BACKGROUND: Lipopolysaccharide binding protein (LBP) plays an essential role in the pulmonary immune response to gram-negative bacterial infection. LBP knockout mice with gram-negative pneumonia have increased mortality compared with wild-type controls. This mortality difference can be abolished with systemic LBP gene therapy. We postulate that LBP knockout mice will develop derangements in lung physiology from gram-negative pneumonia and that these changes can be reversed with systemic LBP gene therapy. METHODS: Twelve- to 16-week-old C57BL/6 wild-type mice and/or sex, age, matched LBP knockout mice were administered 1 x 10(3) colony-forming units/mouse of Klebsiella pneumoniae by intratracheal inoculation. Treated mice were administered 5 x 10(9) plaque-forming units of recombinant adenovirus containing either the gene for LBP or the irrelevant control protein beta-galactosidase by intravenous injection 2 days before bacterial inoculation. Respiratory physiology parameters were measured preinoculation and 24 hours postbacterial inoculation. RESULTS: Administration of LBP by systemic gene therapy to LBP knockout mice improved 7-day survival from Klebsiella pneumonia to a level equivalent to wild-type mice exposed to the same dose of bacteria (42 vs. 43% survival). LBP knockout mice given the LBP gene therapy demonstrated increased 14-day survival from Klebsiella pneumonia when compared with controls treated with beta-galactosidase (28 vs. 0%, p < 0.001). LBP knockout mice developed significant differences in respiratory rate, minute ventilation, and enhanced pause (Penh), when compared with wild-type mice with Klebsiella pneumonia. These respiratory derangements were prevented with adenoviral delivery of the LBP gene before K. pneumoniae inoculation. CONCLUSIONS: Gram-negative pneumonia produces measurable changes in mortality and respiratory physiology between wild-type and LBP knockout mice. These changes can be prevented in LBP knockout mice by systemic gene therapy to restore innate immunity.
BACKGROUND:Lipopolysaccharide binding protein (LBP) plays an essential role in the pulmonary immune response to gram-negative bacterial infection. LBP knockout mice with gram-negative pneumonia have increased mortality compared with wild-type controls. This mortality difference can be abolished with systemic LBP gene therapy. We postulate that LBP knockout mice will develop derangements in lung physiology from gram-negative pneumonia and that these changes can be reversed with systemic LBP gene therapy. METHODS: Twelve- to 16-week-old C57BL/6 wild-type mice and/or sex, age, matched LBP knockout mice were administered 1 x 10(3) colony-forming units/mouse of Klebsiella pneumoniae by intratracheal inoculation. Treated mice were administered 5 x 10(9) plaque-forming units of recombinant adenovirus containing either the gene for LBP or the irrelevant control protein beta-galactosidase by intravenous injection 2 days before bacterial inoculation. Respiratory physiology parameters were measured preinoculation and 24 hours postbacterial inoculation. RESULTS: Administration of LBP by systemic gene therapy to LBP knockout mice improved 7-day survival from Klebsiella pneumonia to a level equivalent to wild-type mice exposed to the same dose of bacteria (42 vs. 43% survival). LBP knockout mice given the LBP gene therapy demonstrated increased 14-day survival from Klebsiella pneumonia when compared with controls treated with beta-galactosidase (28 vs. 0%, p < 0.001). LBP knockout mice developed significant differences in respiratory rate, minute ventilation, and enhanced pause (Penh), when compared with wild-type mice with Klebsiella pneumonia. These respiratory derangements were prevented with adenoviral delivery of the LBP gene before K. pneumoniae inoculation. CONCLUSIONS: Gram-negative pneumonia produces measurable changes in mortality and respiratory physiology between wild-type and LBP knockout mice. These changes can be prevented in LBP knockout mice by systemic gene therapy to restore innate immunity.
Authors: Kendra N Iskander; Florin L Craciun; David M Stepien; Elizabeth R Duffy; Jiyoun Kim; Rituparna Moitra; Louis J Vaickus; Marcin F Osuchowski; Daniel G Remick Journal: Crit Care Med Date: 2013-01 Impact factor: 7.598
Authors: Andreas D Niederbichler; Laszlo M Hoesel; Kyros Ipaktchi; Leovigildo Olivarez; Martin Erdmann; Peter M Vogt; Grace L Su; Saman Arbabi; Margaret V Westfall; Stewart C Wang; Mark R Hemmila Journal: J Surg Res Date: 2009-12-06 Impact factor: 2.192