ADENOVIRUS-MEDIATED BLOCKADE OF TUMOR-NECROSIS-FACTOR IN MICE PROTECTS AGAINST ENDOTOXIC-SHOCK YET IMPAIRS PULMONARY HOST-DEFENSE

A replication-deficient recombinant adenovirus encoding a chimeric pro tein capable of binding tumor necrosis factor (TNF) and lymphotoxin wa s given to mice. Administration of this virus (10(9) pfu intravenously ) yielded high levels of the recombinant protein in plasma and afforde d 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 neutr ophil recruitment and bacterial killing after intratracheal LPS or Pse udomonas aeruginosa, respectively. These data reflect the dual role of many proinflammatory cytokines. This model of TNF inhibition is simil ar to the homozygous 55-kDa TNF receptor deletion; thus, adenovirus-me diated gene transfer of cytokine inhibitors in vivo is a useful tool t o abrogate the function of single or multiple cytokines for investigat ional or therapeutic purposes.