Adenoviral gene transfer of a mutant surfactant enzyme ameliorates pseudomonas-induced lung injury
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),...
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Published in | Gene therapy Vol. 13; no. 12; pp. 974 - 985 |
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Main Authors | , , , , , , |
Format | Journal Article |
Language | English |
Published |
Basingstoke
Nature Publishing Group
01.06.2006
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Subjects | |
Online Access | Get full text |
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Summary: | 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 proteinase-mediated lung injury. The studies are the first demonstration of in vivo gene transfer of a lipogenic enzyme resulting in improved lung mechanics. The studies suggest that augmentation of DPPC synthesis via gene delivery of CCTalpha can attenuate impaired lung function in surfactant-deficient states such as bacterial sepsis. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 0969-7128 1476-5462 |
DOI: | 10.1038/sj.gt.3302746 |