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. 1998 Jun;66(6):2822-6.
doi: 10.1128/IAI.66.6.2822-2826.1998.

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

L L Laichalk  1 , K A Bucknell, G B Huffnagle, J M Wilkowski, T A Moore, R J Romanelli, T J Standiford
Affiliations

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

L L Laichalk et al. Infect Immun. 1998 Jun.

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 (TNF70-80) 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 TNF70-80 would augment lung innate immunity in mice challenged with intrapulmonary Klebsiella pneumoniae. The administration of TNF70-80 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 marked increase in survival compared to that of animals receiving a control peptide i.t. In addition, pretreatment with TNF70-80 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 TNF70-80 intraperitoneally resulted in enhanced rather than decreased lethality of Klebsiella pneumonia compared to that for animals receiving either TNF70-80 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.

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Figures

FIG. 1
FIG. 1
Effect of TNF70-80 on survival in Klebsiella pneumonia. CBA/J mice were treated with control peptide (Ctrl) (10 μg) or 100 ng, 1 μg, or 10 μg of TNF70-80 concomitantly with K. pneumoniae inoculation or with 10 μg of control peptide or TNF70-80 7 days prior to K. pneumoniae inoculation (pre). Animals were inoculated i.t. with 3 × 103 CFU of K. pneumoniae (n = 10 to 24 per group).
FIG. 2
FIG. 2
Log CFU in plasma or lungs of mice challenged with either control peptide or TNF70-80 (10 μg). Values shown for lung CFU represent the total quantity of bacteria per whole lung, whereas those for plasma CFU represent the total quantity of bacteria per milliliter of plasma. n = 16 for the control peptide group (▪), and n = 19 for the groups given TNF70-80 concomitantly with (▨) or 7 days prior to (□) K. pneumoniae administration. ∗, P < 0.05; ∗∗, P < 0.01 (compared to control peptide-treated animals and animals treated with TNF70-80 concomitantly with K. pneumoniae). Error bars indicate SEM.
FIG. 3
FIG. 3
Effect of TNF70-80 on lung MPO activity in Klebsiella pneumonia. CBA/J mice were pretreated 7 days prior to K. pneumoniae inoculation (3 × 103 CFU) with either control peptide (▪) or TNF70-80 (□). Whole lung MPO activity was assayed 48 h after K. pneumoniae inoculation (n = 19 for TNF70-80, n = 16 for control peptide, and n = 6 for saline). ∗, P < 0.05 compared to control peptide-treated animals. Error bars indicate SEM.
FIG. 4
FIG. 4
Effect of TNF70-80 administration on lung TNF, MIP-2, IL-12, and IFN-γ levels in Klebsiella pneumonia. CBA/J mice were pretreated 7 days prior to K. pneumoniae inoculation (3 × 103 CFU) with either control peptide (▪) or TNF70-80 (□), and lung cytokine levels were determined 48 h after K. pneumoniae inoculation (n = 19 for TNF70-80, n = 16 for control peptide, and n = 6 for saline). ∗, P < 0.05; ∗∗, P < 0.01 (compared to control peptide-treated animals). Error bars indicate SEM.
FIG. 5
FIG. 5
Effect of i.p. versus i.t. administration of TNF70-80 on survival in Klebsiella pneumonia. CBA/J mice were passively immunized with either control peptide i.t. (□), TNF70-80 i.t. (▴), or TNF70-80 i.p. (•) 7 days prior to K. pneumoniae inoculation. Animals were inoculated i.t. with 3 × 103 CFU of K. pneumoniae (n = 10 per group).
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