Adenoviral gene transfer of a mutant surfactant enzyme ameliorates pseudomonas-induced lung injury

Gene Therapy
J ZhouRama K Mallampalli

Abstract

Surfactant deficiency is an important contributor to the acute respiratory distress syndrome, a disorder that commonly occurs after bacterial sepsis. CTP:phosphocholine cytidylyltransferase (CCTalpha) is the rate-limiting enzyme required for the biosynthesis of dipalmitoylphosphatidylcholine (DPPC), the major phospholipid of surfactant. In this study, a cDNA encoding a novel, calpain-resistant mutant CCTalpha enzyme was delivered intratracheally in mice using a replication-deficient adenovirus 5 CTP:phosphocholine cytidylyltransferase construct (Ad5-CCT(Penta)) in models of bacterial sepsis. Ad5-CCT(Penta) gene transfer produced high-level CCTalpha gene expression, increased alveolar surfactant (DPPC) levels and improved lung surface tension and pressure-volume relationships relative to control mice. Pseudomonas aeruginosa (PA103) decreased DPPC synthesis, in part, via calpain-mediated degradation of CCTalpha. Deleterious effects of Pseudomonas on surfactant were lessened after infection with a mutant strain lacking the type III exotoxin, Exo U. Replication-deficient adenovirus 5 CTP:phosphocholine cytidylyltransferase gene delivery improved lung biophysical properties by optimizing surface activity in this Pseudomonas model of...Continue Reading

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Citations

Dec 19, 2009·The Journal of Biological Chemistry·Phillip L Butler, Rama K Mallampalli
Dec 17, 2009·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Marianna AgassandianRama K Mallampalli
May 13, 2011·American Journal of Respiratory and Critical Care Medicine·Matthew J WargoDeborah A Hogan
Jun 28, 2003·American Journal of Respiratory Cell and Molecular Biology·Jiming ZhouRama K Mallampalli
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Dec 15, 2006·Cellular Microbiology·Yanghong WuRama K Mallampalli
Sep 29, 2011·Microbes and Infection·Jennifer R Glasser, Rama K Mallampalli
Dec 9, 2016·Human Gene Therapy·Dolan SondhiRonald G Crystal
Jul 27, 2006·Journal of Lipid Research·Florita C HendersonRama K Mallampalli
Feb 20, 2019·Journal of Cardiovascular Development and Disease·Michael G KatzKiyotake Ishikawa

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