This Article Full Text Full Text (PDF) Online Supplement All Versions of this Article: 200803-387OCv1 178/9/929    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Saavedra, M. T. Articles by Nick, J. A. Search for Related Content PubMed PubMed Citation Articles by Saavedra, M. T. Articles by Nick, J. A.

Circulating RNA Transcripts Identify Therapeutic Response in Cystic Fibrosis Lung Disease

¹ Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado School of Medicine, Denver, Colorado; ² Department of Medicine, National Jewish Health, Denver, Colorado; and ³ Department of Preventive Medicine and Biometrics, and ⁴ Division of Pediatric Pulmonary Medicine, University of Colorado School of Medicine, Denver, Colorado

Correspondence and requests for reprints should be addressed to Milene T. Saavedra, M.D., University of Colorado Health Sciences Center, 4200 E. Ninth Avenue, Box C272, Denver, CO 80262. E-mail: saavedram{at}njc.org

Rationale: Circulating leukocyte RNA transcripts are systemic markers of inflammation, which have not been studied in cystic fibrosis (CF) lung disease. Although the standard assessment of pulmonary treatment response is FEV₁, a measure of airflow limitation, the lack of systemic markers to reflect changes in lung inflammation critically limits the testing of proposed therapeutics.

Objectives: We sought to prospectively identify and validate peripheral blood leukocyte genes that could mark resolution of pulmonary infection and inflammation using a model by which RNA transcripts could increase the predictive value of spirometry.

Methods: Peripheral blood mononuclear cells were isolated from 10 patients with CF and acute pulmonary exacerbations before and after therapy. RNA expression profiling revealed that 10 genes significantly changed with treatment when compared with matched non-CF and control subjects with stable CF to establish baseline transcript abundance. Peripheral blood mononuclear cell RNA transcripts were prospectively validated, using real-time polymerase chain reaction amplification, in an independent cohort of acutely ill patients with CF (n = 14). Patients who responded to therapy were analyzed using general estimating equations and multiple logistic regression, such that changes in FEV₁% predicted were regressed with transcript changes.

Measurements and Main Results: Three genes, CD64, ADAM9, and CD36, were significant and independent predictors of a therapeutic response beyond that of FEV₁ alone (P < 0.05). In both cohorts, receiver operating characteristic analysis revealed greater accuracy when genes were combined with FEV₁.

Conclusions: Circulating mononuclear cell transcripts characterize a response to the treatment of pulmonary exacerbations. Even in small patient cohorts, changes in gene expression in conjunction with FEV₁ may enhance current outcomes measures for treatment response.

Key Words: cystic fibrosis • peripheral blood mononuclear cells • biomarkers • pulmonary exacerbation

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Although severe airway inflammation is a hallmark of cystic fibrosis lung disease, no systemic marker of inflammation has been validated. What This Study Adds to the Field We demonstrate that circulating leukocyte RNA transcripts predict treatment response in cystic fibrosis lung disease and may potentially serve as biomarkers to strengthen current outcomes measures in clinical trials.

 

This article has been cited by other articles:

				F. Ratjen Update in Cystic Fibrosis 2008 Am. J. Respir. Crit. Care Med., March 15, 2009; 179(6): 445 - 448. [Full Text] [PDF]