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Systemic disease during Streptococcus pneumoniae acute lung infection requires 12-lipoxygenase-dependent inflammation

Rudra Bhowmick1, Nang Maung2, Bryan P Hurley3

  • 1Department of Molecular Biology and Microbiology, Tufts University, Boston, MA 02111, USA.

Journal of Immunology (Baltimore, Md. : 1950)
|October 4, 2013
PubMed

Insights

Streptococcus pneumoniae infection triggers lung inflammation via Hepoxilin A3 (HXA3), a 12-lipoxygenase (12-LOX) pathway metabolite. Inhibiting this pathway reduces bacterial spread and improves survival.

Area of Science:

  • Immunology
  • Pulmonary Medicine
  • Microbiology

Background:

  • Streptococcus pneumoniae causes severe lung infections with high bacterial loads and polymorphonuclear cell (PMN) influx.
  • Systemic spread (septicemia) is a significant risk during pneumococcal pneumonia.
  • Host mediators driving PMN migration and inflammation in pneumococcal lung infections require elucidation.

Purpose of the Study:

  • To investigate host mediators of S. pneumoniae-induced PMN migration.
  • To determine the role of inflammation in septicemia following pneumococcal lung infection.
  • To explore the involvement of the 12-lipoxygenase (12-LOX) pathway and Hepoxilin A3 (HXA3) in pneumococcal pathogenesis.

Main Methods:

  • Cultured pulmonary epithelial cells and infected mouse lungs were used to assess 12-LOX production.
  • Inhibition of the 12-LOX pathway was employed in vitro and in vivo.
  • PMN transepithelial migration and bacterial translocation were quantified.
  • Mice with suppressed 12-LOX expression were challenged with S. pneumoniae.

Main Results:

  • S. pneumoniae infection upregulated 12-LOX production in pulmonary epithelium and mouse lungs.
  • Inhibition of 12-LOX pathway reduced PMN transepithelial migration and lung inflammation in vivo.
  • PMN transmigration facilitated bacterial translocation across the lung epithelium.
  • Mice with suppressed 12-LOX expression showed reduced bacteremia and increased survival rates.

Conclusions:

  • Hepoxilin A3 (HXA3), a metabolite of the 12-LOX pathway, plays a critical role in S. pneumoniae-induced pulmonary inflammation and PMN migration.
  • Pneumococcal pulmonary inflammation, driven by 12-LOX/HXA3, is essential for high-level bacteremia and systemic infection.
  • Targeting the 12-LOX pathway presents a potential therapeutic strategy against severe pneumococcal infections.

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