Anti-tumor necrosis factor-alpha therapy during murine Klebsiella pneumoniae bacteremia: increased mortality in the absence of liver injury


Moore, TA; Lau, HY; Cogen, AL; Monteleon, CL; Standiford, TJ; (2003) Anti-tumor necrosis factor-alpha therapy during murine Klebsiella pneumoniae bacteremia: increased mortality in the absence of liver injury. Shock (Augusta, Ga), 20 (4). pp. 309-15. ISSN 1073-2322 DOI: https://doi.org/10.1097/01.shk.0000087203.34916.45

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Abstract

Klebsiella pneumoniae is a leading cause of gram-negative bacterial pneumonia, often resulting in bacteremia concurrent with the localized pulmonary infection. The beneficial role of tumor necrosis factor (TNF)-alpha during pulmonary infection has been well documented; however, consequences of TNF-alpha production during systemic bacterial infection are controversial. A murine model of K. pneumoniae was developed to address this important issue. Liver-associated TNF-alpha mRNA was induced within 30 min after intravenous bacterial inoculation and remained elevated through 6 h before returning to near-baseline at 24 h postinfection. Intravenous K. pneumoniae infection induced liver cellular injury that was completely ablated when mice were pretreated with a neutralizing anti-TNF-alpha antibody. Interestingly, this reduction in liver injury failed to translate into improved survival. Mice receiving anti-TNF-alpha continued to succumb to the infection even out to day 10 postinfection. Bacterial clearance after TNF-alpha neutralization was significantly impaired at later time points during infection. Correlating with impaired bacterial clearance was diminished production of liver-associated MIP-2, MIP-1alpha, MCP-1, and interferon-gamma. Further evidence of diminished antibacterial immune responses was noted when the activational status of splenic natural killer cells in anti-TNF-alpha-treated mice was examined 24 h postinfection. Natural killer cells displayed decreased CD69 expression. Combined, these data indicate that the beneficial effects of TNF-alpha during systemic K. pneumoniae infection outweigh the detrimental effects of TNF-alpha-mediated hepatocyte cellular injury. Anti-TNF-alpha therapy, although preventing liver injury during blood-borne bacterial infection, results in a dampened anti-bacterial host response, resulting in decreased bacterial clearance and overall survival.

Item Type: Article
Keywords: Animals, Antibodies, Monoclonal/pharmacology, Bacteremia/immunology/*therapy, Cytokines/biosynthesis, Gene Expression, Killer Cells, Natural/immunology, Klebsiella Infections/immunology/microbiology/*therapy, *Klebsiella pneumoniae/isolation & purification, Liver/immunology/injuries, Mice, Mice, Inbred C57BL, Neutralization Tests, RNA, Messenger/genetics/metabolism, Tumor Necrosis Factor-alpha/*antagonists & inhibitors/genetics, Animals, Antibodies, Monoclonal, pharmacology, Bacteremia, immunology, therapy, Cytokines, biosynthesis, Gene Expression, Killer Cells, Natural, immunology, Klebsiella Infections, immunology, microbiology, therapy, Klebsiella pneumoniae, isolation & purification, Liver, immunology, injuries, Mice, Mice, Inbred C57BL, Neutralization Tests, RNA, Messenger, genetics, metabolism, Tumor Necrosis Factor-alpha, antagonists & inhibitors, genetics
Faculty and Department: Faculty of Infectious and Tropical Diseases > Dept of Clinical Research
PubMed ID: 14501943
Web of Science ID: 185442400003
URI: http://researchonline.lshtm.ac.uk/id/eprint/1758

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