology, National Institute of Environmental Health Sciences, P.O. Box 12233, MD B3-08, Research Triangle Park, NC 27909. 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 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 of patients with usual interstitial pneumonia or nonspecific interstitial pneumonia that was either familial or nonfamilial in origin, and to compare it with gene expression in normal lung parenchyma.

Methods: We profiled RNA from the lungs of 16 patients with sporadic IIP, 10 with familial IIP, and 9 normal control subjects 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/6^CXCR4+/– mice demonstrating significantly less collagen deposition than C57BL/6^CXCR4+/+ mice. Whereas substantial differences exist between familial and sporadic IIPs, we identified only minor gene expression changes between usual interstitial pneumonia and nonspecific interstitial pneumonia.

Conclusions: Taken together, our findings indicate that differences in gene expression profiles between familial and sporadic IIPs may provide clues to the etiology and pathogenesis of IIP.

Key Words: familial interstitial pneumonia • global transcription analysis • interstitial lung disease • lung fibrosis • microarrays

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Idiopathic interstitial pneumonia (IIP) and its familial variants are progressive and largely untreatable disorders with poorly understood molecular mechanisms. What This Study Adds to the Field There are considerable gene expression changes between familial and sporadic IIPs, but the histologic disease subtypes UIP and NSIP are transcriptionally very similar.

 

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When It Comes to Genes—IPF or NSIP, Familial or Sporadic—They're All the Same

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