(Chest. 2002;121:90S-91S.)
© 2002
American College of Chest Physicians
Gene Therapy of Mucus Hypersecretion in Experimental Asthma*
Christopher Evans, PhD;
Farrah Kheradmand, MD;
David Corry, MD;
Michael Tuvim, PhD;
Charles Densmore, PhD;
Clifford Waldrep, PhD;
Vernon Knight, MD and
Burton Dickey, MD
*
From the Baylor College of Medicine and Houston Veterans Affairs Medical Center, Houston, TX.
Correspondence to: Burton Dickey, MD, Chief, Pulmonary and Critical Care Medicine, MS 151, Houston Veterans Affairs Medical Center, 2002 Holcombe Blvd, Houston, TX 77030; e-mail: bdickey{at}bcm.tmc.edu
The
obstruction
of small airways by mucus plays a central pathophysiologic role in most
cases of fatal asthma. T helper type-2 cytokines, such as interleukin
(IL)-4, IL-9, and IL-13, rapidly cause dramatic metaplasia of the
murine airway epithelium from a nonsecretory ciliated phenotype to
mucus-secreting goblet cells in experimental allergic asthma.
Accompanying this metaplasia, we have found that the exocytic
regulatory protein Munc18–2 is strongly induced in the airway
epithelium and that its promoter contains GATA factor, STAT-6,
glucocorticoid receptor, and CREB binding sites. Munc18 protein
expression is determinative for secretory function in model organisms,
such that the absence of functional Munc18 protein causes a complete
failure of secretion, a partial absence of Munc18 causes a partial
failure, and the overexpression of Munc18 also causes a severe
secretory defect. Using optimized polyethyleneimine/DNA ratios that
were administered by aerosol in an atmosphere of 5%
CO2, virtually 100% of murine airway epithelial
cells can be transduced with reporter genes, and approximately 50% of
reporter gene activity remains present after 1 week.1
This
gene delivery system is being used to alter Munc18–2 gene expression
to suppress mucus secretion and to reduce airflow obstruction in murine
models of experimental allergic asthma.
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Footnotes
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Abbreviation: IL = interleukin
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References
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Gautam, A, Densmore, CL, Xu, B, et al (2000) Enhanced gene expression in mouse lung after PEI-DNA aerosol delivery. Mol Ther 2,63-70[CrossRef][Medline]
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References
