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Published ahead of print on December 27, 2002, doi:10.1164/rccm.200210-1217OC

Am. J. Respir. Crit. Care Med., Volume 167, Number 9, May 2003, 1257-1263

A more recent version of this article appeared on May 1, 2003
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Submitted on October 24, 2002
Accepted on December 26, 2002

Imaging Pulmonary Gene Expression With Positron Emission Tomography (PET)

Jean-Christophe Richard1, Zhaouhi Zhou1, Datta E Ponde1, Carmen S Dence1, Phillip Factor2, Paul N Reynolds3, Gary D Luker1, Vijay Sharma1, Tom Ferkol4, David Piwnica-Worms1, and Daniel P Schuster5*

1 Mallinckrodt Institute of Radiology, Washington University School of Medicine, St Louis, Missouri, USA, 2 Pulmonary and Critical Care Medicine, Evanston Northwestern Healthcare, Evanston, Illinois, USA; Northwestern University Medical School, Chicago, Illinois, USA, 3 Division of Human Gene Therapy, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA; Royal Adelaide Hospital, Adelaide, South Australia, Australia, 4 Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri, USA, 5 Mallinckrodt Institute of Radiology, Washington University School of Medicine, St Louis, Missouri, USA; Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA

* To whom correspondence should be addressed. E-mail: schusted{at}msnotes.wustl.edu.

We evaluated positron emission tomographic imaging of pulmonary transgene expression, using an enhanced mutant Herpes Simplex Virus-1 thymidine kinase as the reporter gene, in the lungs of normal rats. Sixteen rats were studied 3 days after intratracheal administration of 5x109 - 1x1011 viral particles of a replication-incompetent adenovirus containing a fusion gene of the mutant kinase and green fluorescent protein. Three rats infected with adenovirus containing no insert (null vector) served as a control. Images were obtained 1 hour after intravenous injection of (9-(4-[18F]-fluoro-3-hydroxymethylbutyl)guanine, an imaging substrate for the viral kinase. After euthanasia, tissue radioactivity was determined in a gamma counter, and thymidine kinase activity and green fluorescent protein levels were measured in lung tissue samples. Imaging and gamma counting radioactivity measurements were strongly and linearly correlated (R2=0.96, p<0.001). Imaging detected thymidine kinase expression above background (null vector) in 15/16 rats, even at low viral doses that produced little to no measurable green fluorescent protein expression. Lung (9-(4-[18F]-fluoro-3-hydroxymethylbutyl)guanine uptake (as assessed by imaging) correlated with in vitro assays of both kinase activity (R2=0.48, p<0.001) and fluorescent protein (R2=0.46, p<0.001). We conclude that positron emission tomographic imaging is a sensitive and quantitative method for detecting pulmonary reporter gene expression non-invasively.
Key words: Positron emission tomography, rats, FHBG, green fluorescent protein, reporter gene




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