INTRAPULMONARY DELIVERY OF TUMOR-NECROSIS-FACTOR AGONIST PEPTIDE AUGMENTS HOST-DEFENSE IN MURINE GRAM-NEGATIVE BACTERIAL PNEUMONIA

Tumor necrosis factor alpha (TNF) has been shown to be an essential cy tokine mediator of innate immunity in Klebsiella pneumonia. Recently, a TNF agonist peptide consisting of the Il-amino-acid TNF binding site (TNF70-80) has been shown to possess many of the leukocyte-activating properties of TNF without the associated toxicity when administered l ocally or systemically. Given the beneficial effects of TNF in gram-ne gative pneumonia, we hypothesize that the intratracheal (i.t.) adminis tration of TNF70-80 would augment lung innate immunity in mice challen ged with intrapulmonary Klebsiella pneumoniae. The administration of T NF70-80 i.t. to CBA/J mice 7 days prior to, but not concomitantly with , the i.t. delivery of 3 x 10(3) CFU of K. pneumoniae resulted in a ma rked increase in survival compared to that of animals receiving a cont rol peptide i.t. In addition, pretreatment with TNF70-80 resulted in i mproved bacterial Clearance, which occurred in association with enhanc ed lung myeloperoxidase activity las a measure of lung polymorphonucle ar leukocyte influx), and increased expression of the important activa ting cytokines TNF, macrophage inflammatory protein-2, interleukin-12, and gamma interferon compared that for animals receiving control pept ide. Finally, the administration of TNF70-80 intraperitoneally resulte d in enhanced rather than decreased lethality of Klebsiella pneumonia compared to that for animals receiving either TNF70-80 or control pept ide i.t. Our studies suggest that the intrapulmonary, but not systemic , administration of the TNF agonist peptide may serve as an important immunoadjuvant in the treatment of murine Klebsiella pneumonia.