Improved survival in mice given systemic gene therapy in a gram negative pneumonia model

Mark R. Hemmila, Ming Hui Fan, Jiyoun Kim, Jian M. Sun, Lars Steinstraesser, Ke Q. Gong, Saman Arbabi, Rebecca M. Minier, Daniel G. Remick, Grace L. Su, Stewart C. Wang

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Background: We previously demonstrated an essential role for lipopolysaccharide binding protein (LBP) in the pulmonary immune response to Gram-negative bacterial infection. LBP knockout mice had significantly higher mortality, greater rates of bacteremia, and higher counts of viable bacteria in their lungs at sacrifice compared with wild-type controls. We postulate that systemic LBP gene therapy will reconstitute a protective innate immune response in LBP knockout mice and that overexpression of LBP in wild-type mice may offer a survival advantage. Methods: 12-16 week old female C57BL/6 wild-type mice and age matched LBP knockout mice were given 5 × 109 PFU of recombinant adenovirus containing either the gene for LBP or the irrelevant control protein β-galactosidase by tail vein injection. 72 hours later each mouse was administered 1 × 103 CFU of Klebsiella pneumoniae by intratracheal injection. Results: Administration of LBP by systemic gene therapy to LBP knockout mice improved survival from Klebsiella pneumonia to a level equivalent or better than wild-type mice exposed to the same dose of bacteria (36 versus 25%). Wild-type mice given the LBP gene therapy demonstrated increased 7 day survival from Klebsiella pneumonia when compared with controls treated with β-galactosidase (68 versus 30%, p = 0.03). Conclusions: Systemic gene therapy with intravenous adenoviral vector transfer of LBP significantly improves survival in LBP knockout mice. Overexpression of LBP in wild-type mice improves survival from Klebsiella pneumonia. Raising levels of LBP in the setting of Gram-negative pneumonia may be of therapeutic benefit.

Original languageEnglish (US)
Pages (from-to)1110-1118
Number of pages9
JournalJournal of Trauma - Injury, Infection and Critical Care
Volume58
Issue number6
DOIs
StatePublished - Jun 1 2005

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Genetic Therapy
Pneumonia
Knockout Mice
Klebsiella pneumoniae
Galactosidases
lipopolysaccharide-binding protein
Gram-Negative Bacterial Infections
Bacteria
Lung
Injections
Bacteremia
Innate Immunity
Adenoviridae
Tail
Veins

Keywords

  • Gene therapy pneumonia lipopolysaccharide binding protein

ASJC Scopus subject areas

  • Surgery
  • Critical Care and Intensive Care Medicine

Cite this

Hemmila, M. R., Fan, M. H., Kim, J., Sun, J. M., Steinstraesser, L., Gong, K. Q., ... Wang, S. C. (2005). Improved survival in mice given systemic gene therapy in a gram negative pneumonia model. Journal of Trauma - Injury, Infection and Critical Care, 58(6), 1110-1118. https://doi.org/10.1097/01.TA.0000170855.37686.91

Improved survival in mice given systemic gene therapy in a gram negative pneumonia model. / Hemmila, Mark R.; Fan, Ming Hui; Kim, Jiyoun; Sun, Jian M.; Steinstraesser, Lars; Gong, Ke Q.; Arbabi, Saman; Minier, Rebecca M.; Remick, Daniel G.; Su, Grace L.; Wang, Stewart C.

In: Journal of Trauma - Injury, Infection and Critical Care, Vol. 58, No. 6, 01.06.2005, p. 1110-1118.

Research output: Contribution to journalArticle

Hemmila, MR, Fan, MH, Kim, J, Sun, JM, Steinstraesser, L, Gong, KQ, Arbabi, S, Minier, RM, Remick, DG, Su, GL & Wang, SC 2005, 'Improved survival in mice given systemic gene therapy in a gram negative pneumonia model', Journal of Trauma - Injury, Infection and Critical Care, vol. 58, no. 6, pp. 1110-1118. https://doi.org/10.1097/01.TA.0000170855.37686.91
Hemmila, Mark R. ; Fan, Ming Hui ; Kim, Jiyoun ; Sun, Jian M. ; Steinstraesser, Lars ; Gong, Ke Q. ; Arbabi, Saman ; Minier, Rebecca M. ; Remick, Daniel G. ; Su, Grace L. ; Wang, Stewart C. / Improved survival in mice given systemic gene therapy in a gram negative pneumonia model. In: Journal of Trauma - Injury, Infection and Critical Care. 2005 ; Vol. 58, No. 6. pp. 1110-1118.
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abstract = "Background: We previously demonstrated an essential role for lipopolysaccharide binding protein (LBP) in the pulmonary immune response to Gram-negative bacterial infection. LBP knockout mice had significantly higher mortality, greater rates of bacteremia, and higher counts of viable bacteria in their lungs at sacrifice compared with wild-type controls. We postulate that systemic LBP gene therapy will reconstitute a protective innate immune response in LBP knockout mice and that overexpression of LBP in wild-type mice may offer a survival advantage. Methods: 12-16 week old female C57BL/6 wild-type mice and age matched LBP knockout mice were given 5 × 109 PFU of recombinant adenovirus containing either the gene for LBP or the irrelevant control protein β-galactosidase by tail vein injection. 72 hours later each mouse was administered 1 × 103 CFU of Klebsiella pneumoniae by intratracheal injection. Results: Administration of LBP by systemic gene therapy to LBP knockout mice improved survival from Klebsiella pneumonia to a level equivalent or better than wild-type mice exposed to the same dose of bacteria (36 versus 25{\%}). Wild-type mice given the LBP gene therapy demonstrated increased 7 day survival from Klebsiella pneumonia when compared with controls treated with β-galactosidase (68 versus 30{\%}, p = 0.03). Conclusions: Systemic gene therapy with intravenous adenoviral vector transfer of LBP significantly improves survival in LBP knockout mice. Overexpression of LBP in wild-type mice improves survival from Klebsiella pneumonia. Raising levels of LBP in the setting of Gram-negative pneumonia may be of therapeutic benefit.",
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AU - Hemmila, Mark R.

AU - Fan, Ming Hui

AU - Kim, Jiyoun

AU - Sun, Jian M.

AU - Steinstraesser, Lars

AU - Gong, Ke Q.

AU - Arbabi, Saman

AU - Minier, Rebecca M.

AU - Remick, Daniel G.

AU - Su, Grace L.

AU - Wang, Stewart C.

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N2 - Background: We previously demonstrated an essential role for lipopolysaccharide binding protein (LBP) in the pulmonary immune response to Gram-negative bacterial infection. LBP knockout mice had significantly higher mortality, greater rates of bacteremia, and higher counts of viable bacteria in their lungs at sacrifice compared with wild-type controls. We postulate that systemic LBP gene therapy will reconstitute a protective innate immune response in LBP knockout mice and that overexpression of LBP in wild-type mice may offer a survival advantage. Methods: 12-16 week old female C57BL/6 wild-type mice and age matched LBP knockout mice were given 5 × 109 PFU of recombinant adenovirus containing either the gene for LBP or the irrelevant control protein β-galactosidase by tail vein injection. 72 hours later each mouse was administered 1 × 103 CFU of Klebsiella pneumoniae by intratracheal injection. Results: Administration of LBP by systemic gene therapy to LBP knockout mice improved survival from Klebsiella pneumonia to a level equivalent or better than wild-type mice exposed to the same dose of bacteria (36 versus 25%). Wild-type mice given the LBP gene therapy demonstrated increased 7 day survival from Klebsiella pneumonia when compared with controls treated with β-galactosidase (68 versus 30%, p = 0.03). Conclusions: Systemic gene therapy with intravenous adenoviral vector transfer of LBP significantly improves survival in LBP knockout mice. Overexpression of LBP in wild-type mice improves survival from Klebsiella pneumonia. Raising levels of LBP in the setting of Gram-negative pneumonia may be of therapeutic benefit.

AB - Background: We previously demonstrated an essential role for lipopolysaccharide binding protein (LBP) in the pulmonary immune response to Gram-negative bacterial infection. LBP knockout mice had significantly higher mortality, greater rates of bacteremia, and higher counts of viable bacteria in their lungs at sacrifice compared with wild-type controls. We postulate that systemic LBP gene therapy will reconstitute a protective innate immune response in LBP knockout mice and that overexpression of LBP in wild-type mice may offer a survival advantage. Methods: 12-16 week old female C57BL/6 wild-type mice and age matched LBP knockout mice were given 5 × 109 PFU of recombinant adenovirus containing either the gene for LBP or the irrelevant control protein β-galactosidase by tail vein injection. 72 hours later each mouse was administered 1 × 103 CFU of Klebsiella pneumoniae by intratracheal injection. Results: Administration of LBP by systemic gene therapy to LBP knockout mice improved survival from Klebsiella pneumonia to a level equivalent or better than wild-type mice exposed to the same dose of bacteria (36 versus 25%). Wild-type mice given the LBP gene therapy demonstrated increased 7 day survival from Klebsiella pneumonia when compared with controls treated with β-galactosidase (68 versus 30%, p = 0.03). Conclusions: Systemic gene therapy with intravenous adenoviral vector transfer of LBP significantly improves survival in LBP knockout mice. Overexpression of LBP in wild-type mice improves survival from Klebsiella pneumonia. Raising levels of LBP in the setting of Gram-negative pneumonia may be of therapeutic benefit.

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