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

J Zhou; Y Wu; F Henderson; D M McCoy; R G Salome; S E McGowan; R K Mallampalli

doi:10.1038/sj.gt.3302746

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

Journal article

Peer reviewed

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

J Zhou, Y Wu, F Henderson, D M McCoy, R G Salome, S E McGowan and R K Mallampalli

Gene therapy, Vol.13(12), pp.974-985

06/2006

DOI: 10.1038/sj.gt.3302746

PMID: 16511521

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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 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.

Calcium-Binding Proteins - metabolism

Acute Disease

Genetic Vectors - administration & dosage

Mice, Inbred C57BL

Pseudomonas Infections - therapy

Male

Choline-Phosphate Cytidylyltransferase - administration & dosage

Lung Diseases - therapy

Genetic Vectors - genetics

Lung - enzymology

Animals

1,2-Dipalmitoylphosphatidylcholine - metabolism

Adenoviridae - genetics

Mice

Choline-Phosphate Cytidylyltransferase - genetics

Pulmonary Surfactants - administration & dosage

Transduction, Genetic - methods

Pseudomonas Infections - enzymology

Calcium-Binding Proteins - genetics

Genetic Therapy - methods

Lung Diseases - enzymology

Details

Title: Subtitle: Adenoviral gene transfer of a mutant surfactant enzyme ameliorates pseudomonas-induced lung injury
Creators: J Zhou - University of Iowa
Y Wu - University of Iowa
F Henderson
D M McCoy
R G Salome
S E McGowan
R K Mallampalli
Resource Type: Journal article
Publication Details: Gene therapy, Vol.13(12), pp.974-985
DOI: 10.1038/sj.gt.3302746
PMID: 16511521
NLM abbreviation: Gene Ther
ISSN: 0969-7128
eISSN: 1476-5462
Publisher: England
Grant note: R01 HL055584 / NHLBI NIH HHS R01 HL080229 / NHLBI NIH HHS T32 HL007344 / NHLBI NIH HHS R01 HL081784 / NHLBI NIH HHS R01 HL068135 / NHLBI NIH HHS
Language: English
Date published: 06/2006
Academic Unit: International Programs; Internal Medicine
Record Identifier: 9983983645102771

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