Local Delivery of GM-CSF Protects Mice from Lethal Pneumococcal Pneumonia Academic Article uri icon

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abstract

  • The growth factor GM-CSF has an important role in pulmonary surfactant metabolism and the regulation of antibacterial activities of lung sentinel cells. However, the potential of intra-alveolar GM-CSF to augment lung protective immunity against inhaled bacterial pathogens has not been defined in preclinical infection models. We hypothesized that transient overexpression of GM-CSF in the lungs of mice by adenoviral gene transfer (Ad-GM-CSF) would protect mice from subsequent lethal pneumococcal pneumonia. Our data show that intra-alveolar delivery of Ad-GM-CSF led to sustained increased pSTAT5 expression and PU.1 protein expression in alveolar macrophages during a 28-d observation period. Pulmonary Ad-GM-CSF delivery 2-4 wk prior to infection of mice with Streptococcus pneumoniae significantly reduced mortality rates relative to control vector-treated mice. This increased survival was accompanied by increased inducible NO synthase expression, antibacterial activity, and a significant reduction in caspase-3-dependent apoptosis and secondary necrosis of lung sentinel cells. Importantly, therapeutic treatment of mice with rGM-CSF improved lung protective immunity and accelerated bacterial clearance after pneumococcal challenge. We conclude that prophylactic delivery of GM-CSF triggers long-lasting immunostimulatory effects in the lung in vivo and rescues mice from lethal pneumococcal pneumonia by improving antibacterial immunity. These data support use of novel antibiotic-independent immunostimulatory therapies to protect patients against bacterial pneumonias.

authors

  • Steinwede, Kathrin
  • Tempelhof, Ole
  • Bolte, Kristine
  • Maus, Regina
  • Bohling, Jennifer
  • Ueberberg, Bianca
  • Länger, Florian
  • Christman, John W
  • Paton, James C
  • Ask, Kjetil
  • Maharaj, Shyam
  • Kolb, Martin Rainer
  • Gauldie, Jack
  • Welte, Tobias
  • Maus, Ulrich A

publication date

  • November 15, 2011