Adenoviral transfer of HSP-70 into pulmonary epithelium ameliorates experimental acute respiratory distress syndrome.
The acute respiratory distress syndrome (ARDS) provokes three pathologic processes: unchecked inflammation, interstitial/alveolar protein accumulation, and destruction of pulmonary epithelial cells. The highly conserved heat shock protein HSP-70 can limit all three responses but is not appropriately expressed in the lungs after cecal ligation and double puncture (2CLP), a clinically relevant model of ARDS. We hypothesize that restoring expression of HSP-70 using adenovirus-mediated gene therapy will limit pulmonary pathology following 2CLP. We administered a vector containing the porcine HSP-70 cDNA driven by a CMV promoter (AdHSP) into the lungs of rats subjected to 2CLP or sham operation. Administration of AdHSP after either sham operation or 2CLP increased HSP-70 protein expression in lung tissue, as determined by immunohistochemistry and Western blot hybridization. Administration of AdHSP significantly attenuated interstitial and alveolar edema and protein exudation and dramatically decreased neutrophil accumulation, relative to a control adenovirus. CLP-associated mortality at 48 hours was reduced by half. Modulation of HSP-70 production reduces pathologic changes and may improve outcome in experimental ARDS.
Weiss
Yoram G
YG
Department of Anesthesia, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Maloyan
Alina
A
Tazelaar
John
J
Raj
Nichelle
N
Deutschman
Clifford S
CS
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000378:metabolism; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000627:therapeutic use; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D008168:Lung / Q000378:metabolism*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012128:Respiratory Distress Syndrome / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy*; D020545:Respiratory Mucosa / Q000378:metabolism*; D018805:Sepsis / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy; D015996:Survival Rate; D014020:Tissue Extracts / Q000378:metabolism
D018840:HSP70 Heat-Shock Proteins; D014020:Tissue Extracts