Adenoviral-mediated interferon-gamma gene therapy augments pulmonary host defense of ethanol-treated rats.
Alcohol has long been recognized as an immunosuppressive drug and a risk factor for a spectrum of infectious diseases. Among these infections, bacterial pneumonias are most closely correlated with alcohol abuse. One potential mechanism of ethanol-induced immunosuppression is through its ability to suppress alveolar macrophage production of tumor necrosis factor (TNF-alpha). This defect can be reversed by priming macrophages with interferon-gamma (IFN-gamma). We hypothesized that macrophage priming in vivo in a model of acute ethanol intoxication could augment pulmonary host defenses. To test this hypothesis, we used adenoviral-mediated gene transfer of the IFN-gamma gene. This strategy resulted in prolonged expression of IFN-gamma in vivo. Moreover, in a model of acute ethanol intoxication, this vector significantly enhanced lipopolysaccharide-induced TNF-alpha responses and lung polymorphonuclear leukocyte recruitment. Furthermore, pulmonary host defenses against Klebsiella pneumoniae were significantly augmented. These enhanced host defenses were not reversed with pretreatment with a polyclonal anti-TNF-alpha antibody, suggesting that IFN-gamma's effect was through a non-TNF-alpha-dependent mechanism. These data demonstrate that ethanol-induced suppression of pulmonary host defenses can be reversed with IFN-gamma gene therapy.
Kolls
J K
JK
Louisiana State University Section of Pulmonary/Critical Care, Louisiana State University Stanley S. Scott Cancer Center Gene Therapy Program, New Orleans 70112, USA.
Lei
D
D
Stoltz
D
D
Zhang
P
P
Schwarzenberger
P O
PO
Ye
P
P
Bagby
G
G
Summer
W R
WR
Shellito
J E
JE
Nelson
S
S
D000256:Adenoviridae / Q000235:genetics; D000437:Alcoholism / Q000276:immunology*; D000818:Animals; D015870:Gene Expression / Q000502:physiology; D015316:Genetic Therapy; D007121:Immunocompetence / Q000235:genetics / Q000276:immunology; D007371:Interferon-gamma / Q000235:genetics*; D007710:Klebsiella Infections / Q000276:immunology*; D007711:Klebsiella pneumoniae / Q000276:immunology*; D016676:Macrophages, Alveolar / Q000276:immunology*; D008297:Male; D018410:Pneumonia, Bacterial / Q000276:immunology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D007371:Interferon-gamma