title: Adenovirus-mediated blockade of tumor necrosis factor in mice protects against endotoxic shock yet impairs pulmonary host defense.
abstract: A replication-deficient recombinant adenovirus encoding a chimeric protein capable of binding tumor necrosis factor (TNF) and lymphotoxin was given to mice. Administration of this virus (10(9) pfu intravenously) yielded high levels of the recombinant protein in plasma and afforded significant protection to a lethal challenge with lipopolysaccharide with or without D-galactosamine. However, this protein inhibitor was readily detectable in the lung and was associated with decreased neutrophil recruitment and bacterial killing after intratracheal LPS or Pseudomonas aeruginosa, respectively. These data reflect the dual role of many proinflammatory cytokines. This model of TNF inhibition is similar to the homozygous 55-kDa TNF receptor deletion; thus, adenovirus-mediated gene transfer of cytokine inhibitors in vivo is a useful tool to abrogate the function of single or multiple cytokines for investigational or therapeutic purposes.
authors.affiliation: Section of Pulmonary/Critical Care Medicine, Louisiana State University, New Orleans.
authors.forename: J K
authors.initials: JK
authors.lastname: Kolls
authors.forename: D
authors.initials: D
authors.lastname: Lei
authors.forename: S
authors.initials: S
authors.lastname: Nelson
authors.forename: W R
authors.initials: WR
authors.lastname: Summer
authors.forename: S
authors.initials: S
authors.lastname: Greenberg
authors.forename: B
authors.initials: B
authors.lastname: Beutler
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D018014:Gene Transfer Techniques; D008168:Lung / Q000276:immunology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D012772:Shock, Septic / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology
chemical_list: D014409:Tumor Necrosis Factor-alpha