Gene therapy with lipopolysaccharide binding protein for gram-negative pneumonia: Respiratory physiology

Mark R. Hemmila, Jiyoun Kim, Jian M. Sun, Jennifer Cannon, Saman Arbabi, Rebecca M. Minter, Grace L. Su, Daniel G. Remick, Stewart C. Wang

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

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 × 10 colony-forming units/mouse of Klebsiella pneumoniae by intratracheal inoculation. Treated mice were administered 5 × 10 plaque-forming units of recombinant adenovirus containing either the gene for LBP or the irrelevant control protein β-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 β-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.

Original languageEnglish (US)
Pages (from-to)598-605
Number of pages8
JournalJournal of Trauma - Injury, Infection and Critical Care
Volume61
Issue number3
DOIs
Publication statusPublished - Sep 1 2006

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Keywords

  • Gene therapy
  • Lipopolysaccharide binding protein
  • Pneumonia
  • Whole body plethysmography

ASJC Scopus subject areas

  • Surgery
  • Critical Care and Intensive Care Medicine

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