title: Local delivery of GM-CSF protects mice from lethal pneumococcal pneumonia.
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: Department of Experimental Pneumology, Hannover Medical School, Hannover 30625, Germany.
authors: Kathrin
authors: K
authors: Steinwede
authors: Ole
authors: O
authors: Tempelhof
authors: Kristine
authors: K
authors: Bolte
authors: Regina
authors: R
authors: Maus
authors: Jennifer
authors: J
authors: Bohling
authors: Bianca
authors: B
authors: Ueberberg
authors: Florian
authors: F
authors: Länger
authors: John W
authors: JW
authors: Christman
authors: James C
authors: JC
authors: Paton
authors: Kjetil
authors: K
authors: Ask
authors: Shyam
authors: S
authors: Maharaj
authors: Martin
authors: M
authors: Kolb
authors: Jack
authors: J
authors: Gauldie
authors: Tobias
authors: T
authors: Welte
authors: Ulrich A
authors: UA
authors: Maus
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology / Q000382:microbiology; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000008:administration & dosage / Q000276:immunology / Q000627:therapeutic use; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000008:administration & dosage* / Q000096:biosynthesis / Q000235:genetics*; D007442:Intubation, Intratracheal; D008168:Lung / Q000276:immunology / Q000382:microbiology / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D011018:Pneumonia, Pneumococcal / Q000276:immunology* / Q000401:mortality / Q000517:prevention & control*; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000627:therapeutic use
chemical_list: D011994:Recombinant Proteins; D016178:Granulocyte-Macrophage Colony-Stimulating Factor