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Published ahead of print on March 24, 2004, doi:10.1164/rccm.200312-1670OC

Am. J. Respir. Crit. Care Med., Volume 170, Number 2, July 2004, 133-140

A more recent version of this article appeared on July 15, 2004
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Submitted on December 9, 2003
Accepted on March 23, 2004

Effects of Interferon Gamma-1b on Biomarker Expression in Idiopathic Pulmonary Fibrosis Patients

Robert M Strieter1*, Karen M Starko2, Richard I Enelow3, Imre Noth4, and Vincent G Valentine5

1 Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA, 2 InterMune, Inc., Brisbane, CA, USA, 3 Department of Medicine, University of Virginia Medical Center, Charlottesville, VA, USA, 4 Department of Medicine, University of Chicago, Chicago, IL, USA, 5 Department of Medicine, Ochsner Clinic Foundation, New Orleans, LA, USA

* To whom correspondence should be addressed. E-mail: rstrieter{at}mednet.ucla.edu.

In a recent study of Interferon gamma-1b (IFN-{gamma} 1b) in 330 idiopathic pulmonary fibrosis (IPF) patients, progression-free survival was unchanged; however, a trend toward lower mortality was seen in IFN-{gamma}1b-treated patients compared with placebo-treated patients (9.9% versus 16.7%; p=0.08). The purpose of this randomized, double-blind, placebo-controlled trial was to characterize molecular effects of subcutaneous IFN-{gamma} 1b (200 µg) thrice weekly for 6 months versus placebo in 32 IPF patients. mRNA in transbronchial lung biopsies and bronchoalveolar lavage cell pellet and protein levels in bronchoalveolar fluid (BALF) and plasma were evaluated. After IFN-{gamma} 1b treatment, interferon-inducible T-cell-alpha chemoattractant /CXCL11 (a chemokine with immunomodulatory, antiangiogenic, and defensin-like antimicrobial properties) increased in BALF (p=0.016) and plasma (p<0.001); BALF levels of epithelial neutrophil-activating protein-78/CXCL5 (p=0.054), platelet-derived growth factor A (p=0.033), and Type I procollagen (p=0.096) were lower; and IFN-{gamma} levels were higher (p=0.093) versus placebo. For mRNA in transbronchial biopsies, trends (p>0.05 and <=0.10) associated with IFN-<= 1b treatment included an increase in interferon-inducible T-cell-alpha chemoattractant /CXCL11, a decrease in elastin, and smaller increases for Type III procollagen and platelet-derived growth factor B. Changes in biomarkers of fibrosis, angiogenesis, proliferation, immunomodulation, and antimicrobial activity suggest that IFN-<= 1b may affect IPF through multiple pathways.
Key words: Interferon-gamma-1b, Proteins, Pulmonary fibrosis, mRNA




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