Age-associated Inflammation and Toll-Like Receptor Dysfunction Prime the Lungs for Pneumococcal Pneumonia

J Infect Dis. 2009 Aug 15;200(4):546-54. doi: 10.1086/600870.

Abstract

Background: Aging is associated with increased inflammation and risk of community-acquired pneumonia. Streptococcus pneumoniae co-opts the nuclear factor kappa B (NFkB)-regulated proteins polymeric immunoglobulin receptor (pIgR) and platelet-activating factor receptor (PAFr) to attach and invade cells. We sought to determine whether aging and chronic inflammation were associated with increased pIgR and PAFr levels in the lungs and increased susceptibility to S. pneumoniae infection.

Methods: Lung protein and messenger RNA levels were quantitated using Western blot and quantitative polymerase chain reaction. NFkB activation was measured by electrophoretic mobility shift assay. Cytokine levels were measured by cytometric bead analysis. To model chronic inflammation, mice were implanted with osmotic pumps that delivered tumor necrosis factor-alpha.

Results: Aged mice and those infused with tumor necrosis factor-alpha had increased levels of pIgR and PAFr in their lungs and were more susceptible to S. pneumoniae infection. During pneumonia, aged mice had reduced levels of pIgR and PAFr and less NFkB activation, despite greater bacterial burden. We determined that aged mice had decreased amounts of lung Toll-like receptors 1, 2, and 4 and reduced capacity to respond to S. pneumoniae with proinflammatory cytokine production.

Conclusions: Aged mice and, potentially, elderly humans are more susceptible to pneumonia because of a priming effect of chronic inflammation and Toll-like receptor dysfunction.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Aging*
  • Animals
  • Bronchoalveolar Lavage Fluid / cytology
  • Gene Expression Regulation
  • Inflammation / metabolism*
  • Lung / cytology
  • Lung / pathology*
  • Mice
  • Mice, Inbred BALB C
  • NF-kappa B / genetics
  • NF-kappa B / metabolism
  • Pneumonia, Pneumococcal / pathology*
  • RNA, Messenger / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Risk Factors
  • Toll-Like Receptors / metabolism*
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • NF-kappa B
  • RNA, Messenger
  • Toll-Like Receptors
  • Tumor Necrosis Factor-alpha