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 (l09 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 SS-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.