Intrapulmonary delivery of tumor necrosis factor agonist peptide augments host defense in murine gram-negative bacterial pneumonia

Abstract

Tumor necrosis factor alpha (TNF) has been shown to be an essential cytokine mediator of innate immunity in Klebsiella pneumonia. Recently, a TNF agonist peptide consisting of the 11-amino-acid TNF binding site (TNF(70- 80)) has been shown to possess many of the leukocyte-activating properties of TNF without the associated toxicity when administered locally or systemically. Given the beneficial effects of TNF in gram-negative pneumonia, we hypothesize that the intratracheal (i.t.) administration of TNF(70-80), would augment lung innate immunity in mice challenged with intrapulmonary Klebsiella pneumoniae. The administration of TNF(70-80) i.t. to CBA/J mice 7 days prior to, but not concomitantly with, the i.t. delivery of 3 x 103 CFU of K. pneumoniae resulted in a marked increase in survival compared to that of animals receiving a control peptide i.t. In addition, pretreatment with TNF(70-80) resulted in improved bacterial clearance, which occurred in association with enhanced lung myeloperoxidase activity (as a measure of lung polymorphonuclear leukocyte influx), and increased expression of the important activating cytokines TNF, macrophage inflammatory protein-2, interleukin-12, and gamma interferon compared that for animals receiving control peptide. Finally, the administration of TNF(70-80) intraperitoneally resulted in enhanced rather than decreased lethality of Klebsiella pneumonia compared to that for animals receiving either TNF(70-80) or control peptide 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.